Dermatopathology:

Dermatopathology

Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the results obtained from use of such information. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this book is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Dermatopathology Editor in Chief Raymond L. Barnhill, MD Professor of Dermatology and Pathology Hôpital Saint-Louis Université Paris Diderot Paris, France

Associate Editors Arthur Neil Crowson, MD Clinical Professor of Dermatology, Pathology and Surgery Director of Dermatopathology University of Oklahoma Chairman of Pathology St John Medical Center President Pathology Laboratory Associates Tulsa, Oklahoma

Cynthia M. Magro, MD Professor Division of Dermatopathology Deptartment of Pathology Cornell University Weill Medical College New York, New York

Michael W. Piepkorn, MD Clinical Professor of Dermatology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington

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To Claire

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CONTENTS

PA RT 2. Predominantly Noninflammatory Conditions 14 Alterations of the Stratum Corneum and Epidermis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .313

CONTENTS

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii Preface to the Third Edition . . . . . . . . . . . . . . . . . . . . . . . . . . xv Preface to the First Edition . . . . . . . . . . . . . . . . . . . . .xvii

Michael W. Piepkorn

PA RT 1. Inflammatory Reactions In the Skin 1 Introduction to Microscopic Interpretation . . . . . .3 Raymond L. Barnhill and Daniel M. Jones

2

Spongiotic Dermatitis . . . . . . . . . . . . . . . . . . . . . .15 Michael Murphy and Jane M. Grant-Kels

3

Interface Dermatitis . . . . . . . . . . . . . . . . . . . . . . .36 Frances I. Ramos-Ceballos and Thomas D. Horn

4

Psoriasiform Dermatitis . . . . . . . . . . . . . . . . . . . .64 Timothy T. Chang and Loren E. Golitz

5 6

Franco Rongioletti and Raymond L. Barnhill

17 Alterations of Collagen and Elastin . . . . . . . . . .387 Kapil Gupta, Laurence Verneuil, Clifton R. White, Jr., and Raymond L. Barnhill

18 Ectopic Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . .408 Jacqueline M. Junkins-Hopkins

PA RT 3. Infections 19 Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . .421

Nodular and Diffuse Cutaneous Infiltrates . . . . .98 Intraepidermal Vesiculopustular Diseases . . . . .136

Subepidermal Blistering Diseases . . . . . . . . . . .156 Mosaad Megahed and Akmal Saad Hassan

9

16 Deposition Disorders . . . . . . . . . . . . . . . . . . . . .362

Superficial and Deep Perivascular Dermatitis . . .81

Terence J. Harrist, Brian Schapiro, Lisa Lerner, Cynthia M. Magro, James Ramirez, and Jenny Cotton

8

A. Neil Crowson, Sarah Zeller, and Raymond L. Barnhill

A. Neil Crowson

Jeff D. Harvell and Raymond L. Barnhill

7

15 Disorders of Pigmentation . . . . . . . . . . . . . . . . .338

Vasculitis and Related Disorders . . . . . . . . . . . .179 Sarah K. Barksdale and Raymond L. Barnhill

10 Disorders of Cutaneous Appendages . . . . . . . .213 David A. Whiting, Douglas C. Parker, Amy K. Reisenauer, and Alvin R. Solomon

11 Panniculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .250 Raymond L. Barnhill and Birgitta Schimdt

12 Cutaneous Drug Eruptions . . . . . . . . . . . . . . . . .281 A. Neil Crowson and Cynthia M. Magro

13 Cutaneous Reactions to Exogenous Agents . . .301 Raymond L. Cornelison and A. Neil Crowson

Ronald P. Rapini

20 Treponemal and Rickettsial Diseases . . . . . . . .446 A. Neil Crowson, Cynthia M. Magro, J. Stephen Dumler, Grace F. Kao, and Raymond L. Barnhill

21 Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . .458 Catherine Lisa Kauffman, Victoria Hobbs Hamet, Steven R. Tahan, Klaus J. Busam, and Raymond L. Barnhill

22 Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . .495 Clay J. Cockerell and James J. Lyons

23 Protozoal and Algal Infections . . . . . . . . . . . . . .517 Ann Marie Nelson, Paul Hofman, and Freddye Lemons-Estes

24 Helminthic Diseases . . . . . . . . . . . . . . . . . . . . . .530 Kapil Gupta and Franz von Lichtenberg

PA RT 4. Proliferations—Hamartomas, Hyperplasias, and Neoplasias 25 Cutaneous Cysts and Related Lesions . . . . . . . .543 Glynis A. Scott

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26 Tumors of the Epidermis . . . . . . . . . . . . . . . . . .556 Alan S. Boyd

27 Tumors of Melanocytes . . . . . . . . . . . . . . . . . . .615 Raymond L. Barnhill

28 Tumors with Hair Follicle and Sebaceous Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . .689

34 Lymphoid, Leukemic, and Other Cellular Infiltrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .905 Werner Kempf, Guenter Burg, Lorenzo Cerroni, Helmut Kerl, Stanislaw A. Buechner, and W.P. Daniel Su

35 Cutaneous Metastases . . . . . . . . . . . . . . . . . . . .960 Michael S. Rabkin

Mark R. Wick and Raymond L. Barnhill

29 Sweat Gland Tumors . . . . . . . . . . . . . . . . . . . . .725 Mark R. Wick and Raymond L. Barnhill

30 Fibrous and Fibrohistiocytic Tumors . . . . . . . .766 Stefan Kraft and Scott R. Granter

CONTENTS

31 Vascular Tumors and Vascular Malformations . . . . . . . . . . . . . . . . . . . . . . . . . .802 Michel Wassef, Steven J. Hunt, Daniel J. Santa Cruz, and Raymond L. Barnhill

32 Tumors of Adipose Tissue, Muscle, Cartilage, and Bone . . . . . . . . . . . . . . . . . . . . . . .857 Shady El-Zayaty and Thomas Krausz

33 Neural and Neuroendocrine Tumors . . . . . . . . .883 Zsolt B. Argenyi and Chris H. Jokinen

PA RT 5. Disorders of Nails and the Oral Mucosa 36 Disorders of the Nail Apparatus . . . . . . . . . . . .983 Aldo González-Serva

37 Disorders of the Oral Mucosa . . . . . . . . . . . . .1002 Mark A. Lerman and Sook-Bin Woo

Appendix 1: Stem Cells and the Skin . . . . . . . . . . . .1022 Laurence Verneuil, Anne Janin, and Raymond L. Barnhill

Appendix 2: Laboratory Methods . . . . . . . . . . . . . . .1024 Klaus J. Busam and Raymond L. Barnhill

Appendix 3: Molecular Biologic Techniques for the Diagnosis of Cutaneous Lymphomas . . . . . . .1033 Gary S. Wood

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1039

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CONTRIBUTORS

Sarah K. Barksdale, MD Dermatopathologist Summit Pathology Greeley, Colorado Chapter 9: Vasculitis and Related Disorders Raymond L. Barnhill, MD Professor of Dermatology and Pathology Hôpital Saint-Louis Universitè Paris VII Paris, France Appendix, Chapters 1, 6, 9, 11, 15, 16, 17, 20, 21, 27, 28, 29, 31 Emmanuelle Bourrat, MD Dermatologist Hôpital Saint-Louis Paris, France Provision of Clinical Photographs Alan S. Boyd, MD Associate Professor Departments of Dermatology and Pathology Vanderbilt University Nashville, Tennessee Chapter 26: Tumors of the Epidermis Stanislaw A. Buechner, MD Professor of Dermatology University of Basel Basel, Switzerland Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 3: Cutaneous Hodgkin Lymphoma)

Guenter Burg, MD Department of Dermatology, University Hospital of Zürich Zürich, Switzerland Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 1: Cutaneous T-Cell Lymphoid Hyperplasia and Cutaneous T-Cell Lymphomas)

Raymond L. Cornelison, Jr. MD Professor and Herzog Chair Department of Dermatology University of Oklahoma College of Medicine Oklahoma City, Oklahoma Chapter 13: Cutaneous Reactions to Exogenous Agents

Klaus J. Busam, MD Professor Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York Chapter 21: Fungal Infections, Appendix

Jenny Cotton, MD, PhD Dermatopathology Department St. Joseph Mercy Hospital Ann Arbor, Michigan Chapter 7: Intraepidermal Vesiculopustular Diseases

Lorenzo Cerroni, MD Associate Professor, Department of Dermatology Medical University of Graz Graz, Austria Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 2: Cutaneous B-Cell Lymphoid Hyperplasia and Cutaneous B-Cell Lymphomas) Timothy T. Chang, MD Dermatopathology Fellow Department of Pathology University of Colorado Health Sciences Center Denver, Colorado Chapter 4: Psoriasiform Dermatitis Clay J. Cockerell, MD Clinical Professor Director of Dermatopathology Division University of Texas Southwestern Medical Center Medical Director, Cockerell & Associates Dallas, Texas Chapter 22: Viral Infections

CONTRIBUTORS

Zsolt B. Argenyi, MD Professor of Pathology and Dermatology Director of Dermatopathology University of Washington Medical Center Seattle, Washington Chapter 33: Neural and Neuroendocrine Tumors

Arthur Neil Crowson, MD Clinical Professor of Dermatology, Pathology and Surgery Director of Dermatopathology University of Oklahoma Chairman of Pathology St John Medical Center President, Pathology Laboratory Associates Tulsa, Oklahoma Chapter 5: Superficial and Deep Perivascular Dermatitis; Chapter 12: Cutaneous Drug Eruptions; Chapter 15: Disorders of Pigmentation; Chapter 20: Treponemal and Rickettsial Diseases J. Stephen Dumler, MD Professor Division of Medical Microbiology Department of Pathology Johns Hopkins University School of Medicine and Johns Hopkins Hospital Baltimore, Maryland Chapter 20: Treponemal and Rickettsial Diseases

ix

Shady El-Zayaty, MD Fellow Department of Pathology The University of Chicago Chicago, Illinois Chapter 32: Tumors of Adipose Tissue, Muscle, Cartilage, and Bone Loren E. Golitz, MD Clinical Professor of Pathology and Dermatology University of Colorado Health Sciences Center Denver, Colorado Chapter 4: Psoriasiform Dermatitis

CONTRIBUTORS

Aldo González-Serva, MD Dermatophathologist Winchester Hospital and Strata Diagnostics Winchester and Waltham, Massachusetts Chapter 36: Disorders of the Nail Apparatus Scott R. Granter, MD Associate Professor Harvard Medical School Associate Pathologist Department of Pathology Brigham and Women’s Hospital Consultant, Dana-Farber Cancer Institute Boston, Massachusetts Chapter 30: Fibrous and Fibrohistiocytic Tumors Jane M. Grant-Kels, MD Assistant Dean of Clinical Affairs Professor and Chair, Department of Dermatology Director of Dermatopathology Director of the Cutanous Oncology Center and Melanoma Program Director, Dermatology Residency University of Connecticut Health Center Farmington, Connecticut Chapter 2: Spongiotic Dermatitis Kapil Gupta, MD Dermatopathologist Dermatology Group of the Carolinas Concord, North Carolina Chapter 17: Alterations of Collagen and Elastin; Chapter 24: Helminthic Diseases Jeff D. Harvell, MD Bethesda Dermatopathology Silver Spring, Maryland Chapter 6: Nodular and Diffuse Cutaneous Infiltrates

x

Akmal S. Hassan MSc, MD Consultant in Dermatology Faculty of Medicine Cairo University Cairo, Egypt Chapter 8: Subepidermal Blistering Diseases

Victoria Hobbs Hamet, MD Division of Dermatology Georgetown University Washington, DC Chapter 21: Fungal Infections Terence J . Harrist, MD Dermatophathologist Winchester Hospital and Strata Diagnostics Winchester and Waltham, Massachusetts Chapter 7: Intraepidermal Vesiculopustular Diseases Paul Hofman MD, PhD Professor Department of Pathology Pasteur Hospital University of Nice Sophia Antipolis, Nice, France Laboratory of Clinical and Experimental Pathology Pasteur Hospital Nice, France Chapter 23: Protozoal and Algal Infections Thomas D. Horn MD, MBA Dermatopathologist CarisCohenDx Newton, Massachusetts Chapter 3: Interface Dermatitis Steven J. Hunt, MD Northern Pathology Laboratory Iron Mountain, Michigan Chapter 31: Vascular Tumors and Vascular Malformations Anne Janin, MD, PhD Professor of Pathology Universitè Paris Diderot Head of Research Unit 728 Inserm Medical Coordinator Pathology and Biology Departments Hôpital Saint-Louis Paris, France Appendix: Stem cells and the skin Chris H. Jokinen, MD Dermatopathology Fellow Department of Pathology University of Washington Seattle, Washington Chapter 33: Neural and Neuroendocrine Tumors Daniel M. Jones, MD Associate Professor Division of Pathology and Laboratory Medicine University of Texas M.D. Anderson Cancer Center Houston, Texas Chapter 1: Introduction to Microscopic Interpretation

Jacqueline M. Junkins-Hopkins, MD Associate Professor Division of Dermatopathology Departments of Dermatology and Pathology Johns Hopkins University School of Medicine and Johns Hopkins Hospital Baltimore, Maryland Chapter 18: Ectopic Tissue Grace F. Kao, MD Director of Dermapathology Department of Pathology and Laboratory Medicine Maryland Veterans Affairs Medical Center Baltimore, Maryland Professor of Dermatopathology and Dermatology George Washington University School of Medicine Washington, DC Chapter 20: Treponemal and Rickettsial Diseases Catherine Lisa Kauffman MD, FACP Chief, Division of Dermatology Associate Professor of Medicine, Dermatology, and Pathology Georgetown University Washington, DC Chapter 21: Fungal Infections Werner Kempf, MD Lecturer and Consultant Physician Department of Dermatology University Hospital of Zürich Zürich, Switzerland Kempf und Pfaltz Histologische Diagnostik Zürich, Switzerland Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 1: Cutaneous T-Cell Lymphoid Hyperplasia and Cutaneous T-Cell Lymphomas) Helmut Kerl, MD Professor of Dermatology Emeritus Department of Dermatology Medical University of Graz Graz, Austria Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 2: Cutaneous B-Cell Lymphoid Hyperplasia and Cutaneous B-Cell Lymphomas) Stefan Kraft, MD Clinical Fellow Harvard Medical School Resident in Pathology Brigham and Women’s Hospital Boston, Massachusetts Chapter 30: Fibrous and Fibrohistiocytic Tumors

Thomas Krausz, MD, FRCPath Professor Director of Anatomic Pathology Department of Pathology The University of Chicago Chicago, Illinois Chapter 32: Tumors of Adipose Tissue, Muscle, Cartilage, and Bone

Michael J. Murphy, MB, BCh, BAO Associate Professor of Dermatology Director of Immunopathology Dermatopathology Laboratory Department of Dermatology University of Connecticut Health Center Farmington, Connecticut Chapter 2: Spongiotic Dermatitis

Freddye M. Lemons-Estes, MD Quest Diagnostics, Inc. North Florida Anatomic Pathology Tampa, Florida Chapter 23: Protozoal and Algal Infections

Ann Marie Nelson, MD Chairman, Department of Scientific Laboratories Chief, Division of AIDS Pathology Armed Forces Institute of Pathology Washington, DC Chapter 23: Protozoal and Algal Infections

Lisa Lerner, MD Dermatopathologist CarisCohenDx Newton, Massachusetts Chapter 7: Intraepidermal Vesiculopustular Diseases James J. Lyons, MD Dermatopathology Fellow University of Texas Southwestern Medical Center Dallas, Texas Chapter 22: Viral Infections Cynthia M. Magro, MD Professor Dermatopathology Division Department of Pathology Cornell University Weill Medical College New York, New York Chapter 12: Cutaneous Drug Eruptions; Chapter 20: Treponemal and Rickettsial Diseases M. Megahed, MD Professor Department of Dermatology and Allergy University of Aachen Aachen, Germany Chapter 8: Subepidermal Blistering Diseases Patrice Morel, MD Professor Department of Dermatology Hôpital Saint Louis Paris, France Provision of Clinical Photographs

Douglas C. Parker, MD, DDS Assistant Professor of Pathology and Dermatology Emory University School of Medicine Atlanta, Georgia Chapter 10: Disorders of Cutaneous Appendages Michael W. Piepkorn, MD Clinical Professor Division of Dermatology University of Washington School of Medicine Seattle, Washington Dermatopathology Northwest Bellevue, Washington Chapter 14: Alterations of the Stratum Corneum and Epidermis Michael S. Rabkin, MD, PhD Director, Rabkin Dermatopathology Laboratory Pittsburgh, Pennsylvania Chapter 35: Cutaneous Metastases James Ramirez, MD Dermatopathology Department St. Joseph Mercy Hospital Ann Arbor, Michigan Chapter 7: Intraepidermal Vesiculopustular Diseases Frances I. Ramos-Ceballos, MD Department of Dermatology University of Arkansas for Medical Sciences Little Rock, Arkansas Chapter 3: Interface Dermatitis Ronald P. Rapini, MD Professor of Pathology Chair, Department of Dermatology University of Texas Medical School MD Anderson Cancer Center Houston, Texas Chapter 19: Bacterial Infections

Franco Rongioletti, MD Professor of Dermatology Section of Dermatology, DISEM University of Genoa Genoa, Italy Chapter 16: Deposition Disorders Daniel Santa Cruz, MD Cutaneous Pathology Maryland Heights, Missouri Chapter 31: Vascular Tumors and Vascular Malformations Brian Schapiro BSc (Med), MBChB Dermatopathology Department St. Joseph Mercy Hospital Ann Arbor, Michigan Chapter 7: Intraepidermal Vesiculopustular Diseases

CONTRIBUTORS

Mark Lerman, DMD Instructor in Oral Pathology Harvard School of Dental Medicine Attending, Division of Oral Medicine and Dentistry Division of Oral Medicine and Dentistry Brigham and Women’s Hospital Boston, Massachusetts Chapter 37: Disorders of the Oral Mucosa

Amy K. Reisenauer, MD Dermatologist St Kihei, Hawaii Chapter 10: Disorders of Cutaneous Appendages

Birgitta Schmidt, MD Instructor Department of Pathology Children’s Hospital Boston Harvard Medical School Boston, Massachusetts Chapter 11: Panniculitis Glynis A. Scott, MD Associate Professor Departments of Dermatology and Pathology University of Rochester School of Medicine Rochester, New York Chapter 25: Cutaneous Cysts and Related Lesions Alvin R. Solomon, MD Professor of Dermatology and Pathology, Emory University School of Medicine, Chief, Dermatology Service Atlanta Veterans Administration Medical Center Atlanta, Georgia Chapter 10: Disorders of Cutaneous Appendages W. P. Daniel Su Professor in Dermatology Mayo Medical School Consultant in Dermatology Mayo Clinic Rochester Minnesota Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 3: Cutaneous Leukemic infiltrates)

xi

Steven R. Tahan Department of Pathology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts Chapter 21: Fungal Infections Laurence Verneuil, MD, PhD Service de Dermatologie CHU Caen Caen, France Appendix; Chapter 17: Alterations of Collagen and Elastin

CONTRIBUTORS

Dominique Vignon-Pennamen, MD Departments of Dermatology and Pathology Hôspital Saint-Louis Paris, France Provision of Clinical Photographs Franz von Lichtenberg Department of Pathology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Chapter 24: Helminthic Diseases

Michel Wassef, MD Associate Professor of Pathology University Paris VII- Denis Diderot Faculty of Medicine Attending Pathologist, Department of Pathology Hôpital Lariboisière Paris, France Chapter 31: Vascular Tumors and Vascular Malformations Clifton R. White, Jr., MD Professor of Dermatology and Pathology Oregon Health Science University Portland, Oregon Chapter 17: Alterations of Collagen and Elastin David A. Whiting, MD University of Texas Southwestern Medical Center Baylor Hair Research and Treatment Center Dallas, Texas Chapter 10: Disorders of Cutaneous Appendages

Mark R. Wick, MD Professor of Pathology University of Virginia Medical Center Charlottesville, Virginia Chapter 28: Tumors with Hair Follicle and Sebaceous Differentiation; Chapter 29: Sweat Gland Tumors Sook-Bin Woo, DMD, MMSc Associate Professor Harvard School of Dental Medicine Division of Oral Medicine and Dentistry Brigham and Women’s Hospital Boston, Massachusetts Staff Pathologist Strata-Pathology Services, Inc. Cambridge, Massachusetts Chapter 37: Disorders of the Oral Mucosa Gary S. Wood, MD Johnson Professor and Chairman Department of Dermatology University of Wisconsin Madison, Wisconsin Appendix: Molecular Biologic Techniques for the Diagnosis of Cutaneous Lymphomas Sarah Zeller, MD, MPH Dermatologist Blue Ridge Dermatology Waynesbore, Virginia Chapter 15: Disorders of Pigmentation

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FOREWORD

Training Program, he has developed the knowledge and skills to interact with pathologists, dermatologists, trainees, and students. The success of his monograph on melanocytic lesions of the skin speaks to the effectiveness of his writing and teaching approaches. For this book, Dr. Barnhill has assembled a stellar roster of authors from various disciplines and has appropriately included both established leaders in the field as well as the cream of our younger generation of dermatopathologists. He himself has coauthored one-third of the chapters of the book, and I know

first hand that he has spent a great deal of effort meticulously editing all chapters for consistency, style, and accuracy. His associate editor, Dr. Neil Crowson, has been instrumental in providing the highquality micrographs for many of the entities in the book, and two young, energetic assistant editors, Drs Klaus Busam and Scott Granter, contributed heavily to the book. I look forward to the publication of this text and wish it the success it truly deserves.

FOREWORD

As senior editor of this new Textbook of Dermatopathology, Dr. Raymond Barnhill brings to the task years of experience as a dermatopathologist, clinical dermatologist, clinical investigator, and author. This has given him an unparalleled understanding of inflammatory and neoplastic diseases of the skin and the ability to teach others. As director of dermatopathology at the Brigham and Women’s Hospital and the Children’s Hospital in Boston, he has had contact with both pediatric and adult dermatologic conditions, and as a member of the Combined Harvard Dermatopathology

Ramzi S. Cotran, MD, 1998

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P R E FA C E T O T H E THIRD EDITION

histopathology and differential diagnosis, critical analysis, balanced perspectives on what is known and what is not, clarity of writing, the use of tables to summarize the key features of major entities, and color photomicrographs” and also to maintain a rather uniform style. In the course of revising the book, a significant effort has been made to improve the overall quality of photographs in the book. The latter has been accomplished by replacing the existing black and white with color images, improving the quality of many existing color images, increasing the overall number of photographs, and finally including new clinical images. All chapters have been superbly revised, and much new information has been included with respect to various inflammatory

conditions, infections, melanocytic, vascular, lymphoid and other neoplastic conditions. Newly described entities have been added to the book where appropriate, and approximately one hundred new color photomicrographs have been incorporated into the third edition. As before, I acknowledge the tremendous efforts of the many people involved in this third edition, without which it would not have been possible. I am especially indebted to all the contributors and to the staff at McGraw-Hill who have made the third edition a reality. I sincerely hope that the information contained in this book may contribute to improved and more enlightened patient care.

PREFACE TO THE THIRD EDITION

The editor and publisher are extremely enthusiastic to offer a third edition of this book to physicians and others in the fields of dermatopathology, dermatology, and allied specialties. It is the express wish of the editors, contributors, and the publisher that the information compiled in this work greatly aides physicians and other health care workers in facilitating the best patient care possible. The editor is deeply appreciative of the prodigious work of the new coeditors Neil Crowson, Cynthia Magro, and Michael Piepkorn and the many eminent contributors in producing an accessible and scholarly book. The third edition has been revised with the same goals as the first and second editions, that is, to provide “descriptive

Raymond L. Barnhill, MD

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P R E FA C E T O T H E FIRST EDITION

pattern recognition as a prologue to algorithms and the description of the major patterns of inflammation of the skin. Christopher French, MD, has, in addition, designed schematic color figures that enhance the recognition of patterns of inflammation of the skin. Another major feature is that associate editor Neil Crowson, MD, has taken high-quality photomicrographs for most of the entities in the book. This is another characteristic that provides a uniform style to the book. I am deeply grateful to Dr. Crowson for this enormous undertaking. Although all major entities have been covered in an erudite fashion in the book, a number of unique features must be mentioned. The chapter on disorders of the skin appendages provides new quantitative information on the alopecias and describes the use of transverse sections in the diagnosis of alopecia. Dr Crowson has written a comprehensive chapter on drug eruptions and included lists of medications implicated in these eruptions. Critical chapters on controversial and difficult topics such as vasculitis, panniculitis, disorders of pigmentation, and melanocytic lesions will provide greater insight and aid to the pathologist dealing with these conditions. Finally, there are more detailed chapters on disorders of the nails and the oral mucosa than are currently available in most other texts. Another modification has been the inclusion of a scholarly section on normal skin histol-

ogy, laboratory methods, immunohistochemistry, and the molecular biology of cutaneous lymphoid infiltrates in an appendix rather than in the text itself. It will become evident to the reader that there is occasionally some overlap or duplication of some conditions among the various chapters, since no method of classification is entirely consistent. My intention has been to allow some duplication since this provides different perspectives on a disease process. Finally and most importantly, I would like to acknowledge the tremendous efforts of many friends and colleagues without whose advice, encouragement, and help this book would not have been possible. First of all, I would like to thank Neil Crowson for his enormous contributions in photography, writing, and for his unflagging encouragement and support throughout the project. I am also indebted to my former fellows Klaus Busam and Scott Granter for their commitment and hard work on the book, and I am most appreciative of my secretaries Robin McCarthy (who has since departed for an undoubtedly easier job!) and Maria Palaima, and the staff at McGraw-Hill for their dedication and efforts in bringing the book to closure. Lastly, I am most grateful to all the contributors who have sacrificed so much of their time and energy to make the book not only possible but a learned work that will have an impact on the field.

PREFACE TO THE FIRST EDITION

The question might be posed, “Why another textbook of dermatopathology?” since a number of books are currently available and would seem to do justice to the subject. Quite simply, I have perceived the need for another book. Following on the success of a monograph on melanocytic lesions of the skin, The Pathology of Melanocytic Nevi and Malignant Melanoma, I believe that there is indeed a need for a general text on dermatopathology emphasizing the same format as the aforementioned monograph: descriptive histopathology and differential diagnosis, critical analysis, balanced perspectives on what is known and what is not, clarity of writing, the use of tables to summarize the key features of major entities, and color photomicrographs. At the same time it must be acknowledged that the scope of such a book goes well beyond that of a monograph on melanocytic lesions. As a result, I have engaged a scholarly group of individuals to help in writing such a book in a timely fashion. Nonetheless, one of my major goals has been to maintain a uniform style in keeping with the philosophy of the book. In recent years I have been impressed with the need to provide some orientation for beginning the process of learning dermatopathology. Thus, the first chapter of this book is devoted to the approach to diagnosis at the microscope. Daniel Jones, MD, PhD, also discusses succinctly the scientific basis of

Raymond L. Barnhill, MD

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1 PART

Inflammatory Reactions In the Skin

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CHAPTER 1 Introduction to Microscopic Interpretation Raymond L. Barnhill Daniel M. Jones

the chapter on a step-by-step approach to microslide review (see Fig. 1-1). Although the correct diagnosis of common skin tumors often can be made by inspection of the microslide with the naked eye or at the lowest scanning magnification, the perceptual processes involved in diagnosis are quite complex. They can be schematized by the simplified algorithm that follows. 1. “Reading” the slide (ie, visual perception/ attention) 2. Processing the acquired visual information

Perhaps in no other area of pathology does one encounter such diverse disease processes and bewildering terminology as in dermatopathology. The classic approach to learning dermatopathology, as in many other areas of medicine, has been disease oriented, a style not easily mastered by beginners or even more advanced students. However, in recent years there has been greater emphasis on using a systematic and logical approach of pattern recognition for diagnosis, particularly for inflammatory conditions in the skin.1-5 The objectives of this chapter are (1) to present an outline of the perceptual principles and pitfalls underlying pathologic diagnoses and (2) to outline a practical step-by-step method for interpreting a microslide and formulating a differential diagnosis using techniques of pattern recognition and algorithms.

Interpretation of the Slide The diagnostic approach of this textbook is to bring a systematic approach to diagnosis of skin lesions. The chapter organization reflects this explicit algorithmic approach, with an emphasis in

4. Testing the preliminary diagnosis with further examination 5. Confirming the diagnosis 6. Attending to secondary features (eg, status of margins, tumor grade) 7. Correlating available clinical information 8. Finalizing the diagnosis

Initial Examination of the Slide with the Naked Eye The histopathologist should first inspect the microslide with the naked eye in order to gain some appreciation of the size, number, and nature of the histologic sections on the slide. Often one can make certain deductions from this gross examination alone. For example, a small specimen is either a curetting, a shave, or a punch biopsy and connotes particular pathologic processes (In contrast, a large specimen generally indicates an excision. Often it is possible to establish the process as epidermal, dermal, or subcutaneous by this examination. The tinctorial properties (histochemical staining) also may provide clues to diagnosis; for example,

Proliferative/ neoplastic

Principally inflammatory

Epidermal alteration

Epidermis normal

Epidermis

 FIGURE 1-1 Algorithmic approach to diagnosis.

Examination of the Microslide at Scanning (2⫻ or 4⫻) Magnification The microslide next should be viewed at scanning magnification, that is, with a 2⫻ or 4⫻ objective. Although a 2⫻ objective may prove optimal for the initial examination of many specimens, particularly large specimens, many microscopes are equipped only with 4⫻ objectives. However, the 4⫻ objective is a reasonable alternative, and additional information generally can be obtained at this magnification. If possible, the specimen always should be studied initially without knowledge of age, gender, or other clinical information in order to gather information objectively and formulate a differential diagnosis. Although the experienced pathologist often does not need to resort to such a method unless a diagnosis is not immediately apparent, the beginner should systematically study a slide with specific goals in mind. 1. First of all, the pathologist should attempt to identify the type of specimen submitted; that is, is it a curettage, punch, shave, or excisional specimen? Determination of the type of specimen is important because it often provides some clue to the type of disease process suspected by the submitting clinician. For example, curettage specimens often are taken for neoplastic processes such as actinic or seborrheic keratoses or basal cell carcinoma. Shave biopsies usually are obtained for diagnosis of keratoses

Noninflammatory

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

3. Arriving at a tentative diagnosis (ie, model building)

INTRODUCTION

bluish cellular aggregates or nodules suggest high nuclear-to-cytoplasmic ratios because of basophilic staining of nuclei and, as a result, processes such as basal cell carcinoma, small cell carcinoma, and infiltrates of small lymphocytes or calcium deposition.

“Normal skin”

Dermis and/or subcutis

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

or basal or squamous cell carcinoma. In general, punch biopsies are submitted for diagnosis of either neoplastic or inflammatory conditions. In some instances they are used to “excise” a proliferation or tumor, and thus margins may need to be assessed. By and large, skin ellipses (excisions) are submitted for suspected tumors but also on occasion for inflammatory processes such as vasculitis or panniculitis.

4

2. Next, the pathologist should inspect the specimen with the idea of determining in general terms from what anatomic site the tissue was taken. In general, based on characteristics such as prominence of sebaceous follicles, relative paucity of hair follicles, thickness of the reticular dermis, and thickness of the stratum corneum, one can recognize the following general regions of the integument: (a) head and neck, (b) trunk and proximal extremities, and (c) acral (including frictional) surfaces. It is evident that many diseases have characteristic site distributions, and knowledge of the particular localization of the lesion or eruption is useful in formulating one’s differential diagnosis. 3. The entire specimen (ie, epidermis, dermis, or subcutis) should be scanned for the principal site of involvement by a disease process, if any, and the nature of the process, whether inflammatory, proliferative, inflammatory and proliferative, or noninflammatory. Although in most instances the site of involvement is obvious, it is important that the specimen is examined systematically when the process is not so obvious. In general, the specimen should be scrutinized in a sequential fashion, for example, beginning with the stratum corneum and then proceeding to the epidermis, dermis, subcutis, and fascia. At scanning magnification, one should be able to appreciate many aspects of the disease process without going to greater magnification. If an inflammatory process is present, one should attempt to recognize the nature of epidermal involvement, for example, spongiosis, interface vacuolopathy, psoriasiform epidermal hyperplasia, or vesicle, blister, or pustule formation; the pattern of the inflammatory infiltrate, whether bandlike (cell-poor or cell-rich/lichenoid), perivascular, interstitial, periadnexal, nodular, or diffuse (pandermal); the depth of the infiltrate, for example, superficial only or superficial and deep; possibly the presence of vascular damage; the

cellular composition of an infiltrate, that is, whether it is comprised of mononuclear cells, suggesting small lymphocytes or larger cells; and alterations of the dermis, for example, by fibrosis or sclerosis resulting in a “square” punch biopsy versus the typical inverted cone configuration, thickening, or atrophy of the dermis or deposition of material such as calcium. A primary proliferative or neoplastic condition also should be obvious in most instances at scanning magnification. After the completion of this exercise, the pathologist is often able to establish the basic nature and localization of the disease process and possibly to develop a preliminary differential diagnosis if he or she has not already arrived at a specific diagnosis. In many instances, this may not be possible at scanning magnification because the changes are too subtle for diagnosis at this or perhaps any magnification or there has been a sampling error. At this point, the pathologist must go to greater magnification in order to confirm an impression or to gain more information that is only possible at increased magnification.

Examination at Intermediate Magnification It cannot be overemphasized that, in general, most information about a pathologic process is obtained at scanning magnification. The tendency to go to higher magnification too soon should be resisted because one often will overlook a crucial feature, and thus, in effect, one “cannot see the forest for the trees.” The reasons for closer inspection of the specimen (with 10⫻ and 20⫻ objectives) are to confirm particular features of pathologic processes, for example, parakeratosis, spongiosis, fibrinoid necrosis, or mucin deposition, and for identification of specific cell types, such as lymphocytes or granulocytes. However, in some instances, greater magnification may be needed in order to identify a morphologic feature not recognizable at low magnification, such as, hyphal elements in the cornified layer, epidermal basal layer vacuolopathy, amyloid deposits in the papillary dermis, or mucinosis in the reticular dermis.

Examination at High Magnification As mentioned for intermediate magnification, use of the high-power objective also should be reserved for specific indications. Such examination is necessary in

order to study the cytologic details of cells, such as, the nuclear contours of lymphocytes or nuclear atypia in general; to confirm the nature of infectious organisms; and to confirm other findings.

Integration of All Information During the preceding exercise of examining the microslide, the histopathologist should take the perspective that he or she is objectively gathering information that can be integrated with other (clinical and laboratory) information to arrive at some conclusion about the disease process and not necessarily to arrive at a single diagnosis. One should, at all times, try to avoid reaching a conclusion too quickly and failing to observe other pertinent findings in the specimen. The pathologist always should try to think expansively of every potential pathologic process that might explain the histologic findings. One should continuously weigh the various points that argue for or against a particular pathologic condition. After completing the preceding examination and reaching some tentative impression (or lack of conclusion) about the specimen without knowledge of clinical parameters, it is then necessary to consider the clinical context of the specimen. Even if the histopathologic diagnosis appears straightforward, such as, for example, basal cell carcinoma, the pathologist always should have certain clinical information before finalizing the case: age, gender, anatomic site, and clinical diagnosis. Without such information, the pathologist is much more prone to blatant errors, such as mislabeled specimens or misdiagnosis. On the other hand, for many conditions, particularly inflammatory processes, detailed clinical information concerning the onset, evolution, distribution, and specific character of the skin lesions is essential in order to arrive at a diagnosis or to formulate a differential diagnosis. Many inflammatory reaction patterns are not specific and may be secondary to several processes. Thus an accurate clinical history is needed to establish the most likely condition or group of conditions that might explain the histologic findings. Finally the histopathologist must recognize the limitations of histopathological interpretation: in some instances specific diagnosis is not possible since either the histological findings are nonspecific and diagnosis rests in the clinical domain, current knowledge about the disease process is inadequate, the biopsy specimen is inadequate, or sampling error has occurred.

PATTERN RECOGNITION IN DERMATOPATHOLOGY

Features of Benign versus Malignant Tumors Although it may appear intuitive and instantaneous, recognition of cutaneous tumors is a highly complex perceptual process that involves more than simple “wallpaper matching.” However, in the diagnosis of cutaneous tumors, the lowpower pattern (tumor silhouette) often can be at least as important if not definitive for diagnosis as high-power cytologic findings.3 Certain tumor growth patterns appear to be intrinsically more readily recognizable and often are the first to be mastered

 FIGURE 1-2 Distinguishing benign from malignant neoplasms by low-power microscopic features. Characteristic acanthosis, hyperkeratosis, and keratin pseudocyst formation in seborrheic keratosis are easy to detect (left). Similar features are evident in a benign keratosis due to chronic irritation (right).

by the student of dermatopathology. This is supported by a large body of perceptual research demonstrating that some visual targets (termed good patterns) are consistently recognized more rapidly than others. Conversely, there is impaired performance of visual tasks that involve recall of “poor” visual targets. Easy recognition of some benign skin tumors (Fig. 1-2, eg, seborreic keratosis, keratoacanthoma, or cylindroma) in contrast to others (eg, a sclerosing melanocytic nevus or desmoplastic melanoma) is due to the visual impact of their particular growth patterns evident at low magnification. Similarly, the presence of ancillary features such as inflammatory infiltrate can be an instantly recognizable clue to search for evidence of tumor invasion (Fig. 1-3). As a pathologist gains experience with dematopathology tumors, the distinction of the range of benign versus malignant growth patterns becomes easier.

Features of Inflammatory and Reactive Lesions Although it also involves pattern recognition, the diagnosis of inflammatory lesions presents a much different challenge. Instead of rendering a definitive diagnosis, the usual approach is descriptive (ie, what kinds of epidermal alterations and inflammatory cells are present and where they are located). In the absence of adequate clinical information, a range of possible diagnoses usually is provided. This is a different perceptual task where the goal is simply not to match a precise stored visual image but to compare the features of a lesion with the clinical entity to which it is (statistically) most similar. Inflammatory lesions are grouped initially into general categories (see Figs. 1-4 to 1-8), and then specific features are sought to narrow (or prioritize) the diagnoses. For instance, once the pattern of

 FIGURE 1-3 Combining epidermal changes and reaction patterns in diagnosis. Even at low magnification, the regular pattern of acanthosis and hyperkeratosis seen in squamous cell carcinoma in situ (right) is contrasted with the irregular squamous proliferation, abnormal maturation, and robust inflammatory infiltrate associated with invasive squamous cell carcinoma (middle). Examination at higher magnification reveals infiltrating tumor cells (right panel, arrow).

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

Accurate perception of the findings on a microslide is obviously the initial step in accurate diagnosis. Many, perhaps most, serious errors in diagnosis are related to a failure to attend to or notice critical histologic findings rather than a misinterpretation of these features. A trivial but common reason for misdiagnosis is simply a failure to examine a relevant tissue fragment or level. Poor tissue preservation and histologic detail or substandard tissue sectioning also can contribute greatly to problems in accurate perception. The visual fatigue and information overload that occur after examining many cases also contributes to perceptual mistakes. As outlined in Fig. 1-1, the initial decision one must make is whether a process is predominantly inflammatory, predominantly proliferative/neoplastic, both inflammatory and proliferative, or noninflammatory/nonproliferative. This is not always possible, but, in general, the vast majority of pathologic processes can be categorized into one of these groups. Thus one is able to proceed along one of the decision trees.

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Vesicle/ blister/ papule

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Intraepidermal Chap. 7

Subcorneal substratum granulosum

Spongiotic dermatitis Chap. 2

Subepidermal Chap. 8

Interface dermatitis Chap. 3

Vacuolar type

Junctional

Dermolytic

Intrastratum spinosum

Suprabasilar, intrabasilar

Conventional spongiosis

Eosinophilic spongiosis

Psoriasiform dermatitis Chap. 4

Lichenoid type

Neutrophilic spongiosis

Follicular spongiosis

Miliarial spongiosis

 FIGURE 1-4 Inflammatory conditions with epidermal alteration.

No vascular damage

Perivascular infiltrates Chap. 5

Disorders of skin appendages Chap. 10

Hair follicle, folliculitis, perifolliculitis, alopecia

Nodular infiltrates Chap. 6

Vascular damage

Diffuse infiltrates Chap. 6

Panniculitis fasciitis Chap. 11

Vasculopathy Chap. 9

Sweat glands, milaria, hidradenitis

Vasculitis Chap. 9

 FIGURE 1-5 Inflammatory conditions of the dermis and/or subcutis without epidermal alterations and with and without vascular injury.

Granulomas/granulomatous inflammation Chap. 6

Sarcoidal epithelioid cell

Tuberculoid caseating

Foreign body

 FIGURE 1-6 Inflammatory infiltrates with granulomas/granulomatous inflammation.

6

Suppurative

Elastolytic

provides detailed descriptions of both the histologic features and clinical appearance of each entity. There are also added complexities to diagnosis of inflammatory lesions in the skin that are related to the nature of the immune responses producing these lesions. These include:

Alterations of stratum corneum and epidermis Chap. 14

Hyperkeratosis with parakeratosis focal or diffuse

Hyperorthokeratosis

Alteration of basal layer melanin

Normal granular layer or hypergranulosis

Hypogranulosis

Hypopigmentation, focal or diffuse Chap. 15

Hyperpigmentation, focal or diffuse Chap. 15

 FIGURE 1-7 Noninflammatory disorders with alterations of stratum corneum and epidermis.

Papillary dermal alteration vs Reticular dermal alteration

Atrophy

Deposition of material Chap. 16

Hypertrophy fibrosis Chap. 17

 FIGURE 1-8 Noninflammatory disorders with dermal alteration.

vacuolar interface dermatitis has been identified, visual search for viral inclusions or apoptotic bodies could support the diagnoses of a viral exanthem or erythema multiforme. Combining the available information on the gross appearance and the clinical differential diagnosis with the histologic diagnosis is the vitally important penultimate stage prior to rendering a final diagnosis. The close linkage in training and expertise between dermatologist and dermatopathologist often makes this process easier because the histopathologist becomes more familiar with the clinical appearance of the lesions in the differential diagnosis. This synergistic effect is most obvious in the rare cases where the biopsy specimen is being diagnosed by the person who has actually examined the patient. However, in all cases, the differential diagnosis provided by the submitting dermatologist may force a reexamination of the microscopic features, and as a result, this book

Pigmentary alterations Chap. 15

2. The severity of the reaction. For inflammatory lesions incited by external or internal antigenic reaction, there is a spectrum of responses ranging from mild to severe (Fig. 1-10). 3. The overlap of benign dermatoses and cutaneous T-cell lymphomas. There are a limited number of epidermal reaction patterns seen in response to infiltration by immune cells or neoplastic lymphocytes. Furthermore, cutaneous T-cell lymphomas (CTCL) often evolve from preceding dermatitis. Therefore, there can be overlap in the histologic features seen in CTCL and reactive inflammatory conditions requiring careful attention to lymphocyte atypia at high magnification (Fig. 1-11). Full maturation of expertise in dermatopathology thus requires not only a

 FIGURE 1-9 Spongiotic dermatitis, acute versus chronic changes. Spongiosis and neutrophilic crust are characteristic of a self-limited contact dermatitis (left). In contrast, chronic spongiotic dermatitis results in dermal fibrosis and vascular proliferation (right).

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

1. The temporal phase of a lesion. Many dermatitis reactions have acute, subacute, and chronic phases with fairly specific histologic correlates (Fig. 1-9). Therefore, it is important to consider the varying histologic appearances that can occur over the life span of a skin lesion.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

epidermis shows one of the following major reaction patterns or is uninvolved by the inflammatory process.

 FIGURE 1-10 Interface dermatitis, mild to severe. Mild graft-versus-host (GVH) disease shows minimal interface lymphoid infiltrate (left panel, arrow). In comparison, severe GVH shows numerous necrotic keratinocytes and subepidermal cleft formation (right).

Table 1-1 Spongiotic Dermatitis

 FIGURE 1-11 Psoriasiform reaction pattern. Psoriasis shows hyperkeratosis with thinned granular layers and elongation of the rete ridges (left). A case of mycosis fungoides shows similar psoriasiform epidermal hyperplasia, with cytologic atypia of the lymphocytes only appreciated on high magnification (inset).

“library” of stored visual images of inflammatory skin lesions that correlate with clinical syndromes but also knowledge of the time-course and spectrum of changes seen for each particular entity. As discussed below, the stepwise approach to learning to diagnose inflammatory lesions in skin emphasizes the importance of mastering the diagnostic differential for each inflammatory pattern.

Major Inflammatory Reaction Patterns in the Skin 8

INFLAMMATORY REACTION PATTERNS OF THE EPIDERMIS Spongiotic dermatitis Spongiotic dermatitis refers specifically to the presence of spongiosis or intercellular edema that stretches apart keratinocytes and sometimes results in the formation of intraepidermal vesicles. Spongiosis is often variable, multifocal, and accompanied by intracellular edema and exocytosis of inflammatory cells. The disease process is dynamic and in general has been categorized according to morphologic features correlating with the stages of its life history (1) acute, (2) subacute, and (3) chronic (Fig. 1-9). Other alterations such as granulocyte infiltration of the epidermis (eg, eosinophilic or neutrophilic spongiosis) or involvement of skin appendages (eg, follicular spongiosis) may be observed. Spongiosis is a relatively nonspecific morphologic alteration observed in a wide variety of conditions (see Table 1-1). It is

Since the pathogenesis of most inflammatory dermatitides is unknown, one must, of necessity, use morphologic criteria for

classification at present. Although most inflammatory conditions can be categorized into one of the major reaction patterns, there are inevitable dermatitides that show overlapping features and some that defy classification. Some inflammatory conditions may be sampled either too early or too late in their evolution to be diagnostic. Inflammatory diseases are dynamic, and knowledge of the point in time when the dermatitis is sampled is critical to optimal microscopic interpretation. The histopathologist should strive to assess specimens with the “fourth dimension” of time always kept in mind. As mentioned previously, one initially attempts to ascertain whether the

Conventional spongiotic dermatitis Allergic contact dermatitis Irritant contact dermatitis Atopic (endogenous) dermatitis Nummular dermatitis Dyshidrotic eczema (pompholyx) Id reaction Seborrheic dermatitis Stasis dermatitis Spongiotic drug eruption Erythroderma Pityriasis rosea Pityriasis alba Photoallergic contact dermatitis Polymorphous light eruption Arthropod bites Gyrate/figurate erythemas Dermatophyte infection Transient acantholytic dermatosis Pigmented purpuric dermatitis Papular and urticarial eruptions of pregnancy Eosinophilic spongiosis Pemphigus group Bullous pemphigoid Allergic contact dermatitis Spongiotic drug eruptions Infestations Cutaneous larva migrans Arthropod bites Incontinentia pigmenti Eosinophilic folliculitis

Neutrophilic spongiosis Psoriasis Reiter syndrome Seborrheic dermatitis Irritant contact dermatitis Phototoxic dermatitis Pemphigus variants (particularly IgA pemphigus) Follicular spongiosis Atopic dermatitis Pityriasis alba Contact dermatitis Infundibulofolliculitis Eosinophilic folliculitis Follicular mucinosis Fox-Fordyce disease

perhaps most characteristic of the group of conditions referred to as eczematous dermatitis. These disorders include endogenous or atopic dermatitis, contact allergic and irritant dermatitis, and nummular dermatitis. Other common dermatitides showing spongiosis include seborrheic dermatitis, spongiotic drug eruptions, and some primary bullous conditions.

Interface dermatitis Interface dermatitis refers to a morphologic alteration at the junction or interface between the epidermis (or epithelium) and dermis. Specifically, one observes vacuolization (vacuoles or discrete clear spaces) either within basilar keratinocytes or within the basement membrane zone. This reaction pattern is often accompanied by a number of other alterations present to variable extent: individually dyskeratotic keratinocytes (which are probably apoptotic cells), disruption of orderly keratinocytic maturation to the surface, and clefts resulting from coalescence of vacuoles. Interface dermatitides may be further subclassified according to the density and pattern of the inflammatory cell infiltrate in the papillary dermis as (1) the vacuolar or cell-poor type, based on perivascular or patchy infiltrates in the papillary dermis or (2) the lichenoid or cell-rich type, which shows a dense bandlike infiltrate that fills the papillary dermis (Table 1-2). As with all inflammatory processes, interface dermatitides also may be characterized according to their severity (Fig. 1-10, illustrating graft-versus-host reaction) or their stage of evolution as acute or early stage, subacute or developed, or chronic or late stage. Certain diseases are prototypic of the two patterns of interface dermatitis

Table 1-3 Psoriasiform Dermatitis

Vacuolar interface dermatitis Erythema multiforme Fixed drug eruption Drug eruptions Viral xanthems HIV interface dermatitis Connective tissue disease Lupus erythematosus Dermatomyositis Graft-versus-host reaction Pityriasis lichenoides Poikiloderma congenitale Bloom syndrome Vitiligo Pigmented purpuric dermatitis Lichenoid interface dermatitis Lichen planus and variants Lichenoid drug eruption Lichenoid keratosis Lichen striatus Lichen nitidus Lichenoid purpura Porokeratosis Histologic regression of many tumors

Psoriasis Reiter syndrome Subacute to chronic eczematous dermatitis Seborrheic dermatitis Lichen simplex chronicus Pityriasis rubra pilaris Parapsoriasis Mycosis fungoides Psoriasiform drug eruption Erythroderma Candidiasis Secondary syphilis Inflammatory linear verrucous epidermal nevus (ILVEN) Scabies Lamellar ichthyosis Clear cell acanthoma Pellagra Acrodermatitis enteropathica Migratory necrolytic erythema Bazex syndrome

mentioned earlier. Erythema multiforme, many drug eruptions, viral exanthems, and connective tissue diseases result in a vacuolar pattern of interface dermatitis. On the other hand, lichen planus, lichenoid drug eruptions, lichen planus-like keratosis, and “halo” nevus are associated with lichenoid patterns of inflammation.

Psoriasiform dermatitis Psoriasiform dermatitis refers to a characteristic pattern of epidermal hyperplasia typified by elongation of the epidermal rete ridges (Fig. 1-11). In general, the topography of the epidermal surface is unaffected, that is, remains essentially flat-topped. This pattern of epidermal alteration may be further described as either regular or irregular. Regular psoriasiform hyperplasia, as the name suggests, indicates elongated epidermal rete ridges of fairly uniform length and thickness and is typical of psoriasis in a well-developed stage. This morphologic feature is accompanied by a number of other histologic alterations notable in psoriasis: broad zones of parakeratosis, absence of the granular layer, exocytosis of neutrophils, pallor of keratinocytes (intracellular edema), thinning of the epidermis above the dermal papillae, prominent dilated and tortuous papillary dermal microvessels, and papillary dermal edema. Irregular psoriasiform epidermal hyperplasia may

be observed in psoriasis but typifies other processes more commonly, such as chronic eczematous dermatitis, lichen simplex chronicus, or mycosis fungoides (Table 1-3, Fig. 1-11). Other conditions that exhibit this reaction in addition to those already mentioned are psoriasiform drug eruptions, lamellar ichthyosis, and secondary syphilis.

Vesicular and bullous dermatitis This reaction pattern refers to the formation of tissue clefts or spaces that may or may not be accompanied by cellular infiltrates such as eosinophils, neutrophils, or lymphocytes. In general, these disorders are classified according to whether the level of cleavage is (1) intraepidermal or (2) subepidermal (Figs. 1-4, 1-12; see also Tables 1-4 and 1-5). Intraepidermal blisters may include, for example, subcorneal or intragranular layer cleavage or cleavage through the superficial layer or suprabasal layer of the epidermis. Subepidermal blisters may be further delineated as cleavage through the lamina lucida of the basement membrane zone or through the superficial dermis. Blistering dermatitides may then be characterized as predominantly inflammatory or noninflammatory. If inflammatory, the composition of the infiltrate and possibly immunofluorescence and serological studies will further aid classification. Finally, one may be able to recognize the mechanism of vesicle/blister formation as spongiotic, acantholytic,

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

Miliarial spongiosis Miliaria

Table 1-2 Interface Dermatitis

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

 FIGURE 1-12 Subepidermal bullous dermatitis. Bullous pemphigoid shows numerous lymphocytes and eosinophils with no necrosis of overlying epithelium (left). Erythema multiforme shows nearly fullthickness epidermal necrosis and mild lymphocytic infiltrate in association with the subepidermal blister.

Table 1-4 Intraepidermal Vesicular and Pustular Dermatitis

Intracorneal and subcorneal vesicles and pustules Impetigo Staphylococcal “scalded skin” syndrome Superficial fungal infection Pemphigus foliaceus Pemphigus erythematosus Subcorneal pustular dermatosis Infantile acropustulosis Erythema toxicum Transient neonatal pustular melanosis Miliaria crystallina Intraepidermal vesicles and pustules Spongiotic vesicles Viral vesicles Palmoplantar pustulosis Friction blister Epidermolysis bullosa

ballooning degeneration, or resulting from prominent basal layer vacuolization or subepidermal edema.

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Other epidermal reactions and overlapping patterns Inevitably the procedure of classification is somewhat artificial, and there are always exceptions and entities that defy categorization. Many inflammatory conditions in the skin show two or more of the patterns of epidermal alteration just discussed. The predominant reaction pattern generally should be used as the basis for categorization, if possible. The following morphologic reactions represent additional subsets:

Table 1-5 Subepidermal Vesicular Dermatitis

Subepidermal blisters with little inflammation Epidermolysis bullosa Porphyria Pseudoporphyria Bullous pemphigoid (cell-poor type) Burns Toxic epidermal necrolysis Bullae associated with diabetes Blisters overlying scars Bullous amyloidosis Subepidermal blisters with lymphocytes Erythema multiforme Fixed drug eruption Lichen planus pemphigoides Polymorphous light eruption Bullous mycosis fungoides Bullous fungal infections Subepidermal blisters with eosinophils Bullous pemphigoid Epidermolysis bullosa acquisita Pemphigoid gestationis Arthropod bites Drug reactions Subepidermal blisters with neutrophils Dermatitis herpetiformis Linear IgA bullous dermatosis Cicatricial pemphigoid and localized cicatricial pemphigoid Pustular vasculitis Bullous lupus erythematosus Sweet syndrome Epidermolysis bullosa acquisita Erysipelas Bullous urticaria Subepidermal blisters with mast cells Bullous mastocytosis Miscellaneous blistering diseases Drug-overdose-related bullae PUVA-induced bulla Etretinate-induced bullae

Pityriasiform dermatitis A small but important group of inflammatory dermatitides shows a constellation of epidermal changes that include focal or spotty parakeratosis, slight epidermal hyperplasia, and variable spongiotic and interface alteration. Depending on which of these features might predominate, various dermatitides in this group also might be classified as a subacute spongiotic, psoriasiform, or interface dermatitis (see Overlapping Patterns below). These conditions generally include pityriasis rosea, pityriasis lichenoides, seborrheic dermatitis, eruptive or guttate psoriasis, pre- or early mycosis fungoides lesions (parapsoriasis), some drug eruptions, subacute eczematous dermatitis, pityriasis rubra pilaris, and superficial fungal infections. Overlapping reaction patterns The four patterns listed below emphasize the prominence of two or more morphologic alterations. Particular patterns often correlate with particular disease processes. For example, spongiotic psoriasiform dermatitis is a typical pattern associated with chronic-active eczematous dermatitis. 1. Spongiotic psoriasiform dermatitis 2. Spongiotic interface dermatitis 3. Spongiotic psoriasiform interface dermatitis 4. Psoriasiform interface dermatitis CHARACTERIZATION OF THE INFLAMMATORY PROCESS IN THE DERMIS After one has examined the epidermis for morphologic alteration, one proceeds to evaluate the inflammatory process in the dermis (and subcutis and fascia, as the case may be). An immediate concern is whether recognizable vascular injury is present or absent.

Absence of vascular injury At this point, one proceeds with the assessment of the pattern, depth, density, and composition of the inflammatory cell infiltrate, as well as whether it is granulomatous or not. The patterns of inflammatory infiltrates in the dermis generally are described as lichenoid, perivascular (Fig. 1-13), periadnexal, interstitial (infiltrating collagen bundles), nodular (Fig. 1-14), or diffuse (occupying the entire dermis) (Fig. 1-15 and Table 1-6). The depth of involvement is important to recognize because many dermatitides correlate with depth. For example, drug eruptions and viral exanthems often show superficial perivascular involvement only, whereas conditions such as lupus erythematosus,

Table 1-6 Dermal Inflammatory Infiltrates without Vascular Injury

 FIGURE 1-13 Superficial perivascular dermatitis. Nonspecific features of mild lymphocytic infiltrate with no atypia and perivascular edema are seen in this case of self-limited drug rash. polymorphous light eruption, and secondary syphilis are prone to involvement of the deep dermal vascular plexus (ie, socalled superficial and deep perivascular pattern). Deep infiltrates also may be indicative of a systemic disease process, as in lupus or secondary syphilis. Density of an infiltrate is difficult to assess except in

rather subjective terms, such as sparse, moderate, or dense. However, recognizing the density of an infiltrate has relevance for particular disease processes, such as acute urticaria (which is sparse), figurate erythema (which is moderately dense), and cutaneous lymphoid hyperplasia or lymphoma (which tends to be dense). a

Further classified according to cell types present, such as lymphocytes, eosinophils, neutrophils, and so on.

 FIGURE 1-14 Nodular dermal infiltrates. Multifocal neutrophil-rich dermal infiltrates centered on destroyed follicles likely representing pustular folliculitis.

 FIGURE 1-15 Diffuse dermal infiltrate. Loose lymphoid infiltrate representing cutaneous infiltration by chronic lymphocytic leukemia (CLL).

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

Superficial or superficial and deep perivascular infiltrates* Urticaria Urticarial reactions Viral exanthems Drug eruptions Gyrate/figurate erythemas Lupus erythematosus Polymorphous light eruption Photosensitive eruptions Chilblains/perniosis Leprosy (indeterminate) Syphilis Borreliosis Leukemia Urticaria pigmentosa Nodular infiltrates Arthropod bite reactions Cutaneous lymphoid hyperplasia Histiocytic infiltrates Neutrophilic dermatoses Lymphoma Diffuse infiltrates a Reactive infiltrates Leukemia Lymphoma Histiocytic infiltrates Mast cell infiltrates

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

The cellular infiltrates in the dermis commonly are composed of lymphocytes, possibly with varying admixtures of other cell types, including monocytes/ macrophages (histiocytes), eosinophils, neutrophils, plasma cells, and mast cells. The particular cellular composition often has diagnostic significance, particularly when integrated with the other features mentioned earlier, such as pattern, depth, and density. Thus a sparse superficial perivascular infiltrate containing lymphocytes and eosinophils (and often neutrophils) would suggest urticaria. Infiltrates with the same cell types but of greater density (moderate) would suggest the broad category of allergic hypersensitivity reactions, and finally, circumscribed superficial and deep perivascular aggregates of epithelioid macrophages would suggest the sarcoidal granulomatous reaction pattern (see Granulomatous Reaction Patterns).

Presence of vascular injury Vascular injury refers to a spectrum of morphologic alterations ranging from endothelial perturbation or activation to frank fibrinoid necrosis and the presence of inflammation for an interpretation of vasculitis (Table 1-7). These changes may be primary or secondary (a distinction not always easily made). In assessing vascular injury, a number of parameters must be considered, and these include caliber and type of vessels involved, degree of vascular injury (as already mentioned), the composition and density of the cellular infiltrate, and the presence or absence of such factors as antineutrophil cytoplasmic antibodies (ANCA). Granulomatous reaction patterns The essential definition of a granuloma is a circumscribed aggregate of macrophages. The cytologic characteristics of such cells vary from mononuclear cells with abundant pale, vacuolated, or lipidized cytoplasm to cells with plentiful pink cytoplasm, resembling epithelial cells and hence the term epithelioid cells (Fig. 1-6). Multinucleated giant cells are commonly present and are generally one of two types: foreign-body

Table 1-7 Vasculitis and Related Disorders

Vasculopathy Small-vessel vasculitis Neutrophilic/leukocytoclastic vasculitis Lymphocytic vasculitis Granulomatous vasculitis Medium-Sized vessel Vasculitis

12

 FIGURE 1-16 Granulomatous reaction pattern. Multifocal histiocytic infiltrates in dermis (arrow) and subcutis caused by bacterial infection (bottom panel shows organisms detected by Fite stain, arrow).

and Langhans giant cells. Granulomas often contain a variable admixture of other cell types, such as lymphocytes, plasma cells, neutrophils, and mast cells. Poorly defined granulomatous infiltrates often are referred to as granulomatous inflammation. Granulomas may be classified in a number of ways, such as infectious (Fig. 1-16) or noninfectious or by morphologic features, acknowledging that there is considerable overlap among many of these entities. A generally accepted scheme is as follows: (1) sarcoidal or epithelioid cell granulomas, (2) tuberculoid or caseating granulomas, (3) foreign-body granulomas, (4) suppurative granulomas, (5) palisading/necrobiotic granulomas, and (6) elastolytic granulomas. In general, these reaction patterns are nonspecific and should prompt a

differential diagnosis and systematic evaluation, as discussed in more detail in Chap. 6 (see Fig. 1-6).

Disorders of skin appendages The skin appendages, principally the hair follicle and the eccrine sweat apparatus, may show primary inflammatory involvement. Disorders of the hair follicle In general, folliculitis is categorized as to whether it is infectious or noninfectious and according to its depth: superficial only or superficial and deep. Acne is an extremely common form of folliculitis that has a multifactorial basis, for example. The hair follicle also may show a peculiar reaction— follicular mucinosis—which may be associated with a number of processes, including mycosis fungoides and inflammatory

panniculitis has been classified as septal or lobular, in fact, in most instances the inflammatory process is both septal and lobular, often spreading from the septae. Particular factors that should be considered when evaluating panniculitis include presence or absence of infection, vascular injury, cold-related injury, factitial disease, or physical injury. Adequate sampling and the stage of disease when the biopsy is taken will influence the morphologic findings observed. The reaction pattern of adipose tissue to injury is rather limited. Initially one observes an influx of neutrophils (erythema nodosum pattern, Fig. 1-17), followed by mononuclear cells (lymphocytes and macrophages), and finally, reparative fibrosis (Fig. 1-18),

depending on the nature and severity of the insult.

Proliferative or Neoplastic Conditions A large category of conditions encompasses hyperplasias, hamartomas, and benign and malignant neoplasms involving the epidermis, melanocytes, skin appendages, dermis, subcutis, and hematopoietic cells in the skin.

Noninflammatory Conditions In the absence of an obvious inflammatory dermatitis or proliferative/neoplastic process, one must proceed along the

Disorders of the sweat apparatus The eccrine duct may be involved primarily in an inflammatory reaction termed miliaria and categorized according to depth of involvement as (superficial) miliaria crystallina, miliaria rubra, and miliaria profunda. Hidradenitis refers to an inflammatory disorder involving the sweat coil as in neutrophilic eccrine hidradenitis, which may be infectious or noninfectious. Panniculitis The primary focus of inflammation may be in the subcutaneous fat, fascia, or both. Although traditionally

 FIGURE 1-17 Panniculitis (erythema nodosum reaction pattern). Dense neutrophil-rich inflammatory infiltrates extending out from the fibrous septae into the fat lobules in a patient undergoing treatment for Hodgkin lymphoma.

 FIGURE 1-18 Panniculitis with fibrous replacement. Histiocyte-rich lobular and septal panniculitis with ischemic fat necrosis and progressive fibrosis and calcification (bottom panel arrow) caused by lipodermatosclerosis (venous insufficiency).

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

conditions such as arthropod bites and lupus erythematosus. Alopecia histologically refers to an overall reduction in the number of terminal anagen hair follicles, which may be reversible or irreversible. Operationally (and perhaps simplistically), alopecia may be classified as nonscarring or scarring. Nonscarring alopecias may result from any number of factors interrupting the hair growth cycle, whether inflammatory, as in the case of alopecia areata, or noninflammatory, as in androgenetic alopecia or telogen effluvium. Scarring alopecia follows a wide variety of processes such as infective follicultis, lupus erythematosus, lichen planus, or traumatic injury.

13

Table 1-8 Differential Diagnosis of “Normal Skin”

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Superficial fungal infection Dermatophytosis and tinea versicolor Porokeratosis Ichthyosis Hypopigmentation Vitiligo Piebaldism Chemical leukoderma Nevus depigmentosus Hyperpigmentation Café-au-lait macule Freckle Melasma Lentigo Macular amyloidosis Onchocerciasis Dermal melanocytosis Urticaria pigmentosa Argyria

Urticaria Anhidrotic ectodermal dysplasia Anetoderma Cutis laxa Connective tissue nevus Dermal mucinosis Myxedema Scleromyxedema Atrophoderma Lipoatrophy

algorithm now considering noninflammatory conditions. Histologic alterations may suggest “normal skin” and may include the so-called invisible dermatoses (Table 1-8).6,7 As already outlined earlier, one generally must resort to systemic study of the specimen beginning with the stratum corneum or perhaps with the subcutis in the reverse order. It goes without saying that the histopathologist

14

Hyphae and spores in stratum corneum Cornoid lamella Slight hyperkeratosis, diminished or absent granular layer Diminished or absent basal layer melanin, melanocytes

Increased basilar melanin and possibly melanocytes

Pink amorphous globules in papillary dermis Pigment incontinence Microfilaria in superficial dermis Dendritic melanocytes in dermis Increased numbers of mast cells in dermis Deposition of silver granules in basement membranes, particularly surrounding eccrine sweat coils Sparse perivascular infiltrate Edema Absence of eccrine sweat glands Focal or diffuse absence of elastic tissue Inflammation present or absent Absence of elastic fibers Increased or decreased collagen and/or elastin Abnormal connective tissue Increased dermal mucin

Decreased thickness of dermis Fat lobules diminished in size

should have some understanding of the regional microanatomy and age-related variations of skin in order to know what is within normal limits. ALTERATIONS OF STRATUM CORNEUM AND EPIDERMIS The stratum corneum is studied for subtle abnormalities such as parakeratosis, hyperkeratosis, and fungal elements. The epidermis is inspected for

acanthosis, atrophy, subtle alterations suggesting an inflammatory or vesicular reaction, alterations of the granular layer as in ichthyosiform dermatitides, peculiar processes such as epidermolytic hyperkeratosis, and finally, pigmentary alterations associated with hypo- and hyperpigmentation. ALTERATIONS OF PAPILLARY DERMIS The papillary dermis is then studied for alterations such as deposition of amyloid, hyalinization of vessels as in porphyria, and incontinence of melanin (melaninladen macrophages in papillary dermis). ALTERATIONS OF RETICULAR DERMIS The reticular dermis is examined systematically for alterations of collagen as in morphea/scleroderma or scleredema, thickening or atrophy of the reticular dermis, alterations of elastic fibers, and deposition of materials such as mucin or amyloid.

REFERENCES 1. Ackerman A, Boer A, Bennin B, Gottlieb G. Histologic Diagnosis of Inflammatory Skin Diseases: A Method of Pattern Analysis. 3rd ed. Philadelphia, PA: Lea & Febiger; 2005. 2. Ackerman AB. An algorithmic method for histologic diagnosis of inflammatory and neoplastic skin diseases by analysis of their patterns. Am J Dermatopathol. 1985; 7(2):105-107. 3. Ackerman AB. Differentiation of benign from malignant neoplasms by silhouette. Am J Dermatopathol. 1989;11(4):297-300. 4. Murphy BW, Webster RJ, Turlach BA, et al. Toward the discrimination of early melanoma from common and dysplastic nevus using fiber optic diffuse reflectance spectroscopy. J Biomed Opt. 2005;10(6): 064020. 5. Nathwani B, Burke J, Winberg C. Architectural features of normal, neoplastic, and nonneoplastic lymph nodes: a practical diagnostic approach. In: Murphy G, Mihm M, eds. Lymphoproliferative Disorders of the Skin. Boston, MA: Butterworths; 1986. 6. Bernhard JD. Invisible dermatoses versus nonrashes. J Am Acad Dermatol. 1983;9(4): 599-600. 7. Brownstein MH, Rabinowitz AD. The invisible dermatoses. J Am Acad Dermatol. 1983;8(4):579-588.

CHAPTER 2 Spongiotic Dermatitis Michael Murphy Jane M. Grant-Kels

INTRODUCTION

neutrophilic spongiosis, respectively. A PAS stain to exclude dermatophytoses should be performed in all biopsies showing spongiosis, particularly those associated with neutrophil exocytosis (Fig. 2-12).

Secondary Changes Because spongiotic dermatoses are often pruritic, secondary changes are common. The most frequently identified secondary changes seen in association with spongiosis include: (a) superimposed infection; (b) lichenification/lichen simplex chronicus, secondary to chronic rubbing (Fig. 2-13 and 2-14); (c) prurigo nodularis, secondary to chronic picking (Fig. 2-15); and (d) erosions or ulcers secondary to excoriations. Patients chronically rub itchy spongiotic dermatoses. As a result, the skin clinically becomes thickened and papular with accentuation of normal skin markings, hyperpigmentation, and scaliness (Table 2-4). Superimposed infection or secondary impetiginization is not an infrequent complication. This change is secondary to the scratching of these often intensely pruritic eruptions. The resultant bacterial infection overlying the changes of the spongiotic dermatitis results in abundant scale-crust laden with bacteria that can be identified on routine staining and highlighted with a Gram stain. In more severe cases vesiculopustules may be identified.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

The term spongiotic dermatitis refers to a large group of inflammatory disorders that share the histopathologic finding of spongiosis, characterized by impairment of cohesion between epidermal keratinocytes and intercellular edema (Fig. 2-1 and Table 2-1). Spongiosis is the hallmark of eczematous dermatitides, but can be seen in a variety of other skin conditions (Table 2-2). The mechanisms underlying the pathogenesis of spongiotic changes have only recently begun to be eludicated.1,2 Skin-infiltrating T-cells damage the epidermis by releasing proinflammatory cytokines and induce keratinocyte apoptosis through “killer molecules.”1,2 There is subsequent cleavage of adhesion molecules, including E-cadherin, on keratinocytes.1,2 Accumulation of extracellular fluid results in widening of the spaces between keratinocytes, causing the epidermis to resemble a sponge histologically.1,2 Other terms used to refer to these diseases include eczema, eczematous dermatitis, or simply dermatitis. The clinical appearance of the spongiotic dermatoses can vary significantly, depending on the duration, etiology, and location of the lesions and the presence of superimposed secondary changes such as excoriation. However, the salient clinical finding is that of epidermal alteration. These primary and secondary epidermal changes may include erythema, vesiculation, scaling, crusting, lichenification, hyperpigmentation, excoriation, oozing, erosions, or fissures. Most lesions of spongiotic dermatitis are poorly demarcated clinically, with the notable exceptions of nummular dermatitis (round well-defined, coinshaped plaques) and some lesions of contact dermatitis. Collectively, the spongiotic dermatoses are among the most common cutaneous disorders presenting to dermatologists and primary care providers. Spongiotic dermatitis is conventionally divided into acute, subacute, and chronic stages (Table 2-3). A single lesion may evolve through these three stages;

however, not all lesions do this. The classic example of acute spongiotic dermatitis is acute allergic contact dermatitis, such as that caused by exposure to poison ivy. Acute spongiotic dermatitis is characterized histologically by significant intercellular edema with formation of spongiotic microvesicles or even macrovesicles (that can be seen clinically) (Figs. 2-2 to 2-3). An associated superficial, perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, some eosinophils, and occasionally associated extravasated red blood cells is noted. Subepidermal edema may also be prominent. The stratum corneum may still be normally cornified without parakeratosis. The clinical lesion reflects these histologic features; appearing as edematous, inflamed oozing papules and plaques, often with visible vesicles. A lesion of subacute spongiotic dermatitis usually demonstrates spongiosis with formation of some microvesicles, and overlying parakeratosis (Figs. 2-4 to 2-6). Mild epidermal acanthosis may be a feature. A superficial perivascular inflammatory infiltrate of lymphocytes, histiocytes, with or without eosinophils is present in the dermis, but papillary dermal edema is not a prominent feature. Good examples of subacute spongiotic dermatitis are lesions of atopic dermatitis and nummular dermatitis present for several weeks. Clinically these lesions are scaling pink-to-red papules and plaques, often with secondary changes such as excoriation. Many lesions of subacute spongiotic dermatitis become chronic (such as the atopic dermatitis) (Figs. 2-7 to 2-9). Chronic spongiotic dermatitis describes lesions that have been present for a time and demonstrate changes of repair and/or secondary changes, in addition to spongiosis. Chronic spongiotic dermatitis lesions can show compact hyperkeratosis, acanthosis with hypergranulosis, spongiosis, and sometimes papillary dermal fibrosis due to chronic rubbing (Fig. 2-10). Spongiosis is usually minimal and only focal in chronic lesions. These lesions present as lichenified, firm papules and plaques with accentuation of skin lines and often with postinflammatory pigmentary changes (hyperpigmentation more commonly than hypopigmentation). The most common inflammatory cells identified in the spongiotic epidermis are lymphocytes, often in association with Langerhans cell microvesicles (Fig. 2-11), but as discussed later in this chapter, other cells may predominate, including eosinophils and/or neutrophils, resulting in changes of eosinophilic spongiosis and

Eosinophilic Spongiosis Eosinophilic spongiosis describes a reaction pattern in which there is exocytosis of eosinophils associated with changes of spongiosis (Figs. 2-16 to 2-17).3-6 These changes can be seen in a variety of inflammatory dermatoses, described in other chapters (Table 2-5).

Neutrophilic Spongiosis A heterogeneous group of dermatoses can demonstrate neutrophilic spongiosis (Figs. 2-12, 2-18, and 2-19), described as the presence of neutrophil exocytosis with epidermal spongiosis (Table 2-6).4,7,8 Occasionally, neutrophils can form collections within the epidermis (ie, spongiform pustules).

Contact Dermatitis Contact dermatitis describes an inflammatory skin reaction to an exogenous agent. Two variants have been described: (1) allergic contact dermatitis and (2) irritant contact dermatitis.9-16 Allergic contact

15

Spongiotic Dermatitis

Proliferation of the superficial vascular plexus, thickened vessel walls, variable amount of lymphocytic infiltrate, hemorrhage, and hemosiderin-laden macrophages:

Superficial perivascular lymphoid infiltrates with hemorrhage and/or hemosiderinladen macrophages: Pigmentary purpura (eczematid variant of Doucas and Kapetanakis)

Chronic stasis dermatitis

Superficial and deep perivascular lymphoid infiltrate, tightly cuffed “coat-sleeve” around vessel: Figurate erythemas Dyskeratotic cells: Polymorphous light reaction Photodrug reaction Many dyskeratotic cells and keratinocytic atypia:

Angiodermatitis

Wedge-shaped superficial and deep perivascular lymphoid infiltrates with eosinophils: Hypersensitivity reaction to arthropod assaults

Superficial perivascular lymphoid infiltrate and intraepidermal or intracorneal neutrophils: Seborrheic dermatitis Early or treated psoriasis Sneddon-Wilkinson disease Contact dermatitis (esp. irritant)

Phototoxic reaction

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

 FIGURE 2-1 Algorithm for spongiotic dermatitis.

Table 2-1 Differential Diagnosis of Spongiotic Dermatoses ENTITY

DISTINGUISHING HISTOLOGIC FINDING

Allergic contact dermatitis

Eosinophilic spongiosis Spongiotic micro- and macrovesiculation Neutrophils Ballooning Necrosis Eosinophilic spongiosis Necrotic keratinocytes Sunburn (necrotic) keratinocytes Pallor of keratinocytes Neutrophils Prominent papillary dermal edema Epidermal acanthosis Prominent vasculature Secondary changes of LSC Follicular infundibular spongiosis None Vesiculopustules Parakeratosis at lips of follicular ostia None None Genital skin Mounds of parakeratosis Extravasated red blood cells Depends on underlying disease Thick-walled venules Extravasated red blood cells Hemosiderin deposition Fibrosis Spongiotic ± interface changes Necrotic keratinocytes Eosinophils Follicular spongiosis Parafollicular parakeratosis Decreased melanization in basal layer Reduction in basal melanocytes Melanophages Spongiotic ± interface changes Lymphocyte exocytosis Papillary dermal edema None Eosinophilic spongiosis Dyskeratotic squamous cells Involvement of eccrine duct

Irritant contact dermatitis

Photoallergic contact dermatitis Phototoxic dermatitis

Dermal/protein contact dermatitis Atopic dermatitis

Fox-Fordyce disease Nummular dermatitis Pompholyx Seborrheic dermatitis Id reaction Asteatotic eczema Sulzberger-Garbe syndrome Pityriasis rosea Exfoliative erythroderma Stasis dermatitis

Spongiotic drug eruptions

Pityriasis alba

Gianotti-Crosti syndrome

PUPPP Incontinentia pigmenti Miliaria

16

Table 2-2 Skin Diseases in which Spongiosis May be Seen Dermatophytosis Erythema neonatorum Grover disease, spongiotic variant Gyrate erythemas Lichen striatus Mycosis fungoides Parapsoriasis Pigmented purpuric dermatoses Pityriasis lichenoides Polymorphous light eruption Primary syphilis Psoriasis, early or treated Reaction to arthropod assault

dermatitis is a type IV delayed hypersensitivity reaction in the skin of a patient who has been previously sensitized to an allergen. Common allergens include nickel, urushiol (poison ivy), and topical medications, including local anesthetics and topical antibiotics. Irritant contact dermatitis is due to exposure to chemical or physical agents that induce direct (non–immunologically mediated) damage to the skin. Common offending agents include detergents, soaps, some sunscreens, acids, and alkalis. Irritant contact dermatitis is the most common mechanism of occupational hand dermatitis. Irritant contact dermatitis occurs more quickly after exposure, tends to resolve more quickly, and is more common than allergic contact dermatitis, but it may be difficult to distinguish allergic and irritant contact dermatitis from each other or from other spongiotic dermatitides on the basis of clinical or histopathologic features. In addition, some agents may act as both an irritant and an allergen.

Superficial perivascular lymphoid infiltrate with or without eosinophils and large, well-formed intraepidermal vesicles:

Superficial perivascular lymphoid infiltrate without eosinophils:

Superficial perivascular lymphoid infiltrate with or without eosinophils

Chronic superficial dermatitis

Atopic dermatitis

Pityriasis lichenoides chronica

Nummular dermatitis

Allergic contact dermatitis

Pruritic urticarial papules and plaques of pregnancy

Pityriasis rosea (especially inflammatory variant)

Dyshidrotic eczema

Gianotti-Crosti syndrome

Pompholyx

Early mycosis fungoides

Grover disease (spongiotic variant)

Impetigo With plasma cells and endothelial cell swelling: Secondary syphilis

Id reaction Hypersensitivity reaction to arthropod assault

A CUTE S P O N G I O T I C DERMATITIS

SUBACUTE SPONGIOTIC DERMATITIS

CHRONIC SPONGIOTIC DERMATITIS

Often normal; sometimes parakeratosis, scale-crust None to minimal

Parakeratosis and scale-crust

Hyperkeratotic orthokeratosis

Mild to moderate

Moderate to marked

Mild to marked Yes ± macrovesicles Lymphocytes and eosinophils

Mild to moderate Yes

Minimal to absent No

Lymphocytes and eosinophils

Lymphocytes and histiocytes

Minimal to marked

Minimal

No

No

No

Yes

(intracellular edema), all three spongiotic (acute, subacute, and chronic) patterns can be seen. Similar to allergic contact dermatitis, skin lesions are typically localized, but may become generalized. Lesions may be prevented if the irritant is identified and avoided, or contact reduced.

Histopathological Features If the irritant is applied in sufficient concentration, the epidermis will show ballooning degeneration of keratinocytes with necrosis, in addition to changes of keratinocyte regeneration. At lower irritant concentrations, acute, subacute, and chronic spongiotic patterns can be seen, depending on the duration of exposure. Histologic clues to distinguishing allergic contact dermatitis from irritant contact dermatitis are:

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

Epidermal acanthosis Spongiosis Intraepidermal microvesicles Dermal perivascular inflammation Papillary dermal edema Papillary dermal thickening

Dermatophytosis With intracorneal gram-positive cocci:

Drug hypersensitivity reaction

Table 2-3 Histopathologic Features in Spongiotic Dermatitis

Stratum corneum

With intracorneal hyphal forms:

1. Variable presence of eosinophils and predominance of spongiosis in allergic contact dermatitis ALLERGIC CONTACT DERMATITIS Clinical Features The skin changes are often localized, with the distribution of the lesions providing clues to the diagnosis and potential etiological agent(s) (Table 2-7). Patients usually have a history of contact with an allergen prior to the cutaneous eruption. Clinical lesions vary depending on the nature and concentration of the allergen and duration of “contact.” Mild skin erythema, erythematous, scaly papules and plaques, vesiculobullous reactions, or any combination of these changes can be seen (Fig. 2-20A). The rash may become generalized if autoeczematization (id reaction) occurs. Long-standing lesions can show skin thickening with scaling and accentuation of skin markings (lichenification). The diagnosis can be confirmed by patch testing, and lesions typically resolve with avoidance of allergens.

Histopathological Features Allergic contact dermatitis is the prototypic spongiotic

reaction pattern. Acute, subacute, and chronic stages of disease can be seen, depending on the duration of contact with the offending allergen, and correlating with the clinical features. The earliest changes are seen in the superficial dermis; with a perivascular lymphohistiocytic and sometimes eosinophilic inflammatory infiltrate, and papillary dermal edema. This is followed by exocytosis of inflammatory cells into the epidermis with varying degrees of intercellular edema, often associated with spongiotic microvesiculation (Figs. 2-20 to 2-21). Parakeratosis with inflammatory cell debris and serum may be present in the stratum corneum. With time, the pathology reflects a progressive reduction in epidermal spongiosis, with irregular (nonpsoriasiform) epidermal hyperplasia, and fibroplasia of the superficial dermis. IRRITANT CONTACT DERMATITIS Clinical Features In addition to “burntype reactions,” necrosis, and ballooning

2. Variable presence of neutrophils and ballooning in irritant contact dermatitis (Fig. 2-19)

PHOTOALLERGIC DERMATITIS Photoallergic eruptions represent either UVA-induced immediate type I or delayed hypersensitivity type IV reactions to either (a) topical agents, such as antihistamines and local anesthetics (contact photoallergy), or (b) systemic medications such as NSAIDs or sulphonamides (systemic photoallergy).17,18

Clinical Features Cutaneous manifestations can include overlapping acute, subacute, and chronic spongiotic and/or lichenoid reactions of sun-protected areas, including the backs of the hands, face, and V-shaped area of the anterior neck. Occasionally, unexposed skin can be affected, in contrast to phototoxic reactions. Generalized erythroderma can also occur.

17

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

UVB and/or UVA non–immunologically mediated reactions to topical agents (ie, tars and certain plants/phytophotodermatitis) or systemic medications (ie, psoralens, thiazides, tetracyclines, NSAIDs).17,18 Cellular damage is induced by the direct reaction between the drug (sensitizer) and UVlight. Pseudoporphyria is a variant of a phototoxic reaction. Some drugs can produce both phototoxic and photoallergic reactions.

Clinical Features A phototoxic eruption resembles a sunburn reaction, with erythema, edema and vesiculation/blistering, occurring within minutes-to-hours after exposure, and confined to sunexposed areas. This is later followed by desquamation and hyperpigmentary changes. In chronic phototoxic eruptions, epidermal atrophy with telangiectasias may be features.

 FIGURE 2-2 Acute spongiotic dermatitis. Marked epidermal intercellular edema with spongiotic microvesicles and superficial perivascular lymphocytic infiltrate. The stratum corneum shows normal basket weave pattern.

 FIGURE 2-3 Acute spongiotic dermatitis. Marked epidermal intercellular edema, with spongiotic microvesicles and macrovesicles, and superficial perivascular lymphocytic and eosinophilic infiltrate. There is focal parakeratosis.

18

Histopathological Features Photoallergic dermatitis shows histologic features similar to those of typical allergic contact dermatitis, with epidermal spongiosis and often eosinophil exocytosis. Clues to a photoallergic eruption can include papillary dermal edema, vascular dilatation, the presence of eosinophils, extension of the inflammatory infiltrate into the deep dermis, and the presence

of a few necrotic keratinocytes (Fig. 2-22). A lichenoid tissue reaction can be seen in some cases. Variable epidermal spongiosis can also be seen in other lightinduced reactions, including polymorphous light eruption and persistent light reaction. PHOTOTOXIC DERMATITIS Unlike photoallergic dermatoses, phototoxic eruptions are

Histopathological Features The hallmark of an acute phototoxic reaction is the presence of necrotic/apoptotic keratinocytes (sunburn cells) in the epidermis. In addition to epidermal spongiosis, other histologic features including pallor of keratinocytes, neutrophil exocytosis, variable vacuolar alteration along the dermoepidermal junction, possible subepidermal vesiculation, papillary dermal edema, and a superficial dermal inflammatory infiltrate containing variable numbers of neutrophils and eosinophils can be seen. Chronic phototoxic reactions can show epidermal thinning with hyperkeratosis, and intradermal melanin deposition with vascular ectasias. Superficial dermal blood vessels may demonstrate basement membrane reduplication. DERMAL/PROTEIN CONTACT DERMATITIS The term “dermal/protein contact dermatitis” describes an unusual variant of allergic contact dermatitis, characterized by more prominent papillary dermal edema than typically seen in the classic form of allergic contact dermatitis (Fig. 2-23).19,20 It can be associated with exposure to fish, vegetables, fruits, plants, meat proteins, zinc and nickel, and topical neomycin. The differential diagnosis includes other causes of epidermal spongiosis associated with papillary dermal edema, including dermatophytosis and spongiotic drug eruptions. ATOPIC DERMATITIS Atopic dermatitis (AD) is a common chronic, relapsing dermatosis, affecting 1% to 2% of the general population, that is associated with asthma and allergic rhinitis (~50% of cases), a family history of atopy (~75% of cases),

 FIGURE 2-4 Subacute spongiotic dermatitis. Parakeratosis, slight epidermal acanthosis, minimal spongiosis, and occasional lymphocyte exocytosis.

Histopathological Features AD can show the typical histologic spectrum of acute, subacute, and chronic spongiotic dermatitides.21-23 Therefore, the changes seen on skin biopsies in AD patients can be indistinguishable from other spongiotic processes (Figs. 2-5 to 2-10). A number of subtle histologic features have been suggested as favoring a diagnosis of AD. These include an increase in epidermal volume (acanthosis); prominent vasculature in the superficial dermis; and a relative paucity of eosinophils in the inflammatory infiltrate (compared with other spongiotic dermatitides, particularly allergic contact dermatitis). In addition, clinically unaffected skin in patients with AD can show a sparse superficial perivascular infiltrate of lymphocytes, histiocytes, and eosinophils.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

papulovesicular lesions on the head, neck, diaper area, and extensor surfaces. In childhood, flexural areas are commonly involved by scaly, lichenified plaques (secondary to chronic rubbing). The disease is characterized by a course of remissions and exacerbations, and resolves in up to 50% of cases by adolescence. AD persisting into adulthood tends to show more widespread disease or may be manifested by chronic hand dermatitis. Skin lesions in AD are largely secondary to the scratching and rubbing in response to the intense pruritus patients with AD experience (Fig. 2-23A). AD is commonly associated with dry skin (xerosis), and an increased susceptibility to secondary dermatophyte, bacterial and viral infections.

FOLLICULAR “ECZEMA” (FOLLICULAR ATOPIC DERMATITIS) Clinical Features A minority of patients with AD will develop small follicularbased, pruritic, flesh-colored to erythematous papules, predominantly on the trunk and/or extremities, with or without the typical lesions of AD, as previously described. Follicular AD is more common in skin of color.  FIGURE 2-5 Subacute spongiotic dermatitis. Mounds of parakeratosis, slight epidermal acanthosis, spongiosis with Langerhans microvesicle, and superficial perivascular lymphocytic infiltrate.

marked pruritus, increased serum IgE antibody levels (~90% of cases), and often exacerbations in the winter months (Table 2-8).21-23 Staphylococcal superantigens are postulated to play a role in the pathogenesis of AD. AD is commonly observed with other dermatological disorders, including pityriasis alba, keratosis pilaris, nipple eczema, and white

dermatographism. Patients with AD show an increased incidence of pompholyx and irritant contact dermatitis of the hands. Patients with ichthyosis vulgaris can have AD-like skin changes.

Clinical Features The disease usually begins within the first 6 months of life.21-23 Infantile AD is characterized by eroded

Histopathological Features There is spongiosis of the follicular infundibulum, with or without involvement of the isthmus, with lymphocyte exocytosis (Fig. 2-24). Mild acanthosis, spongiosis, and focal parakeratosis can be seen in the adjacent epidermis. Differential Diagnosis In addition to AD, follicular spongiosis can be seen in infundibulofolliculitis, Fox-Fordyce disease (apocrine miliaria), and pityriasis alba (Table 2-9). A number of clinical

19

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Compared to AD, Fox-Fordyce disease can show increased numbers of neutrophils as part of the inflammatory response. Lesions of pityriasis alba can show follicular spongiosis, in addition to other changes such as follicular dilatation with plugging, parafollicular parakeratosis, and atrophic sebaceous glands.

 FIGURE 2-6 Subacute spongiotic dermatitis. Hyperkeratosis, slight epidermal acanthosis, lymphocyte exocytosis, spongiosis with microvesicle formation, and superficial perivascular lymphohistiocytic infiltrate.

Histopathological Features There is an intrafollicular keratotic plug with follicular infundibular spongiosis (adjacent to the opening of the apocrine sweat gland). Subsequently, there is dilatation of the upper region of the apocrine duct with cyst formation. PITYRIASIS ALBA Pityriasis alba is a very common disorder characterized by the presence of scaly, faintly erythematous patches that heal with postinflammatory hypopigmentation.26-28 The disease occurs mainly in children, but adults may be affected. While the etiology is unknown, the disease is exacerbated by cold weather and sun exposure, and patients often have a personal and/or family history of atopic dermatitis.

 FIGURE 2-7 Subacute/chronic spongiotic dermatitis. Compact hyperkeratosis, parakeratosis, slight hypergranulosis, epidermal acanthosis, and spongiosis.

20

FOX-FORDYCE DISEASE Clinical Features Fox-Fordyce disease (apocrine miliaria) is characterized by long-standing, itchy, follicular-based papules in areas with high apocrine gland concentrations, including the axillae, areolae, and anogenital regions.24,25 The disease is rare, but greater than 90% of cases have been described in young women. There is a lack of apocrine sweating with folliculocentric retention cyst formation in the epidermis due to keratotic plugging of the apocrine duct opening.

and/or histologic features may aid in the differential diagnosis of these entities. Similar to AD, infundibulofolliculitis is characterized by a widespread pruritic papular eruption on the truck and/or proximal extremities, but usu-

ally occurs in young black patients without an atopic history. Fox-Fordyce disease is typically limited to the axilla and groin (areas with increased numbers of apocrine glands), with 90% of cases occurring in young women.

Clinical Features Three clinical stages of disease lasting from months to several years are described: (1) papular erythematous; (2) papular hypochromic; and (3) macular and patchy hypochromic. The condition may be pruritic. The disease progresses from erythematous to hypopigmented, round-to-oval, scaly 0.5 to 3 cm patches on the face (>50% of cases), neck, upper chest, and arms. The clinical differential diagnosis includes vitiligo, pityriasis versicolor, progressive macular hypomelanosis, and hypopigmented mycosis fungoides. Frequently, folliculocentric papular lesions are seen. The lesions eventually repigment. Histopathological Features Skin biopsy usually shows mild spongiotic features,

middle-aged and older men and women (Table 2-10).29 There is an association with xerosis, atopy, and/or hypersensitivity to nickel. The condition may be exacerbated by cold weather and certain drugs, including gold. The term nummular dermatitis refers to a particular clinical appearance rather than a specific disease.

 FIGURE 2-8 Subacute/chronic spongiotic dermatitis. Compact hyperkeratosis, parakeratosis, epidermal acanthosis, and spongiosis with microvesicle formation and lymphocyte exocytosis.

Histopathological Features The histologic features of nummular dermatitis are similar to the other spongiotic dermatitides at comparable chronologic stages of evolution, with the pathologic changes varying with the activity and chronicity of the disease (Figs. 2-5 to 2-10). POMPHOLYX (DYSHIDROTIC) “ECZEMA” Pompholyx as an isolated finding is a rare disorder, constituting less than 2% of all hand dermatoses (Table 2-11).30,31 However, chronic hand dermatitis is not uncommon in adult atopics. Like all hand eczemas, the disease has been associated with several putative causal factors, including allergens, irritants, friction, drugs, atopy, foodstuffs, and infections (~15% of patients have dermatophytosis). The disease may be associated with hyperhidrosis. It is because of this rare association with sweat gland dysfunction that the disease has been called by some “dyshidrosis.” Up to 15% of cases are idiopathic.

 FIGURE 2-9 Subacute/chronic spongiotic dermatitis. Marked parakeratosis, epidermal acanthosis, spongiosis with lymphocyte exocytosis, and superficial perivascular and interstitial lymphocytic infiltrate.

including hyperkeratosis, focal parakeratosis, minimal spongiosis with lymphocyte exocytosis, decreased melanization of the basilar layer, a slight reduction in basal melanocytes, and a superficial perivascular lymphocytic infiltrate. Occasional melanophages may be present in the superficial dermis. Folliculocentric lesions

can show follicular spongiosis, follicular dilatation with plugging, parafollicular parakeratosis, and atrophic sebaceous glands. NUMMULAR DERMATITIS Nummular dermatitis is most commonly seen in young women (15-30 years), and in both

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

Clinical Features Nummular dermatitis is characterized by well-demarcated, oval to coin-shaped erythematous pruritic patches and plaques, predominantly on the dorsum of the hands and forearms and anterior aspects of the thighs and legs and upper back (Fig. 2-24A). The disease typically evolves from small confluent papules with scaling into larger annular plaques with central clearing, resembling tinea corporis.

Clinical Features The disease is characterized by recurrent crops of vesicles or bullae (on nonerythematous skin) located on the lateral aspects of the fingers and on the palms and soles.30,31 The vesicles may be pruritic or associated with a burning sensation, persist for 1 to 2 weeks, subsequently desquamate, and then recur at irregular intervals. Histopathological Features Pompholyx shows an intraepidermal microvesicle(s) with serum and often few inflammatory cells, typically lymphocytes (Fig. 2-25). A sparse lymphocytic infiltrate within the superficial dermis is seen. Vesicles can

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

(affecting ~3% of the general population), most often distributed to the scalp, ears, nasolabial folds, eyebrows, central chest, and intertriginous areas (“seborrheic” areas) (Table 2-12).32,33 The etiology is unknown, but a causative role for Malassezia spp. (Pityrosporum) has been proposed, and a family history is present in many patients. Exacerbations may be associated with stress. The disease is closely related to infantile SD, and is common in patients with AIDS (20%80% of HIV-infected patients), Parkinson disease, and mood disorders.

 FIGURE 2-10 Chronic spongiotic dermatitis. Marked compact hyperkeratosis and parakeratosis, epidermal acanthosis, minimal spongiosis, and superficial perivascular lymphocytic infiltrate.

 FIGURE 2-11 Langerhans cell microvesicles with adjacent epidermal spongiosis.

22

develop into pustules, with prominent neutrophil exocytosis, and raises the differential diagnosis of pustular psoriasis or pustular dermatophytosis. A PAS stain should be performed in all cases. The disease can mimic acute allergic contact dermatitis. Of note, the presence of epidermal spongiosis adjacent to the

microvesicle and/or the presence of intradermal eosinophils would argue against a diagnosis of pompholyx, and support an interpretation of allergic contact dermatitis. SEBORRHEIC DERMATITIS Seborrheic dermatitis (SD) is a common dermatosis

Clinical Features The condition most commonly occurs within the first 3 months of life and in adults over 30 years old, with males more commonly affected. There is erythema with overlying flaking, yellowbrown, greasy scales in areas of increased sebaceous glands. However, sebaceous gland activity and sebum production do not appear to be altered in SD.32,33 Distribution of lesions is generally symmetrical, and in many patients there is clinical overlap with psoriasis. Dandruff, cradle cap, and some forms of diaper rash are regarded as variants of SD. It is commonly observed with other dermatological disorders, including blepharitis, acne vulgaris, rosacea, and other Malassezia spp.-associated diseases (ie, Pityrosporum folliculitis and tinea versicolor). Histopathological Features The histologic changes vary with the age of the lesion biopsied.32,33 SD can show overlapping histologic features between spongiotic dermatitides (acute, subacute, or chronic spongiotic dermatitis) and psoriasis; including hyperkeratosis, parakeratosis, psoriasiform epidermal hyperplasia, spongiosis, and neutrophilic exocytosis. In SD the parakeratosis is particularly prominent at the margins of follicular ostia (Fig. 2-26). Yeast forms (spores) are common in the stratum corneum, but hyphae are not seen. Early changes of SD may show edema, ectatic blood vessels, and neutrophils within the superficial dermis, reminiscent of early psoriatic lesions. AIDS-associated SD can show increased hyperkeratosis, confluent parakeratosis, follicular plugging, more prominent lymphocyte and neutrophil exocytosis, necrotic and dyskeratotic squamous cells within the epidermis, and greater numbers of plasma cells as a component of the dermal inflammatory infiltrate. Unlike SD in immunocompetent patients, lesional skin of AIDS patients characteristically expresses heat shock proteins (HSP65 and HSP72).

plausible alternative etiology for the secondary inflammatory process.34,35 The pathogenesis of this disorder is a matter of debate, but may be related to activated T-lymphocytes and/or cytokines generated at the primary site.

Histopathological Features The pathologic changes typically mimic those seen in the primary lesions. In addition to spongiotic changes, the secondary (id) lesions often show prominent papillary dermal edema (Fig. 2-27). A combination of these features can also be seen in dermatophytoses, spongiotic drug eruptions, and protein/dermal contact dermatitis.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

 FIGURE 2-12 Dermatophytosis (PAS stain). Spongiosis with neutrophil exocytosis and fungal hyphae within the stratum corneum.

ASTEATOTIC “ECZEMA” Aseatotic “eczema” (eczema craquelé, winter eczema) is an inflammatory dermatosis with xerosis, which may be associated with decreased surface lipid. The lesions can be produced or exacerbated by cold weather, dry indoor heat or air conditioning, and exposure to soaps and detergents, and are usually seen in elderly adults. The condition shows dry criss-crossing scale (resembling the fine cracks of porcelain) on the hands, arms, and legs, often with associated underlying/adjacent erythema and spongiotic changes. A generalized type of asteatotic “eczema” involving the trunk and extremities may be a marker of a visceral malignancy. SULZBERGER-GARBE SYNDROME SulzbergerGarbe syndrome (exudative discoid and lichenoid dermatosis) is a chronic pruritic eczematous dermatitis typically seen in middle-aged to older Jewish men. The condition is characterized by erythematous, often oozing papules and plaques, in addition to discoid and lichenoid lesions. An urticarial phase has been described. Genital lesions are common and considered to be a hallmark of Sulzberger-Garbe syndrome.

 FIGURE 2-13 Lichen simplex chronicus. Marked compact hyperkeratosis, hypergranulosis, irregular epidermal acanthosis, and fibrosis of the superficial dermis with sparse inflammation.

ID REACTION Clinical Features Id reaction (autoeczematization or autosensitization) describes the diffuse, symmetric spread of a papular acute spongiotic eruption, associated with previously localized spongiotic dermatitis. The entity is characterized by (1) a localized spongiotic eruption of known etiology (including dermatophyte infec-

tion, scabies infestation, acute contact dermatitis, stasis dermatitis, or ionizing radiation); (2) the development of a usually distant (but sometimes contiguous) nonspecific acute spongiotic dermatitis, days to weeks after the initial localized dermatitis; (3) the same morphology and pathologic findings in both primary and secondary skin lesions; and (4) lack of a

PITYRIASIS ROSEA Pityriasis rosea (PR) is a mild, acute, self-limited papulosquamous skin disorder of unknown, but possible viral or bacterial etiology (Table 2-13).36,37 There is an increased incidence in pregnant women and bone marrow transplant recipients. PR-like eruptions have also been associated with certain drugs, including captopril, gold, and barbiturates.

Clinical Features The majority (~75%) of cases of PR are seen in children and young adults.36,37 PR is characterized by the development in 80% of cases of an initial 2- to 10-cm single, salmon-pink, oval herald patch or plaque on the trunk

23

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

been devised and validated for PR, including essential clinical features: discrete circular or oval lesions; scaling on most lesions; and peripheral collarette scaling with central clearance on at least two lesions.36 Unusual and uncommon locations include the face, scalp, genitalia, palms, soles, and oral cavity. Inverse PR lesions predominate on the extremities rather than the trunk. Localized and unilateral variants have been described. Individual lesions may be clinically atypical, showing urticarial, papular, pustular, vesicular (particularly in children), and/or purpuric morphology. Some authors have suggested a slight seasonal pattern with cases peaking in the spring and fall.  FIGURE 2-14 Lichen simplex chronicus. Marked compact hyperkeratosis, hypergranulosis, irregular epidermal acanthosis, and sparse inflammation in the superficial dermis.

 FIGURE 2-15 Prurigo nodularis. Marked compact hyperkeratosis, parakeratosis, hypergranulosis, papillated epidermal acanthosis, and dermal fibrosis with vascular ectasias and sparse inflammation.

Table 2-4 Secondary Changes in Spongiotic Dermatitis

24

CLINICAL APPEARANCE

HISTOLOGIC FINDING

Thickened skin with exaggerated skin markings Scaling Hyperpigmentation

Marked epidermal hyperplasia and papillary dermal thickening with coarse collagen bundles Compact orthokeratosis and parakeratosis Epidermal acanthosis and occasional melanophages in superficial dermis

or proximal extremity, followed (7-14 days later; range: 2-84 days) by the appearance of a more generalized eruption of approximately 1-cm, salmonpink, scaly plaques usually on the trunk and proximal extremities along Langer

lines of cleavage, resulting in the characteristic “fir-tree” distribution. The rash typically lasts 6 to 8 weeks. A minority (~5%) of patients have prodromal symptoms, including headache, fever, and malaise. A set of diagnostic criteria has

Histopathologic Features The generalized eruption typically shows slight epidermal hyperplasia, focal spongiosis, and mounds of parakeratosis (Fig. 2-28).37 The dermis shows a superficial perivascular infiltrate of lymphocytes, histiocytes, and occasionally eosinophils, with variable papillary dermal edema and extravasated erythrocytes. Often, lymphocyte and erythrocyte exocytosis is observed. Dyskeratotic keratinocytes are a rare feature. The herald patch has similar histologic features, but may show greater epidermal hyperplasia, less spongiosis, and a deeper inflammatory component in the dermis. ERYTHRODERMA/EXFOLIATIVE DERMATITIS Erythroderma (generalized redness) associated with scaling (exfoliative dermatitis) can occur with a wide variety of cutaneous diseases, including spongiotic dermatitides, especially allergic contact dermatitis, stasis dermatitis, atopic dermatitis, and seborrheic dermatitis.38-42 Other nonspongiotic disorders, most commonly psoriasiform disorders (including psoriasis and pityriasis rubra pilaris), and reactions to topical or systemic medications (~16% of cases), scabetic infestation, lichen planus, pemphigus foliaceus, immunodeficiency states, and lymphoproliferative disorders (including mycosis fungoides, Sezary syndrome, and adult T-cell lymphoma/leukemia in ~10% of cases) can produce a similar exfoliative dermatitis.

Clinical Features The clinical features of erythroderma are typically nonspecific, with little clues to the underlying etiology. There is widespread erythema and slight scaling, often associated with pruritus, fever, and lymphadenopathy. A history of a prior, specific, localized dermatitis can be useful in discerning an underlying pathogenesis. However,

Table 2-5 Skin Diseases with Eosinophilic Spongiosisa

a

See Figs. 2-16 and and 2-17.

 FIGURE 2-16 Eosinophilic spongiosis. Intraepidermal microvesicle with eosinophils and mononuclear cells.

 FIGURE 2-17 Eosinophilic spongiosis. Spongiosis with eosinophil exocytosis.

in up to 15% of cases no underlying disorder can be determined by history, pathologic findings, and/or laboratory studies, and are classified as idiopathic.

Histopathological Features Clinicians may submit multiple skin biopsies in patients

with erythroderma. In the case of a spongiotic dermatosis, biopsy of the generalized eruption usually shows a subacute or chronic spongiotic reaction pattern: minimal spongiosis associated with slight epidermal acanthosis and a superficial perivascular predominantly

lymphocytic infiltrate. Other generalized cutaneous diseases usually show some or all of their characteristic pathologic changes that are seen when the conditions are localized. For example, an eosinophil-rich infiltrate would suggest a generalized drug eruption or scabies, particularly if the inflammatory infiltrate extends beyond the superficial vascular plexus and into the mid-to-deep dermis (Fig. 2-29). The presence of neutrophil exocytosis/microabscesses and/ or neutrophils within the stratum corneum may indicate a psoriasiform diathesis. Epidermotropism of atypical mononuclear cells with the formation of Pautrier microabscesses would favor a cutaneous lymphoproliferative disorder. However, a correlation between the pathologic features and clinical features is found in only up to two-third of cases, and therefore multiple and/or serial biopsies may be necessary for a definitive diagnosis and to exclude cutaneous T-cell lymphoma.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

Allergic contact dermatitis Photoallergic dermatitis Atopic dermatitis Drug reactions Arthropod-bite reactions Urticarial/precursor lesions of pemphigoid group -Bullous pemphigoid, cicatricial pemphigoid, herpes gestationis Urticarial/precursor lesions of pemphigus group PUPPP Incontinentia pigmenti (first stage) Eosinophilic folliculitis Grover disease

STASIS DERMATITIS Stasis dermatitis is a dermatitis of the lower extremities of middle-aged and elderly individuals seen in association with other signs of venous insufficiency, including varicosities and edema (Table 2-14).43-45 This condition is more common in women and believed to be a result of chronic venous insufficiency and venous hypertension. CLINICAL FEATURES The condition most frequently begins on the medial ankle, progressing to involve the lower calf and foot. There are poorly demarcated edematous changes with erythema and

25

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 2-6 Skin Diseases with Neutrophilic Spongiosisa Psoriasis Reiter syndrome Seborrheic dermatitis Irritant contact dermatitis Phototoxic dermatitis Pemphigus variants (particularly IgA pemphigus) Toxic shock syndrome Dermatophytosis Impetigo Acute generalized exanthematous pustulosis (AGEP) Infantile acropustulosis Transient neonatal pustular melanosis a

See Figs. 2-12, 2-18, and 2-19.

 FIGURE 2-18 Neutrophilic spongiosis. Spongiosis with neutrophil exocytosis.

Table 2-7 Allergic Contact Dermatitis

 FIGURE 2-19 Irritant contact vulvitis. Spongiosis with neutrophil exocytosis.

26

sometimes scaling and/or oozing. The deposition of hemosiderin in the superficial dermis, secondary to red blood extravasation, produces the characteristic reddish-brown discoloration. Ulceration and scarring with atrophic changes can give rise to the classic inverted champagne bottle appearance (lipodermatosclerosis). The condition is frequently associated with increased

incidence of allergic contact dermatitis, id reaction (autoeczematization), and secondary infection, including cellulitis. In long-standing lesions, lichenification may occur as a consequence of chronic scratching and rubbing. Chronic venous ulcers may be complicated by squamous and basal cell carcinomas. Occasionally, patients will develop violaceous plaques and nodules on the dorsal feet and legs,

Clinical Features Delayed hypersensitivity reaction (type IV) All ages affected except below age 5 years and the elderly Rash occurs at the site of exposure in previously sensitized host Morphology of rash is eczematous—acute, subacute, or chronic Histopathologic Features Acute Spongiosis often with formation of clinically evident intraepidermal vesicles, superficial perivascular lymphocytic infiltrate usually rich in eosinophils, migration of inflammatory cells into the epidermis Subacute Epidermal hyperplasia with spongiosis, superficial perivascular lymphocytic and eosinophilic infiltrate with variable exocytosis Chronic Psoriasiform hyperplasia with a superficial perivascular lymphocytic and eosinophilic infiltrate; spongiosis is minimal to absent Differential Diagnosis Many forms of eczematous dermatitis Irritant and photoallergic reactions Scabetic infestation Drug reactions Bullous pemphigoid Parasitic infestations

A

B

atypical endothelial cells, and the promontory sign (a normal blood vessel protruding into an atypical vessel) are not features of acroangiodermatitis.

 FIGURE 2-21 Allergic contact dermatitis. Epidermal acanthosis, spongiosis with microvesicles containing eosinophils, and superficial perivascular and interstitial lymphocytic and eosinophilic infiltrate.

called acroangiodermatitis or pseudo– Kaposi sarcoma. These lesions frequently undergo painful ulceration and can be clinically indistinguishable from classic Kaposi sarcoma or changes seen secondary to arteriovenous malformations.

Histopathologic Features Chronic venous stasis results in lobular proliferations of thick-walled blood vessels, extravasated erythrocytes, hemosiderin deposition with siderophages, and fibrosis within the superficial dermis. The changes eventually involve the deep dermis and superficial

subcutaneous tissue. Typical acute, subacute, and chronic spongiotic features can be seen overlying the dermal changes (Figs. 2-30 to 2-31). Chronic rubbing can result in changes of lichen simplex chronicus. Lipodermatosclerosis shows dermal and subcutaneous septal sclerosis, with variably-sized pseudocysts lined by thickened eosinophilic-hyaline, PASpositive material (lipomembraneous change) in the subcutaneous tissue. A biopsy of acroangiodermatitis shows clusters of capillaries that maintain round-to-oval lumina. In contrast to Kaposi sarcoma, slit-like vascular spaces,

SPONGIOTIC (“ECZEMATOID”) DRUG ERUPTIONS Topical or systemic medications can induce immunologically mediated (delayed hypersensitivity type IV reactions) or non–immunologically mediated (ie, direct toxicity) cutaneous reactions. Allergic contact dermatitis-like, seborrheic dermatitis-like, nummular dermatitis-like, and pityriasis rosealike reactions, in addition to phototoxic and photoallergic eruptions, and generalized erythroderma, are described.46-49 Occasionally, morbilliform drug eruptions can show mild spongiosis. Common offending agents include antibiotics, NSAIDs, carbamazepine, captopril, thiazide diuretics, gold, and topical antihistamines.46-49 Up to 10% of cutaneous drug reactions can show spongiotic changes.49 Laboratory studies may reveal a peripheral eosinophilia.

Histopathological Features Cutaneous drug reactions can produce acute, subacute, and chronic spongiotic reaction patterns. One clue to the diagnosis of a spongiotic drug eruption is the presence of eosinophils as a significant component of the inflammatory infiltrate, often with eosinophil exocytosis (eosinophilic spongiosis). However, these reactions can also occur in the absence of eosinophils. Papillary dermal edema and extravasated erythrocytes are variable findings. Occasionally, a mixed reaction pattern with spongiosis and interface changes (the latter identified by vacuolar alteration along the

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

 FIGURE 2-20 Allergic contact dermatitis. (A) Erythematous moist plaques with scale-crust involve the eyelids. (B) Epidermal acanthosis, spongiosis with focal microvesicle containing eosinophils, and superficial perivascular lymphocytic and eosinophilic infiltrate.

27

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 28

be associated with lymphadenopathy and acute anicteric hepatitis.53-56 While initially described as a cutaneous response to hepatitis B virus infection, a number of viral (including hepatitis A and C, Epstein-Barr virus, coxsackieviruses, and HIV) and bacterial infections (including group A ␤-hemolytic streptococci, Mycobacterium aviumintracellulare, Mycoplasma pneumoniae, Bartonella henselae, and Borrelia burgdorferi), and immunizations (including polio, diphtheria, influenza, pertussis, and measles) have been implicated as etiologic agents. The condition occurs primarily in children aged 3 months to 15 years, peaking between ages 1 to 6 years.

 FIGURE 2-22 Photoallergic dermatitis. Parakeratosis, minimal spongiosis, occasional necrotic keratinocytes, and superficial perivascular lymphocytic infiltrate.

dermoepidermal junction and/or necrotic keratinocytes) can be seen (lichenoid and/or fixed drug reaction). Unlike typical spongiotic reactions, the inflammatory infiltrate can extend into to the mid-todeep dermis. Occasionally, a “lymphoma-

 FIGURE 2-23A Atopic dermatitis. The patient demonstrates ill-defined, diffuse xerosis (dryness and fine scaling); erythema; and slight edema of the face. There is an accentuation of skin cleavage lines.

toid” reaction in which mononuclear cells are enlarged and atypical is seen, mimicking a cutaneous T-cell lymphoproliferative disorder.50-52 GIANOTTI-CROSTI SYNDROME GianottiCrosti syndrome, also known as papular acrodermatitis of childhood, is a benign, self-limited infectious exanthem that can

Clinical Features The rash which is usually of sudden onset following an acute infectious illness or immunization typically lasts for 2 to 4 weeks. The disease is characterized by multiple 1 to 5 mm mildly pruritic, symmetrical, flesh-colored to erythematous flat-topped edematous (juicy) papules on the face, buttocks, and extensor surfaces of the extremities. The trunk is usually spared. Histopathological Features The pathologic changes can be variable. There is typically a superficial perivascular lymphocytic infiltrate, as seen in classic morbilliform viral exanthems. Slight epidermal acanthosis, mild spongiosis and focal lymphocyte exocytosis can be seen in some cases. In addition, the infiltrate may focally obscure the dermoepidermal junction, producing a spongiotic-interface

 FIGURE 2-23B Dermal/protein contact dermatitis. Spongiotic microvesicles and macrovesicles, marked papillary dermal edema with hemorrhage, and perivascular and interstitial dermal inflammation.

Table 2-8 Atopic Dermatitis

 FIGURE 2-24A Nummular dermatitis. There is a coalescence of coinshaped erythematous papules and plaques on the distal lower extremity. The lesions exhibit scattered erosions, lichenification, and scaling.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

Clinical Features Common disorder of all ages Associated with allergic rhinitis and/or asthma Family history of atopy common Marked pruritus associated with a variety of lesions Erythematous, scaling areas Edematous, oozing, weepy areas Lichenified areas Dry fissured scaly areas Skin of patients generally lackluster, pruritic, and irritable Abnormalities of vascular and immune responses Histopathologic Features Acute pattern Spongiosis, sometimes spongiotic vesiculation, a usually superficial perivascular lymphocytic and eosinophilic infiltrate, epidermis of normal thickness Subacute pattern Thickened epidermis (usually psoriasiform type), spongiosis, a usually superficial perivascular lymphocytic and eosinophilic infiltrate, variable fibrosis of papillary dermis Chronic pattern Psoriasiform hyperplasia, spongiosis minimal to absent, vascular ectasia, a usually superficial perivascular lymphocytic infiltrate with eosinophils, variable fibrosis of the papillary dermis Differential Diagnosis All other types of eczematous dermatitis Clinicopathologic correlation largely determines the diagnosis Pathologic diagnosis is usually expressed as acute, subacute, or chronic eczematous dermatitis

 FIGURE 2-24B Follicular spongiosis with lymphocyte exocytosis.

overlap (Fig. 2-32). Papillary dermal edema and focal red blood cell extravasation with endothelial cell swelling can be seen, but vasculitis is not a feature. The condition most likely represents a local, type IV, delayed hypersensitivity reaction to a viral or bacterial antigen within the dermis. Direct immunofluorescence studies are negative for immunoreactant deposition, and electron microscopy has not demonstrated virus particles in the skin. PRURITIC AND URTICARIAL PAPULES AND PLAQUES OF PREGNANCY This condition, also known as polymorphic eruption of pregnancy, is characterized by a markedly pruritic eruption that occurs during the last

trimester in a primigravida. The cause and pathogenesis are unknown.57,58 Pruritic and urticarial papules and plaques of pregnancy (PUPPP) need to be distinguished from herpes gestationis (HG). In contrast to PUPPP, HG is associated with a greater prevalence of premature and smallfor-gestational-age babies. In addition, patients with HG have an increased incidence of systemic autoimmune disorders.

Clinical Features Lesions typically begin adjacent to the umbilicus, but with umbilical sparing, and then spread to the remainder of the abdomen, buttocks, and extremities. There are markedly pruritic urticarial papules which coa-

lesce to form plaques, but true bullae are not typical (unlike in HG). Targetoid lesions may be seen. The rash typically resolves within days postpartum.

Histopathologic Features There is variable parakeratosis and epidermal acanthosis, minimal spongiosis with focal lymphocyte exocytosis, edema of the papillary dermis, and a superficial perivascular lymphocytic and sometimes eosinophilic infiltrate with focal exocytosis. The marked pruritus can lead to erosions, with neutrophils as secondary changes. Direct immunofluorescence studies are negative for immunoreactant deposition in peri-lesional PUPPP skin.

29

Table 2-9 Skin Diseases with Follicular Spongiosisa Atopic dermatitis Infundibulofolliculitis Fox-Fordyce disease (apocrine miliaria) Pityriasis alba Infectious folliculitis Eosinophilic folliculitis Follicular mucinosis a

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

See Fig. 2-24

Table 2-10 Nummular (Discoid) Dermatitis

Clinical Features Coin-shaped, pruritic, erythematous patches on the hands, forearms, and legs Patches may have tiny vesicles or erosions, which can evolve to form annular plaques or dry scaly areas Tends to affect men and women 55 years and older as well as women 15-30 years old Histopathologic Features Varies according to the lesion biopsied: acute, subacute, and chronic eczematous patterns Differential Diagnosis All types of eczematous dermatitis Dermatophytosis Figurate erythemas Seborrheic dermatitis

Table 2-11 Dyshidrotic Dermatitis

30

Clinical Features Itchy tense vesicles on the digits, palms, and soles Histopathologic Features Intraepidermal spongiotic vesicles usually on epidermis of normal or increased thickness Variable amount of superficial perivascular lymphocytic infiltrate Differential Diagnosis Atopic dermatitis Allergic contact dermatitis Dermatophytosis Miliaria Other types of acute vesicular eczematous eruptions

 FIGURE 2-25 Pompholyx. Large intraepidermal microvesicle(s) containing serum and inflammatory cells, with adjacent epidermal spongiosis.

Table 2-12 Seborrheic Dermatitis

Clinical Features Common disorder affecting the scalp, face, upper chest, and back Greasy, scaley, red-brown patches Often pruritic Dandruff is one type of seborrheic dermatitis Histopathologic Features Psoriasiform hyperplasia Hyperkeratosis and parakeratosis, especially parafollicular Spongiosis Neutrophilic exocytosis Superficial perivascular lymphocytic infiltrate Differential Diagnosis Psoriasis Eczematous dermatitis Impetigo Dermatophytosis Secondary syphilis Gyrate erythemas Pityriasis rosea Irritant contact dermatitis Drug reaction

Differential Diagnosis HG is the main clinical differential consideration. Unlike PUPPP, it can present in the first or any subsequent pregnancy, and occur in second or third trimester, or even postpartum.

HG is a polymorphous dermatitis and the typical presence of umbilical involvement by the rash in HG helps to distinguish it from PUPPP. Eosinophils at the dermal-epidermal junction are seen more often in HG than in PUPPP. In addition, direct immunofluorescence studies demonstrate linear C3 and/or IgG deposition along the dermoepidermal junction in skin from patients with HG. INCONTINENTIA PIGMENTI Incontinentia pigmenti (IP) is an uncommon X-linked multisystem disorder that is usually seen in females (97% of cases).59,60 Males with the disorder (3% of cases) most likely have acquired spontaneous mutations, as it is believed that males who inherit the abnormal gene die in utero. The skin lesions typically are distributed along Blaschko lines, which is thought to represent the effects of functional X chromosome mosaicism (ie, these are the areas where the abnormal gene that is not inactivated can express its phenotype). Females with incontinentia pigmenti are thought to exhibit functional X chromosome mosaicism.

Clinical Features Cutaneous lesions of IP occur in three stages that usually follow sequentially, but significant overlap can occur. The first stage usually presents at birth or shortly thereafter and is characterized by small vesicles arising on a background of erythema; the changes

Table 2-13 Pityriasis Rosea

 FIGURE 2-27 Id reaction. Spongiosis with microvesicle formation, slight papillary dermal edema, and perivascular and interstitial dermal inflammation.

are more prominent on the extremities and arranged in a whorled pattern following Blaschko lines. The second stage, which follows several months later, shows linear verrucous lesions also predominantly on the extremities. The third stage, again occurring several months later, consists of areas of hyperpigmentation in an irregularly whorled pattern, usually widespread

on the trunk rather than the extremities, again following Blaschko lines. The pigmentation often but not always resolves within several years. Nail dystrophy, alopecia, and extracutaneous manifestations are common associated features.

Histopathologic Features Skin lesions in the first stage of IP show spongiosis

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

 FIGURE 2-26 Seborrheic dermatitis. Epidermal acanthosis with minimal spongiosis, lymphocyte exocytosis, and perifollicular mounds of parakeratosis, scale-crust, and fungal spores (Pityrosporum).

Clinical Features Duration of disease: less than 10 weeks Herald patch Generalized eruption, usually on trunk Multiple salmon-colored macules with fine scale “Fir tree”pattern Atypical pityriasis rosea may exhibit vesicles, pustules, urticarial lesions, purpura Inverse pityriasis rosea refers to a rash that is distributed on the extremities instead of the trunk Drug eruptions may result in a pityriasis rosea–like eruption Histopathologic Features Mild subacute spongiotic dermatitis often with focal parakeratosis (which may tilt upward) Perivascular lymphocytic infiltrate with variable exocytosis Sometimes a microvesicle containing mononuclear cells in the epidermis Atypical forms tend to show vesicles, dyskeratosis, more parakeratosis and infiammation, hemorrhage, and eosinophils Differential Diagnosis Drug reactions Eczematous dermatitis Chronic superficial dermatitis (parapsoriasis) Pityriasis lichenoides Guttate psoriasis Dermatophytosis

with eosinophil exocytosis, spongiotic vesicles containing mostly eosinophils, and isolated and/or collections of dyskeratotic squamous cells within the epidermis (Fig. 2-33). Spongiosis is typically not a histologic feature of the second and third stages of the disease. The skin lesions of the second stage show epidermal hyperplasia with papillomatosis, dyskeratotic cells, vacuolar alteration along the dermoepidermal junction, and a superficial dermal lymphocytic infiltrate with melanophages. Melanophages become a more prominent feature in the third stage of disease.

Differential Diagnosis Similar to the first stage of IP, erythema toxicum neonatorum (ETN) and eosinophilic pustular folliculitis (EPF) can also show an eosinophilrich pustule within the epidermis. In contrast to IP, these changes are typically folliculocentric and are not associated with spongiosis or necrotic keratinocytes

31

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 2-14 Stasis Dermatitis

Clinical Features Legs, especially the inner aspects Red, edematous, scaling lesions Variable oozing Evidence of stasis, such as brown pigmentation, ulcers, varicose veins, and atrophic scars Histopathologic Features Acute, subacute, or chronic eczematous pattern with lobular proliferation of capillaries, hemorrhage, hemosiderin deposition, and fibrosis Differential Diagnosis Granulation tissue next to a leg ulcer Kaposi sarcoma

 FIGURE 2-28 Pityriasis rosea. Slight epidermal hyperplasia, spongiosis, mounds of parakeratosis, with lymphocyte and erythrocyte exocytosis.

Staphylococcus spp. may play a role in the pathogenesis of miliaria, as the PASpositive, diastase-resistant material forming within the intraductal keratotic plug is believed to represent staphylococcal extracellular polysaccharide substance. However, the hyperkeratotic plug could be a late change and not the precipitating cause of the sweat blockage. Three types of miliaria are classified according to the level at which obstruction of the sweat duct occurs: (a) miliaria crystallina, (b) miliaria rubra, and (c) miliaria profunda.61 The clinical and histological features of the subtypes of miliaria differ. Miliaria pustulosa are pustular lesions of miliaria rubra. MILIARIA CRYSTALLINA (SUDAMINA) In miliaria crystallina, the obstruction occurs most superficially, within the stratum corneum portion of the duct.

 FIGURE 2-29 Erythroderma. Epidermal acanthosis, spongiosis, rare eosinophil exocytosis, and perivascular lymphocytic and eosinophilic infiltrate.

in ETN. In addition, cutaneous lesions of ETN resolve spontaneously. EPF in children is usually not related to HIV infection, unlike the condition in adults. Similar to ETN, it can start within the first days of life and produce follicularbased eosinophil-rich pustules. However, in contrast to ETN, the condition can persist for 3 months to 5 years. In addition, scalp and palmoplantar involvement is common in EPF. Miliaria, transient neonatal pustular melanosis, and

32

infantile acropustulosis are childhood dermatoses that form pustules which are neutrophil-rich. MILIARIA Miliaria is a common skin disorder caused by the leakage of eccrine sweat into the epidermis or dermis secondary to the blockage of eccrine sweat ducts (Fig 2-34).61 The condition often occurs in areas of increased heat and humidity. Skin occlusion and excessive sweating can be contributing factors.

Clinical Features This form of the disease is found in newborns less than 2 weeks old and adults who are febrile or those who recently moved to a humid climate. It is characterized by mulitple asymptomatic tiny (1-2 mm), fragile, clear vesicles on noninflamed skin, which tend to occur on the head, neck, and upper trunk. Lesions appear in crops and may become confluent, but without any surrounding erythema. Desquamation follows. Histopathologic Features Biopsies of miliaria crytallina demonstrate an intracorneal or subcorneal vesicle overlying an eccrine duct. The vesicles may contain occasional neutrophils. Obstruction of the eccrine duct within the stratum corneum may be seen.

ments. There are numerous small (1-2 mm), intensely pruritic, erythematous, non-folliculocentric papules and rarely vesicules on a background of erythema. A distinctive prickly or stinging sensation is described. The lesions do not tend to confluence. Affected areas include the scalp, neck, upper trunk, axillae, and groin. There is facial sparing. Lesions resolve within days after the patient is removed from the humid climate.

Differential Diagnosis The spongiotic microvesicles in miliaria rubra can resemble those in other forms of acute spongiotic dermatitis. However, the localization of these vesicles to acrosyringia, with normal intervening epidermis, serves to distinguish miliaria rubra.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

 FIGURE 2-30 Stasis dermatitis. Epidermal acanthosis, spongiosis, and lobular proliferation of blood vessels with fibrosis in the dermis.

Histopathologic Features Lesions of miliaria rubra show spongiosis and spongiotic microvesicles centered on an acrosyringium (the intraepidermal eccrine duct) within the stratum malpighian. There is a predominantly lymphocytic infiltrate around and within the vesicles and in the superficial dermis. Gram-positive bacterial cocci may be seen in the stratum corneum, and a PAS-positive plug may occlude the affected duct lumen.

MILIARIA PROFUNDA Miliaria profunda is caused by occlusion of the eccrine sweat duct at the level of the dermal-epidermal junction. It typically occurs as a complication of repeated episodes of miliaria rubra.

 FIGURE 2-31 Stasis dermatitis. Spongiosis, lymphocyte exocytosis, and lobular proliferation of blood vessels with fibrosis in the dermis.

Differential Diagnosis Subcorneal pustular dermatosis and pustular drug eruptions also demonstrate intracorneal vesicle(s) containing neutrophils. However, the vesicles in miliaria crystallina typically contain more fluid and fewer neutrophils than the vesicles in these latter diseases. Transient neonatal pustular melanosis and infantile acropustulosis are childhood dermatoses that can also

form subcorneal pustules that are neutrophil-rich. MILIARIA RUBRA (PRICKLY HEAT RASH) Obstruction of the sweat duct occurs within the superficial epidermis.

Clinical Features Similar to miliaria crystallina, this form also affects neonates and adults who live in humid environ-

Clinical Features Similar to other variants, miliaria profunda occurs in adults who live in hot, humid climates. Numerous, usually asymptomatic, small (1-3 mm), flesh-colored nonfollicular papules appear on the truck and often extremities. Other features include lymphadenopathy, fever, nausea, and tropical anhidrotic asthenia (the widespread inability to sweat as a result of eccrine ductal rupture). Histopathologic Features There is spongiosis and sometimes vesiculation of the lower portion of the acrosyringium and upper dermal part of the sweat duct. There is a periductal lymphocytic infiltrate, dermal edema, and occasional duct rupture. A PAS-positive, diastaseresistant eosinophilic cast may be seen in the ductal lumen.

33

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

 FIGURE 2-32 Gianotti-Crosti syndrome. Spongiotic-interface reaction pattern: Spongiosis with microvesicle formation, perivascular and interstitial lymphocytic infiltrate that focally obscures the dermoepidermal junction with lymphocyte exocytosis, and papillary dermal edema.

 FIGURE 2-33 Incontinentia pigmenti. Spongiosis with microvesicle, eosinophil exocytosis, and solitary and aggregated dyskeratotic squamous cells within the epidermis. Miliarial Spongiosis (Spongiosis Involving the Acrosyringium)

34

Subcorneal vesicle filled with fluid and < 50% neutrophils by volume in and around the duct:

Spongiosis involving the upper half of the acrosyringium and lymphocytic infiltrate in and around the duct:

Spongiosis involving the lower half of the acrosyringium and lymphocytic infiltrate:

Inflammatory dermatitis which involves the epidermis and the acrosyringium:

Miliaria crystallina

Miliaria rubra

Miliaria profunda

See relevant pattern

 FIG 2-34 Algorithm for miliarial spongiosis.

REFERENCES

44. Beacham BE. Common dermatoses in the elderly. Am Fam Physician. 1993;47: 1445-1450. 45. Bonnetblanc JM. Stasis dermatitis. Ann Dermatol Venereol. 2002;129(1 Pt 1):98-101. 46. Fitzpatrick JE. New histopathologic findings in drug eruptions. Dermatol Clin. 1992;10:19-36. 47. Crowson AN, Brown TJ, Magro CM. Progress in the understanding of the pathology and pathogenesis of cutaneous drug eruptions: implications for management. Am J Clin Dermatol. 2003;4:407-428. 48. Crowson AN, Magro CM. Recent advances in the pathology of cutaneous drug eruptions. Dermatol Clin. 1999; 17:537-560,viii. 49. Kauppinen K, Stubb S. Drug eruptions: causative agents and clinical types. A series of in-patients during a 10-year period. Acta Derm Venereol. 1984;64:320-324. 50. Magro CM, Crowson AN, Kovatich AJ, et al. Drug-induced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of memory and activated T cells. Hum Pathol. 2003;34:119-129. 51. Wolf R, Kahane E, Sandbank M. Mycosis fungoides-like lesions associated with phenytoin therapy. Arch Dermatol. 1985; 121:1181-1182. 52. Welykyj S, Gradini R, Nakao J, et al. Carbamazepine-induced eruption histologically mimicking mycosis fungoides. J Cutan Pathol. 1990;17:111-116. 53. Baleviciene G, Maciuleviciene R, Schwartz RA. Papular acrodermatitis of childhood: the Gianotti-Crosti syndrome. Cutis. 2001; 67:291-294. 54. Brandt O, Abeck D, Gianotti R, et al. Gianotti-Crosti syndrome. J Am Acad Dermatol. 2006;54:136-145. 55. Caputo R, Gelmetti C, Ermacora E, et al. Gianotti-Crosti syndrome: a retrospective analysis of 308 cases. J Am Acad Dermatol. 1992;26(2 Pt 1):207-210. 56. Taieb A, Plantin P, Du Pasquier P, et al. Gianotti-Crosti syndrome: a study of 26 cases. Br J Dermatol. 1986;115:49-59. 57. Winton GB, Lewis CW. Dermatoses of pregnancy. J Am Acad Dermatol. 1982;6: 977-998. 58. Ambros-Rudolph CM, Müllegger RR, Vaughan-Jones SA, et al. The specific dermatoses of pregnancy revisited and reclassified: results of a retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol. 2006;54:395-404. 59. Ehrenreich M, Tarlow MM, GodlewskaJanusz E, et al. Incontinentia pigmenti (Bloch-Sulzberger syndrome): a systemic disorder. Cutis. 2007;79:355-362. 60. Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol. 2002;47: 169-187. 61. Feng E, Janniger CK. Miliaria. Cutis. 1995; 55:213-216.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

1. Trautmann A, Disch R, Bröcker EB, et al. How does eczema arise? J Dtsch Dermatol Ges. 2003;1:8-11. 2. Houck G, Saeed S, Stevens GL, et al. Eczema and the spongiotic dermatoses: a histologic and pathogenic update. Semin Cutan Med Surg. 2004;23:39-45. 3. Ruiz E, Deng JS, Abell EA. Eosinophilic spongiosis: a clinical, histologic, and immunopathologic study. J Am Acad Dermatol. 1994;30:973-976. 4. Machado-Pinto J, McCalmont TH, Golitz LE. Eosinophilic and neutrophilic spongiosis: clues to the diagnosis of immunobullous diseases and other inflammatory disorders. Semin Cutan Med Surg. 1996;15:308-316. 5. Crotty C, Pittelkow M, Muller SA. Eosinophilic spongiosis: a clinicopathologic review of seventy-one cases. J Am Acad Dermatol. 1983;8:337-343. 6. Knight AG, Black MM, Delaney TJ. Eosinophilic spongiosis: a clinical histological and immunofluorescent correlation. Clin Exp Dermatol. June 1976;1: 141-153. 7. Batista G, Santos AN, Sampáio SA. Neutrophilic spongiosis. a new entity? Br J Dermatol. 1986;114:131-134. 8. Hoss DM, Shea CR, Grant-Kels JM. Neutrophilic spongiosis in pemphigus. Arch Dermatol. 1996;132:315-318. 9. Brasch J, Becker D, Aberer W, et al. Contact dermatitis. J Dtsch Dermatol Ges. 2007;5:943-951. 10. Fyhrquist-Vanni N, Alenius H, Lauerma A. Contact dermatitis. Dermatol Clin. 2007;25:613-623. 11. Mark BJ, Slavin RG. Allergic contact dermatitis. Med Clin North Am. 2006;90: 169-185. 12. Saint-Mezard P, Rosieres A, Krasteva M, et al. Allergic contact dermatitis. Eur J Dermatol. 2004;14:284-295. 13. English JS. Current concepts of irritant contact dermatitis. Occup Environ Med. 2004;61:722-726, 674. 14. Mozzanica N. Pathogenetic aspects of allergic and irritant contact dermatitis. Clin Dermatol. 1992;10:115-121. 15. Dahl MV. Chronic, irritant contact dermatitis: mechanisms, variables, and differentiation from other forms of contact dermatitis. Adv Dermatol. 1988;3:261-275. 16. Belsito DV. Occupational contact dermatitis: etiology, prevalence, and resultant impairment/disability. J Am Acad Dermatol. 2005;53:303-313. 17. Stein KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Expert Opin Drug Saf. 2007;6:431-443. 18. Lugovi´c L, Situm M, Ozanic-Buli ´ c´ S, et al. Phototoxic and photoallergic skin reactions. Coll Antropol. 2007;31(Suppl 1): 63-67. 19. Janssens V, Morren M, Dooms-Goossens A, et al. Protein contact dermatitis: myth or reality? Br J Dermatol. 1995;132:1-6. 20. Wüthrich B. Protein contact dermatitis. Br J Dermatol. 1996;135:332-333.

21. Lipozencic´ J, Wolf R. Atopic dermatitis: an update and review of the literature. Dermatol Clin. 2007;25:605-612. 22. Guttman-Yassky E. Atopic dermatitis. Curr Probl Dermatol. 2007;35:154-172. 23. Simpson EL, Hanifin JM. Atopic dermatitis. Med Clin North Am. 2006;90:149-167. 24. Boer A. Patterns histopathologic of FoxFordyce disease. Am J Dermatopathol. 2004;26:482-492. 25. Ozcan A, Senol M, Aydin NE, et al. FoxFordyce disease. J Eur Acad Dermatol Venereol. 2003;17:244-245. 26. Lin RL, Janniger CK. Pityriasis alba. Cutis. 2005;76:21-24. 27. Martin RF, Lugo-Somolinos A, Sanchez JL. Clinicopathologic study on pityriasis alba. Bol Asoc Med P R. 1990;82:463-465. 28. Vargas-Ocampo F. Pityriasis alba: a histologic study. Int J Dermatol. 1993;32:870-873. 29. Sirot G. Nummular eczema. Semin Dermatol. 1983;2:68-74. 30. Guillet MH, Wierzbicka E, Guillet S, et al. A 3-year causative study of pompholyx in 120 patients. Arch Dermatol. 2007; 143:1504-1508. 31. Warshaw EM, Ahmed RL, Belsito DV, et al. North American Contact Dermatitis Group. Contact dermatitis of the hands: cross-sectional analyses of North American Contact Dermatitis Group Data, 1994-2004. J Am Acad Dermatol. 2007;57:301-314. 32. Gupta AK, Bluhm R. Seborrheic dermatitis. J Eur Acad Dermatol Venereol. 2004;18: 13-26. 33. Schwartz RA, Janusz CA, Janniger CK. Seborrheic dermatitis: an overview. Am Fam Physician. 2006;74:125-130. 34. Moschella SL, Hurley HJ. Autoeczematization. In: Dermatology. 3rd ed. Philadelphia, PA: WB Saunders; 1992:484-485. 35. Belsito DV. Autosensitization dermatitis. In: Fitzpatrick’s Dermatology in General Medicine. 5th ed. New York, NY: McGraw-Hill; 1999:1462-1464. 36. Chuh A, Lee A, Zawar V, et al. Pityriasis rosea—an update. Indian J Dermatol Venereol Leprol. 2005;71:311-315. 37. González LM, Allen R, Janniger CK, et al. Pityriasis rosea: an important papulosquamous disorder. Int J Dermatol. 2005;44:757-764. 38. Rothe MJ, Bialy TL, Grant-Kels JM. Erythroderma. Dermatol Clin. 2000;18: 405-415. 39. Milavec-Puretic´ V, Zoric´ Z, Zidanic´ M, et al. Exfoliative erythroderma. Acta Dermatovenerol Croat. 2007;15:103-107. 40. Zip C, Murray S, Walsh NM. The specificity of histopathology in erythroderma. J Cutan Pathol. 1993;20:393-398. 41. Walsh NM, Prokopetz R, Tron VA, et al. Histopathology in erythroderma: review of a series of cases by multiple observers. J Cutan Pathol. 1994;21:419-423. 42. Vasconcellos C, Domingues PP, Aoki V, et al. Erythroderma: analysis of 247 cases. Rev Saude Publica. 1995;29:177-182. 43. Yi JU, Lee CW. Acroangiodermatitis. A clinical variant of stasis dermatitis. Int J Dermatol. 1990;29:515-516.

35

CHAPTER 3 Interface Dermatitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Frances I. Ramos-Ceballos Thomas D. Horn

A large group of skin diseases is characterized by histologic changes categorized as interface dermatitis (Fig. 3-1). At a minimum, a variable combination of leukocyte infiltration of the dermis, vacuolar change of the basilar epidermis, accumulation of melanophages in the upper dermis, and necrosis of keratinocytes must be observed. The term interface dermatitis is therefore apt because these findings occur at the interface between the epidermis and dermis. This common thread binds otherwise disparate entities together. Other terms applied to this group of disorders include vacuolar dermatitis, vacuolar interface dermatitis, and lichenoid tissue reaction. Before considering specific diseases, definition and illustration of the common histologic findings are in order.

LEUKOCYTE INFILTRATION The term leukocyte infiltration of the dermis is cumbersome but more generally accurate than inflammation because, in the case of mycosis fungoides, some portion of the infiltrating lymphocytes is neoplastic and not inflammatory in nature. In all other

disorders considered here, lymphoid infiltration represents inflammation. Some degree of upper dermal perivascular accumulation of leukocytes is observed in interface dermatitides. Extension of cells into surrounding collagen may impart a bandlike appearance (or lichenoid appearance, given the similarity to lichen planus) to the infiltrate. Density, pattern, and composition of the infiltrate are variable elements of interface dermatitis that aid in establishing more specific diagnosis.

VACUOLAR ALTERATION Vacuolar alteration of the basilar epidermis is also termed basal vacuolization. At the junction between the epidermis and dermis, small, often contiguous, discrete vacuoles are observed. The vacuolization imparts a ragged appearance to the base of the epidermis. When there is sufficient vacuolar destructive interface change, subepidermal clefts form, best exemplified by lesions of bullous lichen planus and grade 3 or 4 lesions of graft-versushost disease. Melanin generally resides mostly in keratinocytes and to a lesser degree in melanocytes. Damage to basilar keratinocytes, as part of an interface dermatitis, results in deposition of melanin granules in the upper dermis. The pigment is phagocytosed by macrophages, which become progressively more melanin-laden and are termed melanophages. Recognition of melanophages correlates with stage in evolution of the interface dermatitis and constitutive degree of pigmentation.

The presence of many melanophages suggests that the process is well established. Extension of leukocytes into the epidermis is also termed exocytosis. The definition of exocytosis also encompasses extension of erythrocytes into the epidermis. The small, round nuclei of lymphocytes are seen to intercalate between keratinocytes, admixed with variable but generally little spongiosis in the case of interface dermatitis. This infiltration may be subtle or pronounced and may be confined to the basilar epidermis or may extend throughout the thickness of the epidermis. Direct apposition of lymphocytes to necrotic keratinocytes is termed satellite cell necrosis (ie, lymphocyte satellitosis). A nonviable keratinocyte exhibits an irregularly shrunken, hyperchromatic nucleus positioned adjacent to dense eosinophilic, refractile cytoplasm. The nucleus may not be observed. The cytoplasmic change is most apparent and is progressive as the cell dies. A variety of terms exists to describe a degenerated/ dead keratinocyte. Based solely on histologic observation, there is little validity to the many names. Important and real differences in pathophysiology exist for these terms and are not discernible on routine light microscopic assessment. Among the various terms are keratinocyte necrosis, dyskeratosis (dyskeratotic keratinocyte), apoptosis (apoptotic keratinocyte), Civatte body, and colloid body. For purposes of this discussion we will use the term keratinocyte necrosis. Understanding the individual histopathologic elements of interface dermatitis

Interface dermatitis

Vacuolar interface dermatitis

Vacuolar interface dermatitis Erythema multiforme Fixed drug eruption Drug eruptions Viral xanthems HIV interface dermatitis Connective tissue disease Lupus erythematosus Dermatomyositis Graft-versus-host reaction Pityriasis lichenoides Vitiligo

36

Poikilodermatous interface dermatitis Poikiloderma of Civatte Poikiloderma congenitale Bloom syndrome Dyskeratosis congenita Dermatomyositis Mycosis fungoides Radiation dermatitis

 FIGURE 3-1 Interface dermatitis: diagnostic algorithm.

Lichenoid interface dermatitis

Lichenoid interface dermatitis Lichen planus and variants Lichenoid drug eruption Lichenoid keratosis Lichen striatus Lichen nitidus Lichenoid purpura Porokeratosis Histologic regression of many tumors

A

B

is the framework on which to build a detailed description of the specific entities described in this chapter. Considerable variation exists in histologic expression of specific diseases depending on body site sampled, adequacy of the sample, and most important, stage of evolution of the lesion sampled. This chapter is organized such that diseases with shared histologic features are considered as a group, with the proposed prototype discussed first. The first general categorization to be made lies in the distinction between a lichenoid-interface dermatitis, which is heavily inflamed (cell-rich) relative to a vacuolar-interface dermatitis, which contains few inflammatory cells (cell-poor) (see Fig. 3-2).

LICHENOID-INTERFACE DERMATITIS Lichen planus serves as the prototype for several disorders (Table 3-1). The main findings in samples from fully evolved lesions include a fairly continuous band of lymphoid cells in the upper dermis, overlying interface changes, and further characteristic epidermal changes consisting of acanthosis, pointed rete ridges, an expanded granular layer, and hyperkeratosis.

Lichen Planus and Variants CLINICAL FEATURES Lichen planus, an inflammatory disorder of uncertain cause, consists of variably distributed erythematous to violaceous polygonal papules and plaques, typically well defined in contour and often grouped on flexor surfaces,

Table 3-1 Lichen Planus and Variants

Clinical Features Lichen planus Prominent pruritus Violaceous polygonal papules Flexural surfaces favored Oral and genital involvement frequent Atrophic lichen planus (actinicus) Atrophic erythematous patches Sun-exposed skin Hypertrophic lichen planus Verrucous plaques Extensor surfaces favored Bullous lichen planus Bullae within erythematous patches Histopathologic Features Lichen planus Band of lymphocytes in upper dermis, melanophages Acanthosis, hypergranulosis, “sawtoothing” of rete ridges Basal vacuolization Atrophic lichen planus (actinicus) Lichenoid interface dermatitis Epidermal atrophy Hypertrophic lichen planus Lichenoid interface dermatitis Irregular acanthosis Hyperkeratosis Bullous lichen planus Lichenoid interface dermatitis Subepidermal cleft Differential Diagnosis Lichen planus Lichenoid drug eruption Lichenoid keratosis Lichenoid actinic keratosis Lupus erythematosus

Atrophic lichen planus (actinicus) Lupus erythematosus Lichen sclerosus Hypertrophic lichen planus Lichen simplex chronicus Verrucous lupus erythematosus Bullous lichen planus Paraneoplastic pemphigus Erythema multiforme Toxic epidermal necrolysis Fixed drug eruption

especially the wrists (Fig. 3-2A). The genitalia are frequently involved. Scale is generally absent, but surface change consisting of white lines or grooves known as Wickham striae are often observed. The patient frequently complains of intense pruritus. Oral and nail changes may accompany the cutaneous eruption. Rare cases of esophageal and ocular involvement are reported.1,2 Lacy, white patches commonly involve the buccal mucosa. Dystrophy of the nail plate may develop with ridging and distal splitting. Variants include hypertrophic, atrophic, and bullous forms. Hypertrophic lichen planus commonly occurs on the lower legs and consists of erythematous hyperkeratotic plaques that are quite pruritic. Lichen planus actinicus (actinic lichen planus) is an unusual variant localized to sun-exposed skin. Scarring alopecia in association with lichen planus, known as lichen planopilaris, is discussed in Chap. 10. Associations between lichen planus and hepatitis C infection, as well as vaccination against hepatitis B, occur.3,4

CHAPTER 3 ■ INTERFACE DERMATITIS

 FIGURE 3-2 Lichen planus. (A) Note violaceous flat-topped polygonal papules with slight whitish scale. The papules show characteristic coalescence into plaques. (B) The most notable feature is a bandlike infiltrate of lymphocytes that obscures the dermal-epidermal junction.

37

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

HISTOPATHOLOGIC FEATURES A fully evolved lesion will display a perivascular and interstitial infiltration of the upper dermis by lymphocytes and histiocytes, forming a band of cells positioned in the papillary and upper reticular dermis (Figs. 3-2 through 3-4). Interspersed melanophages are usually present, and eosinophils may accompany the mononuclear elements of the infiltrate. The inflammatory cells extend up to and

38

infiltrate the lower epidermis. Significant perivascular inflammation of the middle or deep reticular dermis is uncommon. The density of the infiltrate partially or totally obscures the junction between the epidermis and dermis. Exocytosis of lymphocytes is noted, with scattered necrotic keratinocytes generally concentrated in the lower epidermis but possibly arrayed at all epidermal levels (see Fig. 3-4). Necrotic keratinocytes may be observed

 FIGURE 3-3 Lichen planus. This lesion shows hyperkeratosis, hypergranulosis, some acanthosis, and a bandlike infiltrate that fills the papillary dermis and obscures the dermal-epidermal junction.

 FIGURE 3-4 Lichen planus. There is basal layer vacuolization. The epidermis is slightly acanthotic, and there is tendency to a saw-tooth pattern of the lower epidermis.

in the upper dermis and stratum corneum. Direct immunofluorescence studies reveal shaggy deposits of fibrin along the basement membrane zone and complement and immunoglobulin reactivity of eosinophilic globular remnants of necrotic keratinocytes in the superficial dermis 5,6 Destruction of the basilar and parabasilar epidermis results in exposure of the spinous layer to the subjacent dermis defining the concept of “squamotization.” Lymphocyte satellitosis around necrotic keratinocytes is not uncommon. A constellation of additional epidermal changes is also evident. Acanthosis with wedge-shaped hypergranulosis occurs. The rete ridges become pointed with sharply tapering tips, the so-called sawtooth pattern. Hyperkeratosis is seen, but significant parakeratosis is absent. The combination of a band of mononuclear cells confined to the upper dermis, interface changes, and these characteristic epidermal features represent a theme uniting several entities, as discussed later, but should prompt consideration of lichen planus first. Specimens from early lesions display less inflammation and incompletely evolved epidermal changes; melanophages may be absent. Old lesions generally show reparative changes in the papillary dermis and vascular ectasia, contain numerous melanophages with little inflammation, and display variable epidermal alteration. Biopsy specimens from mucosa and nail display similar changes.7 In hypertrophic lichen planus, irregular acanthosis is pronounced but is accompanied by the elements of interface dermatitis and a band of lymphocytes (Fig. 3-5). This combination of findings represents an element of lichen simplex chronicus in addition to lichen planus. Epidermal atrophy typifies actinic lichen planus.8 Inflammation of the deep vascular plexus and adnexae is absent. However a lichenoid interface may involve the acrosyringium, superficial straight eccrine duct, and hair follicle. In bullous lichen planus, the basal vacuolization becomes confluent, leading to separation of the epidermis from the dermis (Fig. 3-6). The clefts, or MaxJoseph spaces, may remain microscopic or become clinically apparent. As mentioned, the infiltrating lymphocytes express CD3, with a majority of cells in the T-helper/inducer phenotype (CD4+). Terminal effector mechanisms are not completely understood. Typical cytokines patterns are found in affected tissue, referable to aberrant keratinocyte and lymphocyte physiology.9 These cytokines may affect epidermal keratin expression, which tends to resemble keratin

Alteration in the structure and distribution of type VII collagen, a6b4 integrin, and kalinin is reported in lichen planus.

 FIGURE 3-6 Bullous lichen planus. There is dermal-epidermal separation leading to formation of a blister cavity. Otherwise, features typical of lichen planus are present.

expression in wound healing.10 Additionally, the pattern of intercellular adhesion molecule 1 (ICAM-1) expression is restricted to basilar keratinocytes in lichen planus, in contrast to lupus erythematosus and erythema multiforme, where

more diffuse staining at upper epidermal levels is attributed to the effects of photosensitivity and herpes simplex virus triggers, respectively.11 The interface change leads to disruption of the normal integrity of epidermal anchoring mechanisms.12

CHAPTER 3 ■ INTERFACE DERMATITIS

 FIGURE 3-5 Hypertrophic lichen planus. The epidermal surface is slightly papillomatous, and there is irregular hyperplasia of the epidermis.

DIFFERENTIAL DIAGNOSIS The fully evolved histopathology of lichen planus generally allows confident diagnosis in the correct clinical setting. Specimens of lichenoid (lichen planus-like) keratosis and lichenoid drug eruption may strongly resemble lichen planus, requiring accompanying clinical information. The lichenoid keratosis is often distinguished from lichen planus by the presence of parakeratosis, delicate laminated hyperkeratosis, a normal granular layer, and in some cases, remnants of a solar lentigo. Most lichenoid keratoses are solitary lesions developing on sun-exposed skin. The anterior chest is a common site. The lesion is often mistaken for basal cell carcinoma, actinic keratosis, or melanocytic nevus clinically. Lichenoid drug eruptions cannot be reliably distinguished from lichen planus but more commonly display the following features: parakeratosis, a normal granular layer, eosinophils, and plasma cells in the inflammatory infiltrate. Inflammation is also more likely to be perivascular and bandlike, in contrast to only bandlike in lichen planus. In general, epidermis involved with lichen planus contains a greater number of Langerhans cells than seen in lichenoid keratosis and lichenoid actinic keratosis.13 Lichenoid actinic keratosis should possess the diagnostic elements of an actinic keratosis, with crowding of keratinocytes and nuclear atypia in addition to the elements of interface dermatitis. Since chronic ulcerating lichen planus of mucosal surfaces is rarely associated with the development of squamous cell carcinoma, epithelial dysplasia in these sites must be sought and noted.14 In lupus erythematosus, the pattern of inflammation is quite variable but in the discoid variant the inflammation often extends to involve the deep vascular plexus and eccrine coil. In general, the degree of upper dermal inflammation and number of necrotic keratinocytes in the systemic and discoid variants of lupus erythematosus is less than in lichen planus; however in subacute cutaneous lupus erythematosus a dense lichenoid pattern may be observed although usually there is variable attenuation and hyperplasia of the epidermis and the granular cell layer is not increased. Epidermal atrophy suggests the diagnosis of lupus erythematosus, keeping in mind that an atrophic form of lichen planus exists and generally lacks inflammation

39

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

of the deep vessels and adnexa. Basement membrane thickening and increased dermal mucin also suggest connective tissue disease rather than lichen planus. Hypertrophic (verrucous) lupus erythematosus may show many of the same features of hypertrophic lichen planus but is discriminated by foci of cell-poor interface dermatitis, whereby the papillary dermis has an almost hyalin-like appearance, vascular ectasia, basement membrane thickening, dermal mucin, and deep extension of the inflammatory infiltrate. Overlap of lupus erythematosus and lichen planus is possible and must be diagnosed based on clinicopathologic correlation. Erythema multiforme and toxic epidermal necrolysis (see below) are characterized by more keratinocyte necrosis relative to the degree of inflammation than lichen planus. The inflammation in a specimen of fixed drug eruption often involves the deep vascular plexus and may be polymorphous with occasional eosinophils, neutrophils, and plasma cells. At times, confident discrimination among these disorders requires clinicopathologic correlation. Any skin biopsy specimen with an upper dermal interstitial infiltrate of lymphocytes should prompt consideration of mycosis fungoides. Interface changes are variably present in mycosis fungoides, although the destructive epidermal changes of lichen planus generally are absent. Other discriminating features include many hyperconvoluted cerebriform lymphocytes assuming a passive pattern of epidermal colonization typically present in epidermal lacunae. One of the other characteristic hallmarks is a narrow grenz zone of uninvolved papillary dermis, which separates the neoplastic bandlike infiltrate from the overlying epidermis. Significant nuclear atypia of lymphocytes and aggregation of lymphocytes in epidermal lacunae are absent in lichen planus.

Lichenoid Drug Eruption CLINICAL FEATURES Drug eruptions with clinical and histologic features similar to lichen planus have been described15,16 (see also Chap. 12). Various components of drugs of abuse also may cause lichenoid reactions. Photodistribution is observed frequently. Discontinuation of the offending medication results in resolution of the eruption.

40

HISTOPATHOLOGIC FEATURES Lichenoid drug eruptions may resemble lichen planus. Parakeratosis and inflammation around the middle and deep vascular plexus occur regularly. Eosinophils are

variably present. The absence of eosinophils does not preclude the diagnosis of lichenoid drug eruption. Lichenoid drug eruption often displays epidermal atrophy. DIFFERENTIAL DIAGNOSIS Observation of parakeratosis, epidermal atrophy, eosinophils including foci of eosinophilic spongiosis, and deep dermal inflammation suggest the diagnosis of lichenoid drug eruption when lichen planus is also a consideration. Adequate clinical history is imperative for accurate diagnosis.

Lichenoid Keratosis (Lichen Planus-Like Keratosis) and Lichenoid Actinic Keratosis CLINICAL FEATURES Lichenoid keratoses typically occur as solitary lesions on the chest and arms but may develop elsewhere. Women are affected more frequently than men.17 The clinical lesion is not specific, consisting of an erythematous papule or plaque. The clinical impression of basal cell carcinoma is common. Lichenoid actinic keratosis occurs mostly in actinically damaged skin as an erythematous scaling patch or plaque. HISTOPATHOLOGIC FEATURES A lichenoid keratosis may greatly resemble lichen planus.13 As in lichenoid drug eruption, the presence of parakeratosis and middermal inflammation is a subtle clue to help in the differentiation. Because solar lentingines may evolve into lichenoid keratoses, the epidermis of a lichenoid keratosis may show changes of solar lentigo with elongated rete ridges and basilar hypermelanosis. Atrophic, bullous, lupus erythematosus-like, and atypical variants have been described.18 The infiltrating lymphocytes in benign lichenoid keratosis are predominantly CD8+, in contrast to lichen planus.19,20 A lichenoid actinic keratosis should possess the epidermal characteristics of the usual actinic keratosis along with a moderately dense band of lymphocytes in the upper dermis and overlying interface change. In some instances reactive maturational disturbance of the epidermis in lichenoid keratosis may mimic a lichenoid actinic keratosis. DIFFERENTIAL DIAGNOSIS The distinction of lichenoid keratosis from lichen planus and lichenoid drug eruption often relies in large measure on accompanying clinical history (see differential diagnosis of lichen planus). In lichenoid keratosis, the density of the infiltrate and pattern of

epidermal alteration are often not as fully evolved as in lichen planus, but the similarities frequently are striking. It is important to scan the epidermis and dermis for melanocytic proliferation and features of an inflamed or regressing melanocytic nevus or melanoma because the inflammation in such nevi or melanoma may assume an interface pattern and may partially obscure the tumor. Any suspiscion for regressing melanoma should prompt consideration of step sections in an effort to clearly identify residual melanoma. If clear epidermal features of seborrheic keratosis are observed, yet underlying inflammation is present in an interface pattern, the diagnosis of inflamed seborrheic keratosis is preferable because a true lichenoid keratosis bears greater resemblance to lichen planus in its epidermal findings.

VACUOLAR INTERFACE DERMATITIS Compared with lichen planus, the diseases considered under this heading generally display less intense inflammation without the dense, bandlike pattern. Interface change, especially necrosis of keratinocytes, is prominent relative to the degree of inflammation, and this difference, along with the absence of epidermal changes characteristic of lichen planus, helps to distinguish between diseases in these groups.

Erythema Multiforme CLINICAL FEATURES Clinical and histologic subtypes of eruptions identified as erythema multiforme are likely to exist, and the description of target lesions oversimplifies the range of clinical findings.21,22 Erythema multiforme exhibits a fairly nonspecific histologic pattern, hence the wide clinical spectrum. The classic target lesion consists of at least three zones of color change: a peripheral rim of erythema with an inner rim of relative pallor and a central erythematous macule. This concentric pattern imparts a “bull’s eye appearance”(Fig. 3-7A). Variation from this pattern is described with erythematous patches, some with a dusky, violaceous center, but no distinct target appearance. Blisters, when present, form centrally in most cases, but a peripheral pattern also may occur. The distribution of erythema multiforme is frequently acral, with concentration on the palms and soles, but widespread lesions occur commonly.

A

B

The disease is self-limited but often recurrent. Involvement of mucosal and conjunctival surfaces occurs and, if extensive, leads to classification of the disease as “major” (possibly synonymous with the term Stevens-Johnson syndrome) versus the “minor” form with less severe extracutaneous disease. Universally accepted criteria distinguishing major from minor erythema multiforme and major erythema multiforme from toxic epidermal necrolysis do not exist. The most common causes of erythema multiforme include herpes simplex virus infection, medications, and other infectious agents, especially Mycoplasma pneumoniae.23 Typical target lesions were associated more frequently with herpes simplex virus infection and “atypical” lesions with drug etiology in one study.23 The pathophysiology of erythema multiforme is likely one of cytotoxic cellmediated immunity (type IV immune reaction). The relative roles of autoimmune triggers, actual presence of virus in clinical lesions,24 and genetic susceptibility are unclear. In vitro, herpes virus-infected peripheral blood mononuclear cells upregulate ICAM-1 (CD54) and major histocompatability (MHC) class I molecules on dermal microvascular endothelial cells with increased binding avidity.25 HISTOPATHOLOGICAL FEATURES At low magnification, there is a perivascular infiltrate of lymphocytes with some extension between collagen bundles, but a bandlike infiltrate is not observed (Fig. 3-7). Eosinophils are observed in drug-associated cases but should not be the predominant infiltrating leukocyte. In herpes-associated erythema multiforme eosinophils are typically absent. The papillary dermis is often edematous with dilated capillaries. Subepidermal edema may be marked in

some instances, leading to subepidermal blisters. Exocytosis and spongiosis are evident, and variable degrees of epidermal necrosis may be observed. At higher magnification, many elements of interface dermatitis are noted (Fig. 3-8). Necrotic keratinocytes generally are present at all epidermal levels, including the stratum corneum, and may be solitary or grouped. The number of necrotic keratinocytes is variable, depending on the age of the lesion and the lesional site selected for sampling. In early lesions, the stratum corneum will retain its basketweave appearance. One of the characteristic hallmarks is direct lymphocyte satellitosis around necrotic keratinocytes.

Samples from early lesions and from the periphery of established lesions show less keratinocyte necrosis than tissue from the center of fully evolved targets. As the number of necrotic keratinocytes increases, so do the number and size of basal vacuoles. Corresponding to the clinical appearance of blisters are the histologic findings of confluent (or nearly confluent) keratinocyte necrosis and basal vacuolization leading to separation of the epidermis from the dermis. The relative contribution of lymphocytic infiltrate and interface change to the histopathology in a given specimen is quite variable and may relate to underlying cause. For example, drug-induced

 FIGURE 3-8 Erythema multiforme. High magnification shows basal layer vacuolization and scattered necrotic keratinocytes.

CHAPTER 3 ■ INTERFACE DERMATITIS

 FIGURE 3-7 Erythema multiforme. (A) Classic target lesions consist of at least three zones of color change: a peripheral rim of erythema with an inner rim of relative pallor and a central erythematous macule. This concentric pattern imparts a “bull’s eye appearance.” (B) This lesion exhibits an acute interface dermatitis with basal layer vacuolization, subepidermal edema, and a predominantly lymphocytic infiltrate in the superficial dermis.

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erythema multiforme may be associated with a greater number of eosinophils and more pronounced keratinocyte injury and relative lack of dermal perivascular inflammation. In contrast, in herpes simplex-associated erythema multiforme the degree of epithelial injury may be less. There is greater perivascular inflammation and a relative lack of eosinophils.22 Immunophenotypic analysis fails to clearly identify a specific effector lymphocyte population. CD4+ and CD8+ T lymphocytes as well as natural killer (NK) cells are reported. Autoantibodies to desmoplakin I and II may play a role in erythema multiforme major.26 Overexpression of Fas antigen in keratinocytes may be important to the pathogenesis of druginduced erythema multiforme.27 Increased soluble Fas ligand has been observed in the serum and epidemis of herpes simplex virus-induced erythema multiforme.28 DIFFERENTIAL DIAGNOSIS The differential diagnosis of erythema multiforme includes toxic epidermal necrolysis, fixed drug eruption, graft-versus-host reaction, viral exanthem, pityriasis lichenoides, and connective tissue disease (Table 3-2). The relationship between erythema multiforme and toxic epidermal necrolysis is controversial. Some authors consider erythema multiforme and toxic epidermal necrolysis to be distinct entities, whereas others maintain that they are part of the same disease continuum. In general,

typical toxic epidermal necrolysis shows full-thickness necrosis of the epidermis with a scant inflammatory cell infiltrate, although areas of classic erythema multiforme–like interface dermatitis can be seen in some cases. In comparison, erythema multiforme shows less epidermal necrosis (except centrally in a given lesion), usually with single and occasionally clumped necrotic keratinocytes and a denser infiltrate. There are interposed zones of completely viable epidermis. The histologic changes in both disorders constitute a spectrum, and in some instances, discrimination between the two diseases is exceedingly difficult in the absence of clinical information. Superficial samples from central portions of lesions of fixed drug eruption also may strongly resemble erythema multiforme. The presence of a more polymorphous and deep inflammatory cell infiltrate typifies fixed drug eruption. Melanophages accumulate progressively in the upper dermis in both conditions but are somewhat more numerous in a fixed drug eruption. In addition, eosinophils and neutrophils, including foci of intraepidermal eosinophilic spongiosis, are more common in fixed drug eruption. A final discriminating feature is one of chronic epidermal changes including benign epidermal hyperplasia with hyperkeratosis and hypergranulosis. Histologic differentiation of an acute graft-versus-host reaction from erythema multiforme is generally unnecessary

Table 3-2 Comparison of Erythema Multiforme and Toxic Epidermal Necrolysis ERYTHEMA MULTIFORME

TOXIC EPIDERMAL NECROLYSIS

Clinical Features Erythematous patches with dusky centers Target lesions Bullae and erosions Mucosal and conjunctival involvement

Diffuse erythematous patches with diffuse, full-thickness epidermal denudation Mucosal and conjunctival involvement

Histopathologic Features Upper dermal interstitial infiltrate of lymphocytes Basal vacuolization Single and clusters of necrotic keratinocytes Full-thickness epidermal necrosis possible

Toxic Epidermal Necrolysis Little or no inflammation Vacuolar interface dermatitis Full-thickness epidermal necrosis typical Scattered necrotic keratinocytes at periphery

Differential Diagnosis

42

Toxic epidermal necrolysis Fixed drug eruption Graft-versus-host reaction Viral exanthem Pityriasis lichenoides

because these disorders are clinically distinct; the histopathology is quite similar, although a graft-versus-host reaction generally contains fewer lymphocytes and necrotic keratinocytes. Nonspecific viral exanthems may greatly resemble erythema multiforme. The presence of specific viral cytopathic effects, such as multinucleated keratinocytes in herpesvirus infections, allows more specific diagnosis. Erythema multiforme lacks significant inflammation around the deep vascular plexus and around adnexal epithelium, aiding in the differentiation from pityriasis lichenoides et varioliformis acuta (PLEVA) and lupus erythematosus. Erythema multiforme also usually does not exhibit parakeratosis-containing granulocytes, as is typically observed in pityriasis lichenoides. Tissue from pityriasis lichenoides chronica (PLC) typically displays denser upper dermal inflammation and hemorrhage in the dermal papillae with extension of erythrocytes into the epidermis. A haphazard epidermotropic pattern of lymphocyte migration into the epidermis with some degree of lymphoid atypia, including cells with a cerebriform appearance, is seen in the classic lesion of pityriasis lichenoides. Features favoring connective tissue disease over erythema multiforme include hyperkeratosis, follicular plugging, epidermal atrophy, and increased dermal mucin. Correlation with clinical findings is often necessary. Other miscellaneous conditions requiring differentiation from erythema multiforme include coma bulla, in which variable necrosis of eccrine glandular epithelium occurs in association with overlying epidermal keratinocyte necrosis and sparse inflammation. Additionally, many specimens of paraneoplastic pemphigus will only display features of interface dermatitis and will strongly resemble erythema multiforme; tissue from paraneoplastic pemphigus generally is more heavily inflamed.

Erythema multiforme Fixed drug eruption

CLINICAL FEATURES Toxic epidermal necrolysis typically presents as diffuse erythema, becoming dusky over time. The patient often complains of painful skin. Erythema and injection of mucosal surfaces and conjunctivae are common early. As the disease worsens, the eruption becomes generalized, blistering develops, and mucosal surfaces ulcerate. The blisters are occasionally discrete and flaccid, but sheets of sloughing skin, leaving a glistening, occasionally bleeding base, is a common presentation. Toxic epidermal necrolysis is reported in patients with

HISTOPATHOLOGIC FEATURES The essential features include substantial or fullthickness necrosis of the epidermis with little or no inflammation (Figs. 3-9 and 310; see also Table 3-2). A pattern of single-cell necrosis may occur at the periphery of lesional skin. Mild inflammation around the eccrine apparatus is noted, with necrosis of distal elements of the duct a common finding.35 Sparse numbers of eosinophils might be present. Pathologists often are called on to interpret frozen sections from the blister roof in order to obtain rapid laboratory support for the clinical impression. These sections should reveal full-thickness necrosis of epidermis with occasional evidence of individual keratinocyte necrosis, often in aggregates. DIFFERENTIAL DIAGNOSIS The final diagnosis of toxic epidermal necrolysis is made based on clinical examination, with consideration given to erythema multiforme and fixed drug eruption based on histopathology. Specimens

 FIGURE 3-9 Toxic epidermal necrolysis. This lesion shows dermal-epidermal separation, necrosis of the overlying epidermis, and almost no inflammation in the dermis.

CHAPTER 3 ■ INTERFACE DERMATITIS

AIDS, and HIV-1 may be detected in blister fluid. The patient is generally systemically ill. Widespread denudation of the epidermis results in significant risk of sepsis, fluid and electrolyte derangement, and hemodynamic instability. Despite aggressive supportive measures, many patients die. Most cases of toxic epidermal necrolysis are caused by drugs,29 and there is evidence that an inability to detoxify certain drugs is a predisposing factor in the development of toxic epidermal necrolysis.30 Moreover, drug-specific cytotoxicity by T lymphocytes against autologous cells plays a role in mediating tissue damage.31 Compared with serum, blister fluid contains significantly elevated levels of interleukin 6 (IL-6), tumor necrosis factor alpha, and IL-10.32 Apoptosis of keratinocytes appears to be mediated by the interaction of Fas/CD95 with its ligand; a potential beneficial effect from intravenous gammaglobulin (IVIG) may relate to the presence of anti-Fas antibodies in the administered gammaglobulin.33 Serum tumor necrosis factor alpha is also increased. Other soluble mediators such as perforin and granzyme may contribute to the injury. High concentrations of mononuclear cells typically CD8 lymphocytes exhibiting drug-specific MHC classic 1 restricted cytotoxicity toward autologous epidermal keratinocytes have been described. Certain drugs are characteristically implicated and as well there may be an underlying genetic predisposition.34

 FIGURE 3-10 Toxic epidermal necrolysis. There is full-thickness necrosis of the epidermis.

from staphylococcal scalded-skin syndrome reveal subcorneal or granular layer blister formation with minimal necrosis of keratinocytes. Other causes of full-thickness epidermal necrosis include environmental trauma, such as excoriation or thermal injury, and application of a caustic substance to the epidermis (acid). Such injury creates a picture of uniform keratinocyte necrosis without individual cell death. True vasculitis may produce sufficient

ischemic damage to the epidermis to cause full-thickness epidermal necrosis. Toxic epidermal necrolysis lacks vessel destruction as an integral part of its histopathology.

Fixed Drug Eruption CLINICAL FEATURES (See Chap. 12) A fixed drug eruption consists of variable number of well-defined erythematous to violaceous edematous plaques with central

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duskiness and bulla formation. These plaques often recur in the same anatomic site on second ingestion of the causative drug. New plaques may develop on reexposure. As the inflammatory stage resolves, hyperpigmentation, often quite intense, ensues. The plaques may arise at any site but frequently occur on the genitalia and other acral locations. Barbiturates, phenolphthalein, tetracyclines, sulfonamides, and nonsteroidal anti-inflammatory agents are implicated most commonly. Since many of these medications are compounded in overthe-counter formulations, a detailed history of drug ingestion is necessary. HISTOPATHOLOGIC FEATURES All elements of interface dermatitis are evident in a fixed drug eruption. As with erythema multiforme, the degree of epidermal damage varies with the site of sampling within the individual lesion—full-thickness epidermal necrosis may occur in the central bullous zone. Adequate sampling will allow inspection of the reticular dermis, where a moderately intense superficial and deep perivascular and interstitial inflammatory cell infiltrate is generally seen. The composition of this infiltrate is variable. A superficial and deep perivascular lymphocytic infiltrate is common, but inflammation is often polymorphous with lymphocytes, eosinophils, and neutrophils. Neutrophils and eosinophils may predominate, and some karyorrhexis may be evident. Foci of eosinophilic spongiosis may be observed. Chronic epidermal changes are observed including hyperplasia, hyperkeratosis, and hypergranulosis. No vasculitis is seen (Fig. 3-11). Samples from early lesions will display few melanophages in the upper dermis. Over time and with continued damage to the basilar epidermis, melanophages accumulate progressively in the papillary and upper reticular dermis (Figs. 12-5 and 12-6). Specimens from late stages of a fixed drug eruption may only contain melanophages.

DIFFERENTIAL DIAGNOSIS In comparison with erythema multiforme and toxic epidermal necrolysis, fixed drug eruption displays heavier and more polymorphous inflammation. Involvement of the deep vascular plexus also helps distinguish these entities. It is difficult to make confident distinctions based on the degree of melanophage accumulation. While numerous melanophages

44

 FIGURE 3-11 Fixed drug eruption. Interface dermatitis and a superficial and deep perivascular lymphocytic infiltrate.

typify the fixed drug eruption, stage of the lesion sampled and constitutive differences among individuals make this finding a variable component of any interface dermatitis.

Interface Dermatitis of HIV Infection CLINICAL FEATURES Variably distributed but often widespread erythematous patches and plaques characterize this incompletely understood cutaneous eruption associated with HIV-1 infection. The lesions become violaceous over time and result in hyperpigmentation. This hyperpigmentation often involves the face and is of significant cosmetic concern. The eruption is accompanied by pruritus and frequently assumes a photodistribution. The precise cause of the interface dermatitis associated with HIV infection is unknown but may relate to medications, many of which are capable of photosensitization.36 HISTOPATHOLOGIC FEATURES The principal features include basal layer vacuolization, occasional necrotic keratinocytes, and a superficial perivascular and interstitial predominantly lymphocytic infiltrate. The infiltrate may involve the deeper reticular dermis and often is polymorphous with admixed histiocytes, eosinophils, neutrophils, and plasma cells. Vasculitis is usually absent; melanophages may accumulate progressively in the upper dermis.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes true lichenoid drug eruption, infectious diseases (including viruses), and connective tissue disease. Given adequate clinical information, this combination of findings is reasonably distinct. The occasional presence of plasma cells raises the possibility of syphilis. Cutaneous inflammatory cell infiltrates in the HIV-1–infected person are often polymorphous, making correlation with clinical impression vital for the final diagnosis.

Acute Graft-versus-Host Disease CLINICAL FEATURES Erythematous macules and patches usually develop within the first month after marrow transplant as a manifestation of acute disease. The skin is the earliest and most commonly involved organ in graft-versus-host disease (GVHD), making accurate interpretation of skin biopsy specimens important in patient management. The erythematous patches may remain localized, often acrally, or may generalize to cause erythroderma. Increasing severity is manifested by the formation of blisters and a clinical picture of toxic epidermal necrolysis. Reliable criteria for distinction between a blistering acute cutaneous graft-versushost reaction (GVHR) and toxic epidermal necrolysis do not exist. The clinical features of the acute cutaneous GVHR are similar after allogeneic and autologous marrow transplants, although the clinical severity is greater in the former setting. It is imperative that

 FIGURE 3-12 Acute graft-versus-host reaction. Scanning magnification shows a relatively subtle interface dermatitis. There is a relatively sparse lymphocytic infiltrate in the dermis.

Confluence of the basal vacuoles and separation of epidermis from dermis define grades 3 and 4, respectively. Follicular epithelium is similarly involved. This cytotoxic folliculitis is the earliest manifestation in acute cutaneous GVHR, and it is advisable to study many tissue profiles from a given sample in search of this finding. Loss of polarity of keratinocytes resulting in disordered maturation of the epidermis from small cuboidal keratinocytes

to flattened squamous epithelial cells, is attributable to antineoplastic chemotherapy effect because these drugs disrupt the keratinocyte cell cycle. Individual keratinocyte necrosis accompanies this change, and the diagnosis of a GVHR is best made in unaffected portions of the epidermis, or not at all, if this change is diffusely present. Similarly, within the first 3 weeks after marrow transplant, increased numbers of necrotic keratinocytes are

CHAPTER 3 ■ INTERFACE DERMATITIS

the pathologist be aware of immunologic manipulation of autologous marrow transplants, which results in higher incidences and greater severity of cutaneous disease than in unmanipulated scenarios. For example, administration of moderate doses of cyclosporine increases the incidence and severity of cutaneous eruptions, presumably by promoting autoreactive T-cell clones in the peripheral circulation. This autoimmunity can be enhanced by the addition of interferon-γ, resulting in erythroderma after autologous marrow transplantation, an otherwise uncommon event.37 Accurate identification of histopathologic changes compatible with a GVHR is vital for determining the outcome of clinical trials in the field of autologous marrow transplantation. Apposition of a lymphocyte to a necrotic keratinocyte may be observed in the epidermis, consistent with “satellite cell necrosis.” Despite great effort to identify the effector cell responsible for a GVHR, no clear cell population emerges. Epidermal damage mediated by CD8+ T cells is a widely held concept that lacks mechanistic confirmation. To what extent CD4+ T cells and NK cells play a role is unclear. It is unlikely that one specific lymphocyte population acts as the sole effector cell. The mechanism of cytotoxicity is also unclear. Cytokines elaborated by infiltrating lymphocytes may play a role, as may molecules directly damaging cell membranes, such as perforin. HISTOPATHOLOGIC FEATURES A grading scheme exists (Table 3-3) by which all specimens taken for the diagnosis of acute GVHR may be classified.38 The minimum criteria to establish the diagnosis are codified as grade 2, namely, basal vacuolization, keratinocyte necrosis (at least four necrotic keratinocytes per linear millimeter of epidermis), and a lymphocytic infiltrate in the upper dermis with variable exocytosis39,40 (Figs. 3-12 and 3-13).

Table 3-3 Acute Cutaneous Graft-versus Host Reaction Grade 0 No pathologic change or diagnosis unrelated to GVHR Grade 1 Basal vacuolization Grade 2 Basal vacuolization, necrotic keratinocytes, dermal inflammation Grade 3 Confluence of basal vacuoles Grade 4 Separation of epidermis from dermis

 FIGURE 3-13 Acute graft-versus-host reaction. The epidermis shows some disturbance in the maturation of keratinocytes, slight spongiosis, vacuolization of the basal layer, and a relatively scant superficial perivascular lymphocytic infiltrate.

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referable to ionizing radiation, making quantification helpful41,42. The matter is made simpler by the requirement for significant dermal inflammation because neither chemotherapy artifact nor acute radiation change is accompanied by large numbers of lymphocytes in the dermis. DIFFERENTIAL DIAGNOSIS The diagnostic specificity of the interface dermatitis recognized as the acute cutaneous GVHR is debated (Table 3-4). The effect of potentially confounding variables such as prior marrow ablative chemotherapy and ionizing radiation must be kept in mind when interpreting these skin biopsy specimens. Neither preparative regimen induces significant cutaneous inflammation, whereas inflammation is necessary for the diagnosis of a GVHR. Similarity to erythema multiforme is great, but clinically, the diffuse erythema of a GVHR is rarely confused with the more discrete patches and plaques of erythema multiforme. The development of blisters makes clinical and histologic distinction of a GVHR from toxic epidermal necrolysis nearly impossible—concomitant development of voluminous watery diarrhea and elevated liver transaminase values typify GVHD and are more helpful than histologic examination of the skin. Samples containing grade 1 changes may require further tissue acquisition over time or may reflect the eruption of lymphocyte recovery, not a true GVHR.

Early after marrow infusion, samples from cutaneous eruptions may display eosinophils in the upper dermis. The presence of eosinophils generally is not compatible with the diagnosis of a GVHR and often is interpreted as drug hypersensitivity. This situation requires caution because subsequent marrow engraftment may lead to a switch in histologic findings with a clear diagnosis of GVHR and explosive GVHD, whereas meanwhile the cutaneous eruption has persisted largely unchanged.

Chronic Graft-versus-Host Disease CLINICAL FEATURES Chronic GVHD is divided into lichenoid and sclerodermoid forms. A lichenoid GVHR resembles lichen planus in that the primary lesion is a relatively small, discrete, erythematous to violaceous flat papule without scale. Oral changes identical to lichen planus also occur and often are the predominant manifestation of the disease. The lichenoid GVHR typically arises 60 days or more after marrow transplantation but may occur earlier or later. The development of acute GVHD predisposes to chronic GVHD, but chronic disease may arise de novo. Development of lichenoid GVHD is associated with a lower incidence of tumor relapse. A sclerodermoid GVHR typically begins 100 days or more after marrow transplantation, but again, the time of onset is variable. Progressive cutaneous

Table 3-4 Acute versus Chronic Graft-versus Host Reaction ACUTE GVHR

CHRONIC GVHR

Clinical Features Variably distributed erythematous patches Acral accentuation Blisters rarely

Discrete erythematous to violaceous papules of variable distribution Lacy white patches on buccal mucosa

Histopathologic Features Upper dermal perivascular and interstitial infiltrate of lymphocytes, often mild Basal vacuolization, keratinocyte necrosis Subepidermal bullae rarely

Denser band of lymphocytes in upper dermis Epidermal features of lichen planus Dermal sclerosis, especially involving superficial dermis, in sclerodermoid variant

Differential Diagnosis Erythema multiforme Toxic epidermal necrolysis Viral exanthema

46

Lichen planus Lichenoid drug eruption Lichenoid keratosis Morphea/scleroderma

sclerosis resembles systemic scleroderma. Fasciitis accompanies the skin changes and is a major cause of morbidity leading to joint contractures. Progressive cutaneous sclerosis leads to ischemia and chronic erosion and ulceration of the skin—particularly the scalp and feet. Alopecia is common. Spontaneous resolution of cutaneous sclerosis with completely normal skin examination may occur. In both forms of chronic GVHD, death is usually due to the accompanying smoldering immunoincompetence that predisposes to frequent infectious complications, including sepsis. HISTOPATHOLOGIC FEATURES The fully evolved picture of a lichenoid GVHR resembles lichen planus (Figs. 3-14 and 3-15; see also Table 3-4). The diagnosis rests on (1) the correct clinical setting and (2) epidermal changes of lichen planus, namely, acanthosis with pointed rete ridges, hypergranulosis, and hyperkeratosis. The infiltrate in a lichenoid GVHR is sparse compared with the typical case of lichen planus. As with acute graft-versus-host disease the interface process can show follicular accentuation (Fig. 3-14B and Fig. 3-14C). Oral changes resemble those of oral lichen planus. In addition, it is not uncommon to see areas of epidermal flattening with loss of the rete ridge pattern along with some component of superficial subepidermal fibroplasia. Samples from the oral mucosa are submitted commonly because this site may be the only manifestation of chronic GVHD. The sclerodermoid reaction is characterized by progressive thickening of collagen bundles with loss of the normal interstices. This progression reportedly begins in the papillary dermis and extends toward the subcutis, in contrast to progressive systemic sclerosis and morphea, in which the collagen alteration proceeds upward from a superficial panniculitis. Full histologic expression of the sclerodermoid GVHR includes a thickened dermis with loss of pilosebaceous apparatus and loss of adipose tissue around eccrine glands, so-called entrapment. Invariably, there is evidence of interface damage as well. While active inflammation is sparse, the epidermal-dermal junction will display basal vacuolization with occasional necrotic keratinocytes and upper dermal melanophages. This finding raises the interesting possibility that an epidermal cytokine mediates the pathologic collagen alteration during and after chronic damage to the interface. Fasciitis is characterized by lymphocytic inflammation and thickening of collagen bundles.43 Myositis also may be observed in these samples.

B

A

CHAPTER 3 ■ INTERFACE DERMATITIS

C  FIGURE 3-14 Chronic graft-versus-host reaction. (A) This lesion shows hyperkeratosis, acanthosis, and a sawtooth pattern reminiscent of lichen planus. However, a bandlike infiltrate typical of lichen planus is not present. (B) In this case of chronic graft-versus-host disease there is prominent follicular involvement. A destructive lichenoid process involves the outer root sheath epithelium with resultant thinning of the follicle. (C) Note the adjacent perifollicular epidermis appears attenuated with hypergranulosis and hyperkeratosis. The basal layer has a squamotized appearance reflecting antecedent epidermal injury.

 FIGURE 3-15 Lichenoid graft-versus-host reaction. This biopsy shows hypergranulosis, slight acanthosis, a sawtooth pattern of the epidermis, and prominent interface dermatitis.

DIFFERENTIAL DIAGNOSIS To what extent the lichenoid chronic GVHR is reliably separable from acute disease is uncertain (Horn, unpublished observations). Both conditions are interface dermatitides, with the main difference residing in the extent to which epidermal change resembles lichen planus. This distinction is important because therapy differs depending on whether the process is called acute or chronic. It is the rare biopsy specimen that fulfills all criteria for the diagnosis of a lichenoid chronic GVHR. Therefore, when uncertain, it is advisable to make a diagnosis of “interface dermatitis consistent with graft-versus-host reaction” and allow the clinician to establish the final diagnosis. The differential diagnosis includes lichen planus and lichenoid drug eruption. As noted earlier, the density of the inflammatory cell infiltrate is relatively less in the lichenoid chronic GVHR. In addition, the epidermis is altered be it in the context of

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hyperplasia or attenuation which is not the case in acute GVHD. A biopsy from lesions of chronic GVHD typically involve much of the entire lateral breadth in contradistinction to the more focal nature of the interface process observed in acute graft-versus-host disease. Provided that an adequate sample was submitted, the diagnosis of sclerodermoid disease generally is not difficult. One pitfall resides in a biopsy of skin that appears normal histologically and which represents normal skin overlying fasciitis. Fascial sampling is rarely necessary because the diagnosis is evident clinically, but it should be requested when appropriate. Other causes of increased fibrosis in the dermis and subcutis should be considered, including morphea, progressive systemic sclerosis, and porphyria.

Lupus Erythematosus and Related Entities The entities discussed here share similarities in pattern of inflammation and/or epidermal atrophy, all in association with interface changes, and thus they bear a resemblance to lupus erythematosus (Table 3-5). The epidermal changes typical of lichen planus combined with the dense band of lymphocytes are not the usual features of this group of disorders. Furthermore, inflammatory infiltrates in the conditions considered in this section tend to display more specific and reproducible distribution within the dermis than erythema multiforme and allied entities. The common theme of interface dermatitis persists.

Lupus Erythematosus

48

CLINICAL FEATURES Cutaneous involvement in lupus erythematosus presents several differing clinical pictures. While photodistribution is common, any form of lupus erythematosus may display generalized distribution of lesions. In acute systemic lupus erythematosus (acute cutaneous lupus erythematosus), diffuse erythematous macules and patches are common, often with alopecia. Little surface change is present, and the eruption is evanescent. Photoaccentuation is common, leading to the malar “butterfly” distribution (Fig. 3-16A). Fully evolved systemic disease is common, and serologic tests reveal positive antinuclear antibodies in high titer and antibodies to double-stranded DNA. Patients with systemic lupus erythematosus rarely develop a blistering eruption. The bullous disorder of lupus erythematosus is discussed in Chap. 8.

Table 3-5 Lupus Erythematosus and Variantsa

Clinical Features Systemic lupus erythematosus Diffuse erythematous macules, atrophy possible In general, sun-exposed skin for all variants Subacute lupus erythematosus Psoriasiform lesions Arcuate or serpiginous plaques Ro/La+ Discoid lupus erythematosus Erythematous plaques with atrophy, scarring, alopecia, and dyspigmentation Histopathologic Features Systemic lupus erythematosus Mild upper dermal perivascular and interstitial infiltrate of lymphocytes Mild epidermal atrophy Dermal mucin Thickened basement membrane Subacute lupus erythematosus Denser lymphocytic infiltrate Periadnexal inflammation possible Dermal mucin Moderate regular acanthosis in psoriasiform variant Discoid lupus erythematosus Hyperkeratosis, follicular plugging Epidermal atrophy Features of vacuolar interface dermatitis (above) with dense perivascular interstitial and periadnexal inflammation Thickened basement membrane Dermal mucinosis Loss of adnexae Differential Diagnosis Systemic lupus erythematosus Dermatomyositis Mixed connective tissue disease Viral exanthem Reticular erythematous mucinosis Subacute lupus erythematosus Dermatomyositis Neonatal lupus erythematosus PLEVA Syphilis Lymphocytic infiltrate of Jessner Figurate erythemas Discoid lupus erythematosus Lichen planus Lichen sclerosus Polymorphous light eruption Chilblains Deep gyrate erythema Pityriasis lichenoides Syphilis a At times, dermatomyositis may resemble any variant of lupus erythematosus.

Subacute cutaneous lupus erythematosus may bear similarity to psoriasis clinically or may manifest as arcuate and serpiginous plaques, typically in a photodistribution. These patients typically have antibodies to Ro and La (SSA and SSB). Discoid (chronic) lupus erythematosus is characterized by varying numbers of lesions, usually erythematous plaques, often with atrophy, scale, and dyspigmentation and usually involving the face and scalp. Systemic disease is rare in patients presenting with discoid lupus erythematosus, although patients with systemic disease may develop discoid lesions. While some patients possess reactive antinuclear antibody titers, no serologic test is reliably positive in this subtype. A hypertrophic (or verrucous) variant exists in which the primary lesions have a verrucous surface. Lupus panniculitis (profundus) is usually associated with discoid lupus erythematosus but may evolve in patients with systemic disease. Lupus panniculitis is discussed in Chap. 11. In neonatal lupus erythematosus, the infant is born with or quickly develops variably distributed erythematous scaling macules and patches. Annular erythema is common. The mother may or may not have an established diagnosis of lupus erythematosus prior to birth, but the large majority will have Ro or La autoantibodies. In most instances, the cutaneous eruption resolves over weeks to months in the child. The major complication of neonatal lupus erythematosus is congenital heart block manifested by bradycardia in about 40% of cases. Heart block and the cutaneous eruption occur independently in neonatal lupus erythematosus, with only occasional patients exhibiting both clinical manifestations. The risk for subsequent connective tissue disease later in the life of the affected child is uncertain. Deposition of immunoreactants (immunoglobulin and complement) in the skin of patients with lupus erythematosus is well described but may be of limited value as a diagnostic aid. A granular deposition pattern is observed for IgG, IgA, and/or IgM along with components of complement activation including C3 and C5b9 along the dermal epidermal junction. The most common form of a positive lupus band test is one where there are prominent deposits of IgM within the basement membrane zone unaccompanied by other immunoglobulins. An important caveat is that IgM in isolation from other immunoglobulins can be seen in other settings including

B

 FIGURE 3-16 Acute lupus erythematosus. (A) In acute systemic lupus erythematosus, diffuse erythematous macules and patches with photoaccentuation and a characteristic malar “butterfly” distribution involving the cheeks are observed as in this photograph. Striking facial edema is present. (B) This lesion exhibits hyperkeratosis, atrophy of the epidermis, homogenization of the papillary dermis near the dermal-epidermal junction, and a mononuclear cell infiltrate in the papillary dermis.

CHAPTER 3 ■ INTERFACE DERMATITIS

A

sun-exposed skin of healthy adults. This pattern occurs in most lesional skin of all subtypes as well as in nonlesional, sun-exposed skin from patients with systemic lupus erythematosus (the lupus band test). In systemic lupus erythematosus patients in whom a positive lupus band test is also observed on nonlesional sun-protected skin there is a significant correlation with active renal disease. Improved serologic tests have largely supplanted the diagnostic utility of direct immunofluorescence testing. HISTOPATHOLOGIC FEATURES There is debate whether the clinical subtypes can be reliably distinguished based on histologic criteria44,45 (Figs. 3-16 through 3-20). Although there is sufficient overlap of histologic features such that confident distinction is difficult, typical histologic patterns are recognized in fully evolved clinical lesions from the various subtypes. The descriptions that follow are intended to characterize these findings according to subtype of disease, realizing that clinical practice-specific diagnoses require correlation with the entire clinical picture and with serologic tests. An interface dermatitis is common to all forms of lupus erythematosus.46

 FIGURE 3-17 Acute lupus erythematosus. Higher magnification shows atrophy of the epidermis, basal layer vacuolization, and eosinophilic homogenization of the papillary dermis near the dermalepidermal junction.

ACUTE SYSTEMIC LUPUS ERYTHEMATOSUS Subtle histologic changes often characterize acute disease. A mild upper dermal perivascular and interstitial infiltrate of lymphocytes is present with little or

no epidermal change, imparting a nonspecific picture. Some degree of basal vacuolization and keratinocyte necrosis is present. Atrophy of the epidermis, edema of the upper dermis, and an

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 50

 FIGURE 3-18 Subacute lupus erythematosus. The epidermis shows hyperkeratosis and a lymphoid infiltrate that is primarily superficial.

increase in mucin in the upper reticular dermis may be observed (see Figs 3-16 and 3-17). In aggregate, these findings allow the diagnosis of lupus erythematosus in the correct clinical setting. The subtle histologic findings often belie the severity of clinical disease; this disparity should be expected. Marked accumulation of mucin throughout the reticular dermis in the absence of significant inflammation may occur in systemic lupus erythematosus (and occasionally skin-limited disease). Mild overlying interface dermatitis is present. This variant is known as tumid lupus erythematosus. Systemic lupus erythematosus is also reported to display elements of granulomatous dermatitis with neutrophils accompanying the mononuclear inflammation.47 Patients with systemic lupus erythematosus may also exhibit cutaneous lesions resembling Kikuchi disease. The characteristic hallmarks are those of striking periadnexal and perivascular infiltrates of serpentine-like mononuclear cells with concomitant leukocytoclasia. Many of the histiocytes contain engulfed nuclear debris. There is typically supervening mucin deposition and an interface dermatitis. The mononuclear cells show a phenotypic profile

 FIGURE 3-19 Discoid lupus erythematosus. This lesion is notable for hyperkeratosis and rather dense lymphoid infiltrates in the dermis.

 FIGURE 3-20 Discoid lupus erythematosus. There is prominent follicular hyperkeratosis and basement membrane thickening.

compatible with a plasmacytoid dendrocyte exhibiting CD4, myxovirus protein, and CD123 positivity.

SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS In contrast to the acute subtype, subacute disease displays more inflammation. A lymphocytic infiltrate is present and primarily surrounds the superficial vascular plexus, with possible extension to deeper dermal levels and the subcutis (see Fig. 3-18). It is not uncommon to see areas of frank lichenoid inflammation although typically with interposed areas of cell-poor interface dermatitis. In general, eosinophils are absent. While lymphocytes extend between collagen bundles in the upper dermis, formation of a dense band of lymphocytes is uncommon. Epidermal interface changes and increased dermal mucin may be observed. The lymphocytic infiltrate extends around pilosebaceous and eccrine epithelium as well but generally is not as dense as in discoid disease. The histopathologic features of neonatal lupus erythematosus resemble those of subacute disease. In the psoriasiform variant, moderate regular acanthosis is present, with a diminished granular layer and parakeratosis, again with interface change at the dermal-epidermal junction. The arcuate form often displays slight epidermal atrophy. Thus, in comparison with acute systemic lupus erythematosus, subacute disease is characterized by a heavier lymphocytic infiltrate with a more distinct superficial perivascular and periadnexal pattern. Subacute cutaneous lupus erythematosus is associated with antibodies

Differential diagnosis Subacute lupus erythematosus shares histologic features with dermatomyositis. Dermatomyositis is generally less heavily inflamed and lacks significant periadnexal inflammation (see Figs. 3-21 and 3-22). Interface dermatitis accompanied by a superficial and deep perivascular lymphocytic infiltrate also characterizes PLEVA and syphilis. Accumulation of mucin and periadnexal patterning of the infiltrate favor the diagnosis of lupus erythematosus. Rarely, mucin deposition may be observed in pityriasis lichenoides. Furthermore, PLEVA and syphilis tend to display heavier exocytosis and more keratinocyte necrosis than any variant of lupus erythematosus. Plasma cells, while typical of syphilis, may occur in lupus erythematosus. Lymphocytic infiltrate of Jessner, a condition of uncertain nosology, is best distinguished from subacute lupus erythematosus by the absence of significant epidermal interface change. Otherwise, the pattern of the lymphocytic infiltrate and increase in mucin greatly resemble subacute lupus erythematosus. Polymorphous light eruption and chilblains are distinguished by the presence of

upper dermal edema with hemorrhage and lack of significant interface dermatitis. Periadnexal inflammation is also not characteristic of either polymorphous light eruption or chilblains. Certain figurate erythemas may mimic the superficial and deep perivascular nature of the infiltrate in subacute lupus erythematosus, but interface changes are absent, and in the case of erythema chronicum migrans, the infiltrate may contain plasma cells and eosinophils. Psoriasis is easily distinguished from the psoriasiform variant of subacute lupus erythematosus by the presence of interface dermatitis and mucin deposition in the latter entity. Occasional photosensitive drug eruptions, such as, those induced by thiazide diuretics and antihistamines, may closely resemble and possibly induce subacute lupus erythematosus. These drug eruptions are discriminated by clinical history and possibly the presence of eosinophils. DISCOID LUPUS ERYTHEMATOSUS Discoid lupus erythematosus is the most common subtype and thus is sampled most frequently. Fully evolved changes include a moderately intense superficial and deep perivascular and interstitial infiltrate of lymphocytes with distinct periadnexal inflammation (Fig. 3-19). The infiltrate extends along the pilosebaceous apparatus, and all elements of interface dermatitis may be found here. Lymphocytes track along eccrine ductal

 FIGURE 3-21 Dermatomyositis. This lesion exhibits atrophy, eosinophilic homogenization of the subjacent papillary dermis, pigment incontinence, and relatively little inflammation.

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Differential diagnosis Distinction between acute systemic lupus erythematosus and dermatomyositis is not possible based solely on histopathology. Mild interface change and scant inflammation may occur in viral exanthems and phototoxic reactions. The observation of increased dermal mucin narrows the focus to connective tissue disease. Tumid forms of lupus erythematosus must be distinguished from reticular erythematous mucinosis, myxedema associated with the treatment of hyperthyroidism, and localized mucinosis. Reticular erythematous mucinosis has both mucin and mononuclear infiltrates in common with lupus erythematosus but lacks interface dermatitis and evidence of a systemic disease. The mucin accumulation in papular mucinosis and scleromyxedema is accompanied by a concomitant increase in fibroblasts; this cellular proliferation is absent in lupus erythematosus. These conditions lack significant interface dermatitis.

directed against Ro/La, SSA/SSB epitopes. Exposure of keratinocytes in tissue culture to ultraviolet B (UVB) radiation results in enhanced expression of these antigens, possibly explaining the photosensitivity in this subtype.48

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A

B

C  FIGURE 3-22 Dermatomyositis. (A and B) The basement membrane zones of A and B). In these two biopsies of dermatomyositis, the vessels of the superficial vascular plexus exhibit ectasia and endothelial the vessels have a thickened appearance, reflecting the sequelae of prior episodes of immunebased microvascular injury. (C) The presumptive basis of the vascular injury in dermatomyositis is one related to antiendothelial cell antibodies. The image is an indirect immunofluorescent assay using human umbilical vein endothelial cells as substrate. A positive reaction following incubation of the patient’s serum tagged with a fluoresceinated human anti-IgG antibody.

52

epithelium and surround glandular epithelium as well. Significant keratinocyte necrosis in eccrine ductal and glandular epithelium generally is absent. Aggregates of lymphoid cells may be sufficiently dense to resemble cutaneous lymphoid hyperplasia, including foci of germinal center formation. Closer inspection reveals the interface nature of the inflammation. Over time, destruction of follicular epithelium ensues, leading to loss of follicles. As a primary manifestation in the scalp, this process leads to the scarring alopecia associated with lupus erythematosus. The perifollicular inflammation primarily targets sebaceous epithelium and follicular epithelium above the entry of sebaceous glands. It is interesting to note that the same pattern is observed in lichen planopilaris and that both lichen planopilaris and lupus erythematosus result in scarring alopecias primarily due to an inflammation directed against the pilosebaceous apparatus. To what extent damage to the follicular bulge and its stem cell population explains this observation is uncertain. Interface change in lupus erythematosus is characterized by basal vacuolization and exocytosis with necrosis of keratinocytes but at lower levels than lichen planus and erythema multiforme. Additional epidermal changes are variable. While atrophy of the epidermis is typical in combination with the interface change, acanthosis also may develop, or the epidermal thickness may be normal. When present, atrophy may be striking, with only two to three layers of keratinocytes evident. Ulceration may develop with crust formation, underlying granulation tissue, and ultimately, dermal fibrosis. With atrophy, orthohyperkeratosis is frequently present, forming a sharp contrast to the thinned stratum spinosum. The hypertrophic variant displays irregular acanthosis with papillomatosis and orthohyperkeratosis; interface change is evident. However, in the hypertropic variants small zones of epidermal attenuation is common. Superficial specimens from the hypertrophic subtype may be mistaken for keratoacanthoma or squamous cell carcinoma.49 Rarely, squamous cell carcinoma arises in long-standing discoid lupus erythematosus. An additional finding at the dermal-epidermal junction is thickening of the basement membrane, seen as a somewhat refractile eosinophilic band hugging basal keratinocytes. Periodic acid–Schiff (PAS) stain highlights this finding. Another variable finding typical of the fully evolved discoid lesion is dilated and keratin-filled epidermal

Differential diagnosis The differential diagnosis includes dermatomyositis, lichen planus, lichen sclerosus, polymorphous light eruption, chilblains, deep gyrate erythemas, pityriasis lichenoides, certain viral exanthems, drug eruption, and syphilis. The fully evolved picture of discoid lupus erythematosus is diagnostic. Dermatomyositis lacks heavy inflammation and significant periadnexal patterning, but in rare instances may greatly resemble discoid lupus erythematosus. As mentioned, the occasional case of lupus erythematosus may contain sufficient lymphoid aggregation to warrant consideration of lymphocytoma. Hypertrophic lupus erythematosus is distinguished from hypertrophic lichen planus by basement membrane thickening, deep dermal and periadnexal inflammation, and dermal mucin deposition.

Dermatomyositis CLINICAL FEATURES Dermatomyositis is a syndrome consisting of variably distributed erythematous macules and plaques with photoaccentuation,50 inflammation of skeletal muscle, and malignant neoplasms.51 Dermatomyositis in association with Lyme disease has been reported.52 The cutaneous manifestations

vary in terms of extent and location, but the typical presentation consists of erythematous infiltrated plaques usually on the face but possibly generalized. The location of the erythema on the face is often periorbital, assuming a violaceous hue, the so-called heliotrope. Atrophic papules with scale on the knuckles are characteristic and are known as Gottron papules. Poikiloderma as a manifestation of dermatomyositis is considered below. Myositis may accompany the skin changes or may precede or follow them. Severe proximal muscle weakness may ensue, and determination of serum levels of muscle-derived enzymes and degradation products aids in diagnosis. Muscle biopsy may be necessary to establish the diagnosis. An electromyogram also may be a useful adjunct. On occasion, cutaneous findings or muscle findings may be absent, prompting the terms polymyositis and dermatomyositis sine myositis, respectively.53 A careful search for visceral malignant neoplasms is necessary if they are not apparent at the time of diagnosis. The neoplasm may predate the onset of the symptoms or may be concomitant or follow the diagnosis of dermatomyositis. A wide range of incidence figures exists for the association between dermatomyositis and malignant neoplasms. The relative risk was 2.4 in men and 3.4 in women in one study.54 While ovarian cancer is overrepresented in comparison with the general population, the proportion of other malignant neoplasms parallels that of age-matched controls. Dermatomyositis occurs in children, unassociated with malignant neoplasms. Vasculitis and severe calcinosis cutis often accompany the juvenile form. Drug-induced dermatomyositis, which has a similar histopathologic appearance to classic dermatomyositis, has been reported in the literature.55 HISTOPATHOLOGIC FEATURES Dermatomyositis is characterized by a variable but often mild degree of lymphocytic inflammation in the upper dermis with overlying epidermal atrophy, interface change, and increased mucin deposition in the dermis, largely indistinguishable from lupus erythematosus (Figs. 3-21 and 3-22). This increased ground substance may be more evident than the inflammatory changes. Massive dermal edema may develop in the heliotrope region. Inflammation around the deep vascular plexus and adnexa may occur. The central portion of a Gottron papule displays atrophy and superficial dermal inflammation

with overlying interface change.56 A septal and lobular panniculitis with lymphoid infiltrates has been described (see Chap. 11). Immunoreactants, including complement components, are identified in lesional skin on direct immunofluorescence testing.57 In particular, vascular deposition of C5b9 appears to confer high sensitivity and specificity for dermatomyositis.58 It has been shown that microvascular injury likely attributable to antiendothelial cell antibodies may play an important role in the pathogenesis of the cutaneous lesions of dermatomyositis. Endothelial cell injury, vascular ectasia, and vascular fibrin deposition were observed in the superficial vascular plexus more frequently in dermatomyositis than in cases of lupus erythematosus59 (Figs.3-22A, 3-22B , and 3-22C). Dermal fibrosis has also been noted in dermatomyositis in the absence of clinical features of scleroderma, correlating with a more severe disease course and possibly implicating TGF-β in the pathogenesis of the sclerosis.60 DIFFERENTIAL DIAGNOSIS As discussed earlier, confident distinction of dermatomyositis from acute lupus erythematosus may be difficult; however the vascular changes along with the immunofluorescent profile may be helpful discriminating features.

CHAPTER 3 ■ INTERFACE DERMATITIS

invaginations associated with follicular orifices. These follicular “plugs” are often identified macroscopically. The associated follicular epithelium is usually thinned, and the dilatation generally extends to the level of the sebaceous gland entry in correctly oriented specimens (Fig. 3-20). Increased dermal mucin generally is present to a variable degree. The dermal vessels may display swelling of endothelium, but true vasculitis usually is absent. If subcutis is included in the specimen, panniculitis is encountered frequently with mixed septal and lobular inflammation composed of lymphocytes, plasma cells, and histiocytes, including lipophages. When panniculitis is the primary histologic manifestation, a specific diagnosis of lupus erythematosus may be difficult to establish without adequate clinical information, especially if the characteristic findings of lupus profundus are not observed. The latter is discussed in detail elsewhere. In brief, there is a necrotizing and eosinophilic hyalinizing lobular lymphocytic panniculitis with numerous admixed plasma cells and germinal center formation. Thickened collagen bundles and increased eosinophilia of collagen bundles of the lower reticular dermis often accompany the panniculitis. Dystrophic calcification may ensue.

Mixed Connective Tissue Disease While many overlap syndromes are recognized among the connective tissue diseases, mixed connective disease is the most common, consisting of features of systemic lupus erythematosus, scleroderma, polymyositis, and rheumatoid arthritis. Facial erythema, heliotrope, acral telangiectases, and scleroderma are the more common cutaneous manifestations. These patients possess high-titer antinuclear antibodies with antibodies to ribonucleoprotein (RNP) as well. HISTOPATHOLOGIC FEATURES There are certain characteristic findings seen in mixed connective tissue disease. The hallmarks include an interface dermatitis which ranges in quality from areas of lichenoid inflammation to zones of cellpoor interface dermatitis in concert with variable dermal sclerosis (Fig. 3-23). The direct immunofluorescence testing will demonstrate characteristic reactivity of epidermal keratinocytes for IgG and C5b9 along with prominent vascular deposits of C5b9.

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 FIGURE 3-23 Mixed connective tissue diseae. In this biopsy of mixed connective tissue diseae there is both an atrophying interface dermatitis along with a scleroderma like-reaction involving the superficial dermis.

Lichen Sclerosus CLINICAL FEATURES Lichen sclerosus (LS) has protean clinical manifestations ranging from localized disease in the perineum to widespread erythematous plaques. The primary lesion in any site is an erythematous patch or plaque, often with an edematous center. This central zone may display pallor and thus impart a white color. Over time, dermal fibrosis may ensue, resulting in the clinical impression of sclerosis resembling scleroderma; rare lesions of LS blister, often with hemorrhagic contents. Most commonly, LS occurs in the genital skin of women, but men and children are also affected.61 On the penis, LS is termed balanitis xerotica obliterans. There is a reported association between squamous cell carcinoma and chronic LS of the vulva, with the incidence estimated at 3% to 4%. Involved vulvar skin displays a higher expression of p53 in association with increased epidermal cell proliferation.62 In North America, tissue from LS lacks evidence of borrelial infection.63 An association is reported between increased severity of disease and presence of specific IL-1 receptor alleles.64 HISTOPATHOLOGIC FEATURES Histologic alterations parallel the age of the lesion. Early, there is an upper dermal perivascular and interstitial lymphocytic infiltrate immediately below the epidermis. Overlying interface change is evident, and the epidermis may be of normal thickness. A fully evolved lesion displays an interstitial band of lymphocytes in the upper to middle reticular dermis

(Figs. 3-24 and 3-25). The epidermis is usually atrophic with hyperkeratosis and dilated and keratin-filled acrotrichial and acrosyringeal ostia. Melanophages are present in a variably edematous dermis. The nature of connective tissue alteration in LS is variable. Initially, the papillary and upper reticular dermis display edema, imparting a light, airy, and indistinct quality to the collagen

bundles. This zone of alteration lies above the band of lymphocytes, is of variable thickness, and usually contains ectatic vascular channels. The edema may lead to subepidermal bulla formation, often with hemorrhage in the blister cavity. Over time, this wispy, edematous collagen gives place to a more dense, homogeneous, and deeply eosinophilic collagen that continues to overlie the zone of inflammation.65 Evidence exists that abnormal fibrillin, elastin, collagen I, and collagen III contribute to the dermal changes observed in LS.66 Older lesions of LS may no longer contain inflammation, or the band of lymphocytes may localize more deeply within the reticular dermis. There is loss of pilosebaceous units and marked atrophy of the epidermis with numerous upper dermal melanophages. The nature of the collagen alteration is often fibrotic rather than edematous. Overlap of histologic features between LS and morphea occurs and generally consists of a combination of the changes described earlier, as well as collagen alteration consistent with morphea in the deep reticular dermis, including superficial panniculitis and entrapped eccrine coils.67 Given the occasional development of squamous cell carcinoma in genital lichen sclerosus, the presence of epidermal

 FIGURE 3-24 Lichen sclerosus. The lesion shows typical features of lichen sclerosis, hyperkeratosis, epidermal atrophy, prominent homogenization of the papillary dermis, and a subjacent, bandlike lymphoid infiltrate.

atypia, exaggerated acanthosis, and loss of the dermal edematous-sclerotic band should be sought because these features are observed more commonly in the vicinity of an associated carcinoma.68 DIFFERENTIAL DIAGNOSIS Lupus erythematosus may mimic LS, but the characteristic collagen alteration is absent, and periadnexal inflammation is more pronounced in the former disease. Otherwise, the epidermal changes are quite similar. Chronic radiation dermatitis may closely resemble LS with fibrotic alteration of the upper dermal collagen, vascular ectasia, and interface change. Radiation fibroblasts and the thickened, waxy blood vessel walls are absent in LS. The interstitial pattern of inflammation typical of LS is absent in radiation dermatitis. Sufficient overlap of histologic features in LS and morphea make confident distinction difficult on occasion. In general, the predominance of upper dermal collagen alteration in association with interface change and dilated keratin-filled follicular ostia distinguishes LS from the predominantly deep dermal alterations of morphea. Both diagnoses may be rendered in certain samples, usually as “lichen sclerosus-morphea overlap.” The nosology of this entity is unclear.

Acrodermatitis Chronica Atrophicans Acrodermatitis chronica atrophicans occurs mostly commonly in Europe, where an association between this disease and

borrelial infection (Borrelia afzellii subspecies of B burgdorferi) exists.69,70 (See Chap, 20.)

Pityriasis PLEVA and Related Diseases PLEVA serves as the histologic prototype for several diseases also characterized by interface dermatitis. One distinguishing feature of this group of disorders is marked exocytosis of lymphocytes into the epidermis as compared with the diseases described thus far. All other elements of interface dermatitis are present in the fully evolved lesion. The pattern of dermal inflammation typically involves the superficial and deep vascular plexuses with interstitial extension in the upper reticular and papillary dermis. Unlike lupus erythematosus, periadnexal inflammation is not a prominent feature, although inflammation involving vessels in the adventitial dermis, especially of the pilosebaceous apparatus, may be noted. Hemorrhage in the papillary dermis accompanies the inflammation in fully evolved lesions. PITYRIASIS LICHENOIDES ET VARIOLIFORMIS ACUTA Clinical features The primary lesion of PLEVA is an erythematous papule that undergoes central vesiculation, pustulation, erosion, and ulceration, forming a crust. PLEVA is abrupt in onset

Histopathologic features At scanning magnification, a pattern of dermal inflammation is seen that involves the superficial and deep vascular plexuses and includes extension of lymphocytes between collagen bundles in the upper reticular and papillary dermis (Fig. 3-26). The degree of inflammation is variable but usually intense in the fully evolved lesion.74 Extension of lymphocytes into the overlying epidermis typically is marked, leading to the impression of equal numbers of keratinocyte and lymphocyte nuclei in the epidermis. A characteristic finding in PLEVA is a confluent parakeratotic scale usually containing degenerated lymphocytes (Fig. 3-26B). Basal vacuolization and necrosis of keratinocytes are evident. A characteristic finding is the presence of cohesive collections of Langerhans cells with a few admixed lymphocytes localized to the upper layers of the epidermis (Figs. 3-26C and 3-26D). The inflammatory infiltrate is composed of T lymphocytes with a predominant CD3+ and CD8+ phenotype, in contrast to pityriasis lichenoides chronica, in which the inflammatory infiltrate has relatively more CD4+ infiltrating T lymphocytes in the dermis and epidermis than CD8+ T lymphocytes.75,76 Reports of clonal T-cell populations, the presence of cells with atypical nuclear forms, and a diminution in the expression of the pan T-cell markers CD7 and CD62L has led to speculation that this condition like PLC is a form of cutaneous

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 FIGURE 3-25 Lichen sclerosus. Higher magnification shows the homogenous eosinophilic hyalinization of the papillary dermis.

with generalized distribution and clustering of lesions in flexural areas. Fever and malaise may accompany the eruption. The papules may enlarge to form nodules, but most lesions remain less than 1 cm in largest diameter. The papules occur in successive crops, with individual lesions resolving with hyperpigmentation and scarring over several weeks’ time. Systemic symptoms may occur.72 The pattern of scarring is randomly scattered, as are the active lesions, imparting similarity to varicella. New papules appear as older papules resolve, resulting in an often polymorphous clinical appearance. PLEVA typically occurs in children and young adults but may develop at any age. The cause is unknown. An infectious agent has been postulated, but no clear pathogen has been clearly implicated, including herpesviruses.73 If untreated, PLEVA may resolve in several months or persists for years. Since the clinical appearance of PLEVA resembles that of lymphomatoid papulosis, periodic skin biopsy specimens are indicated in persistent cases to confirm the diagnosis.

55

C

B

D

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

E

56

 FIGURE 3-26 Pityriasis lichenoides et varioliformis acuta. (A) The lesion displays confluent parakeratosis, basal layer vacuolization, some exocytosis of lymphoid cells, and a perivascular lymphoid infiltrate in the dermis. (B) Classic changes of pityriasis lichenoides. Note the psoriasiform hyperplasia. There are classic changes of pityriasis lichenoides as defined by a psoriasiform pattern of epithelial hyperplasia and striking migration of lymphocytes to involve all layers of the epidermis with preferential localization of lymphocyte migration within the upper layers of the epidermis. As well the epidermis is surmounted by a leukocyte-imbued scale crust. Extensive red cell extravasation is noted amidst a superficial interstitial and perivascular lymphocytic infiltrate. (C) In pityriasis lichenoides the pattern of lymphocyte migration is epidermotropic. In this particular photomicrograph there is passive migration of lymphocytes and histiocytes into the epidermis with lymphoid forms extending into the upper layers of the epidermis. Note the focal red cell extravasation and overlying parakeratotic scale. (D) One of the characteristic hallmarks of pityriasis lichenoides is the presence of pseudo Pautrier-like microabscesses within the superficial layers of the epidermis. As opposed to a true Pautrier microabscess, the composition is one of small lymphocytes and histiocytes closely aggregated in contradistinction to a true Pautrier microabscess which is composed exclusively of atypical lymphoid forms. (E) In this case of pityriasis lichenoides there is a loss of expression of CD7 amidst the lymphocytes.

Differential diagnosis The differential diagnosis includes drug eruptions, viral exanthems, secondary syphilis, papulonecrotic tuberculid, arthropod bite reactions, polymorphous light eruption, connective tissue disease, and erythema multiforme. Drug eruptions and viral exanthems usually do not exhibit the degree of keratinocyte necrosis, parakeratosis with neutrophils, and degree of inflammation encountered in PLEVA. Drug eruptions generally contain eosinophils. Lesions of PLEVA and PLC do not contain eosinophils. Secondary syphilis may closely mimic the pattern of inflammation seen in PLEVA. The presence of numerous plasma cells suggests the diagnosis of syphilis. Correlation with results of serologic examinations and, possibly, tissue silver stains is indicated. Papulonecrotic tuberculid and occasional necrotic arthropod bite reactions may closely simulate PLEVA. Clinicopathologic correlation is helpful. PLEVA lacks the upper dermal edema characteristic of polymorphous light eruption. Polymorphous light eruption also should not display the degree of interface change typical of PLEVA. Both PLEVA and lupus erythematosus have superficial and deep lymphocytic infiltrates. PLEVA lacks the accompanying changes of follicular plugging, epidermal atrophy, basement membrane thickening, periadnexal

Table 3-6 Pityriasis Lichenoides et Varioliformis Acuta versus Pityriasis Lichenoides Chronica PLEVA

PLC

Clinical Features Abrupt onset of erythematous papules Central vesiculation and ulceration Scarring

More gradual onset of erythematous papules with dusky center

Histopathologic Features Superficial and deep perivascular and intersitial infiltrate of lymphocytes; wedge-shaped Upper dermal hemorrhage Features of interface dermatitis with marked exocytosis Parakeratotic scale with neutrophils Central confluent keratinocyte necrosis

Less inflammation, mostly upper dermal Interface dermatitis and hemorrhage persist

Differential Diagnosis Syphilis Drug eruption Viral exanthem Papulonecrotic tuberculid Arthropod bite reaction Polymorphous light eruption Connective tissue disease Erythema multiforme

inflammation, and increased dermal mucin often seen in lupus erythematosus. In contrast to PLEVA, the inflammatory infiltrate of erythema multiforme usually is restricted to the upper dermis and is less dense. Other features more characteristic of erythema multiforme include upper dermal edema and retention of the basketweave stratum corneum. Distinction of PLEVA from pityriasis lichenoides chronica (Table 3-6) is generally based on the degree of inflammation, with pityriasis lichenoides chronica displaying fewer lymphocytes in general, especially in the deep dermis. The pattern of upper dermal inflammation as well as hemorrhage resembles PLEVA. Vesiculation, confluent epidermal necrosis, and ulceration are uncommon in pityriasis lichenoides chronica. PLEVA lacks a significant number of atypical lymphocytes. Lymphomatoid papulosis is characterized by numerous atypical lymphocytes expressing the CD30 antigen (Reed-Sternberg–related antigen and a marker of “activated lymphocytes”). The occasional case of PLEVA will contain a subset of “activated lymphocytes” that possess larger irregular nuclear contours than that usually observed in most cases of PLEVA. These cells may express CD30, but should represent a clear

Erythema multiforme Syphilis Drug eruption Viral exanthem Lichenoid pigmented purpuric dermatitis Pityriasis rosea

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T-cell lymphoid dyscrasia (Fig. 3-26E).77,78,79 One case of PLEVA is noted with enrichment of T cells bearing the g/d receptor.78 Hemorrhage in the upper dermis is typical of fully evolved lesions. Erythrocytes extend into the epidermis along with lymphocytes. Endothelial cells are plump, partially or entirely occluding vessel lumina. This change has prompted consideration of PLEVA as a “lymphocytic vasculitis.” True vessel destruction, with fibrin deposition and loss of integrity of the vessel wall, generally is not seen, and thus categorization of PLEVA in the spectrum of vasculitis is of questionable validity. Rare cases may display histologic changes of vasculitis and are associated with infarction, resulting in more epidermal and dermal necrosis typical of the ulceronecrotic type of PLEVA. As the lesion ages, the keratinocyte necrosis becomes confluent centrally, leading to vesiculation, ulceration with associated crust formation, and granulation tissue. The inflammation becomes progressively less intense. Resolution of the ulceration leaves dermal fibrosis consistent with a scar. The overlying epidermis may be flattened with variable melanin content.

minority of the overall lymphocyte population. Examination of multiple samples, especially over time, may be necessary to clearly distinguish PLEVA from lymphomatoid papulosis. Clonal populations of T cells have been identified by T-cell receptor gene rearrangement studies in tissue samples of PLEVA.79 PITYRIASIS LICHENOIDES CHRONICA Clinical features PLC is more common than PLEVA. The primary lesion of PLC is an erythematous papule, 3 to 10 mm in diameter, that evolves to form a pinpoint dusky center but rarely displays vesiculation or ulceration. The eruption is widely distributed and chronic. Lesions resolve with dyspigmentation over several weeks, but little or no scarring ensues. The nosology of this entity is uncertain, especially its relationship to PLEVA. Because of the somewhat nonspecific clinical appearance of PLC, diagnosis may be difficult. PLC may evolve from PLEVA but also may arise without an antecedent inflammatory condition. PLC may occur at any age and is especially common in children and adolescents. The cause is unknown; however recent studies have suggested that this condition may represent a distinct form of cutaneous T-cell lymphoid dyscrasia. The basis of this categorization includes

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Secondary Syphilis

58

CLINICAL FEATURES A more comprehensive discussion of syphilis is presented in Chap. 20. Secondary syphilis presents with a wide range of clinical findings but most commonly a papulosquamous eruption of variable distribution. Involvement of the palms and soles is typical. Obtaining a skin biopsy specimen in search of the diagnosis of secondary syphilis is less reliable than serologic testing. However, since the diagnosis is occasionally not suspected clinically and often falls within the clinical differential diagnosis of entities that are separable histologically, the pathologist will be asked to identify cutaneous eruptions of secondary syphilis.

 FIGURE 3-27 Pityriasis lichenoides chronica. This lesion exhibits prominent hyperkeratosis, occasional necrotic keratinocytes, and slight basal layer vacuolization.

the persistent waxing and waning nature of the eruption in the absence of an obvious trigger, lymphoid atypia, phenotypic abnormalities including variable losses of CD7 and CD62L, clonality, and occasional cases progressing to mycosis fungoides, especially in the pediatric setting.80

Histopathologic features In contrast to PLEVA, the features of an interface dermatitis are more subtle in PLC (Fig. 3-27). One observes parakeratotic scale, occasional or rare necrotic keratinocytes, slight basal layer vacuolization, and a predominantly superficial perivascular infiltrate of lymphocytes. As with PLEVA, the degree of exocytosis of lymphocytes can be striking. Hemorrhage around capillaries and venules of the upper dermis occurs with extension of erythrocytes into the epidermis. In typical PLC, aggregation of keratinocyte necrosis, vesiculation, and ulceration are uncommon. PLEVA and PLC may form part of a disease spectrum termed pityriasis lichenoides. This concept allows for overlapping histologic and clinical features and subacute variant of pityriasis lichenoides: pityriasis lichenoides subacuta. The dermal and epidermal infiltrating T lymphocytes are predominantly CD4+ and have been shown to exhibit phenotypic abnormalities and clonality.75,76 Differential diagnosis The distinction of PLC from PLEVA was discussed earlier. Epidermal features of lichen planus are absent in PLC. The degree and pattern of inflammation may resemble erythema multiforme, but significant epidermal

necrosis, especially in greater proportion than the degree of inflammation, should not be observed in PLC. As with PLEVA, consideration of secondary syphilis is warranted in the presence of plasma cells. PLC may be classified among the pityriasiform dermatitides (see Chap. 1), and thus the following entities should be considered in the differential diagnosis: pityriasis rosea, certain drug eruptions, superficial gyrate erythema, subacute spongiotic dermatitis, guttate or eruptive psoriasis, pityriasis rubra pilaris (PRP), and early mycosis fungoides. The distinction of PLC from the later stages of pityriasis rosea can be difficult. In general, pityriasis rosea shows greater spongiosis and less interface change with confluent parakeratosis than PLC. This distinction is also true for superficial gyrate erythema and subacute spongiotic dermatitis. The typical drug eruption will contain eosinophils. PRP may be quite nonspecific but often displays follicular plugging, alternating ortho- and parakeratosis, and little inflammation. Guttate and early psoriasis may show parakeratosis, as is the case with PLC, but often exhibit exocytosis of neutrophils, papillary dermal edema, dilated upper dermal vessels, and no significant interface change. PLC may enter the differential diagnosis of circumscribed hypopigmentation. Consideration of tinea versicolor, vitiligo, leprosy, and mycosis fungoides may be necessary (see Chaps. 15, 19, and 34). Clonal T-cell populations are identified frequently in tissue from PLC.81 Whether PLC represents a form of cutaneous T-cell lymphoma remains unproven.

HISTOPATHOLOGIC FEATURES Any cutaneous infiltrate that contains significant numbers of plasma cells warrants consideration of syphilis. The typical pattern of secondary syphilis is that of an interface dermatitis with a superficial and deep perivascular and to some extent interstitial infiltrate of lymphocytes, including plasma cells.82,83 The absence of plasma cells does not definitively exclude the diagnosis of syphilis. Psoriasiform epidermal hyperplasia with marked exocytosis of lymphocytes is observed commonly. Endothelial cells are enlarged and partially or totally obliterate vessels. In older lesions of secondary syphilis, histiocytes accumulate, often leading to the formation of granulomas. These granulomas generally are not well formed when compared with the granulomas of sarcoidosis; rather, they consist of a variable admixture of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells in a loose and somewhat poorly circumscribed aggregate. DIFFERENTIAL DIAGNOSIS The similarities between secondary syphilis and PLEVA and PLC were noted earlier. Occasional skin biopsies specimens will contain heavy infiltration by plasma cells. Consideration should be given to plasmacytoma, especially if some degree of atypia is observed. Determination of monoclonality by demonstration of lightchain restriction or immunoglobulin gene rearrangement should be sought.

DISEASES CHARACTERIZED BY POIKILODERMA The term poikiloderma does not imply a specific diagnosis. Poikiloderma is a clinical and histologic finding with many causes. Clinically, poikiloderma consists

Poikiloderma of Civatte Poikiloderma of Civatte occurs as patches of wrinkled skin with mottled pigmentation and telangiectases in sun-exposed sites, frequently on the necks of women. Samples from poikiloderma of Civatte show solar elastosis and lack significant inflammation. This form of poikiloderma is poorly understood but most likely is due to chronic sun exposure.

Poikiloderma Congenitale (Rothmund-Thomson Syndrome) Childhood onset of poikiloderma, photosensitivity, osteosarcoma, short stature, juvenile cataracts, skeletal defects, nail dystrophy, and hypogonadism combine to characterize poikiloderma congenitale. The poikilodermatous changes typically are photodistributed and, viewed histologically, lack significant inflammation.84 Rothmund-Thomson syndrome is inherited in an autosomal recessive manner and is associated with mutations in the DNA helicase gene RECQL4.85

Congenital Telangiectatic Erythema (Bloom Syndrome) Facial telangiectasia beginning in infancy or early childhood with photosensitivity and progression to a poikilodermatous appearance characterizes the cutaneous

manifestations of congenital telangiectatic erythema. Skin biopsy specimens reveal interface dermatitis with some features of poikiloderma as noted earlier. Other features include short stature, genomic instability, development of malignant neoplasms, variable immunoglobulin deficiencies, and mutations in the gene-encoding DNA helicase RECQL3.85 Bloom syndrome is inherited in an autosomal recessive manner and is associated with sister-chromatid exchange.86

Dyskeratosis Congenita A retiform erythema with mottled pigmentation is characteristic of dyskeratosis congenita. Recognition of this syndrome is crucial because there is a high incidence of squamous cell carcinoma arising in dysplastic oral and anal mucosal epithelium. The oral changes consist of white plaques that display variable keratinocyte atypia progressing to full-thickness dysplasia and invasive carcinoma. Skin biopsy specimens of the poikiloderma show the typical findings. Additional features of this syndrome include nail dystrophy bone marrow failure, lacrimal duct atresia, and mutation in the gene encoding dyskerin (DKC 1).85,87 Dyskeratosis congenita is inherited in an X-linked recessive manner.85

Poikiloderma Accompanying Dermatomyositis Poikiloderma may represent a prominent clinical finding in patients with dermatomyositis. The poikiloderma generally arises in long-standing plaques of erythema. The histopathology of poikiloderma in the setting of dermatomyositis is often remarkable for other changes typical of the connective tissue disorder, namely, more pronounced interface change and increased dermal mucin deposition.

Poikiloderma Accompanying Mycosis Fungoides Poikiloderma as the primary clinical manifestation of cutaneous T-cell lymphoma is rare. Many observers consider this finding to be an involutionary or regressive phase of the disease process. With any clinical description of poikiloderma, it behooves the pathologist to consider the diagnosis of cutaneous T-cell lymphoma. In addition to the constellation of findings typical of poikiloderma, the diagnosis rests mainly on identification of a band of atypical lymphocytes in the upper dermis with variable epidermotropism including the formation

of Pautrier microabscesses. The epidermal changes typical of fully evolved cutaneous T-cell lymphoma are generally less pronounced in poikilodermatous forms of the disease, an argument for the resolving-lesion theory. Nonetheless, a diagnosis of cutaneous T-cell lymphoma must rest on recognition of a neoplastic T-cell population in the skin regardless of specific pattern or density of the infiltrate (see Chap. 34).

MISCELLANEOUS DISEASES WITH FEATURES OF INTERFACE DERMATITIS Some of the entities considered in this section are covered more extensively elsewhere in this text but display interface change as an integral part of their histopathology. No specific pathophysiology unifies these diseases.

Lichen Nitidus CLINICAL FEATURES Lichen nitidus consists of discrete 1- to 2-mm, skin-colored to minimally erythematous papules of variable distribution and extent but often grouped and located on the genital and acral skin. Lichen nitidus occurs commonly in children and is seen often on the penis. Cases of generalized lichen nitidus have been reported.88,89,90 The disease is self-limited. Overlap with lichen planus occurs, and both conditions may be recognized in a given patient. HISTOPATHOLOGIC FEATURES A discrete interstitial aggregate of mononuclear cells expands one dermal papilla to form the typical lesion of lichen nitidus (Fig. 3-28). This expansion causes the adjacent epidermal rete ridges to bow outward and give the appearance of extension underneath the inflammatory cell aggregate as a collarette (so-called ball-and-claw effect). This discrete anatomic localization corresponds to the clinical picture of pinpoint papules and is distinct from the histopathology of lichen planus.91 The infiltrate filling two adjacent dermal papillae may fuse to form a larger lesion on occasion. Initially, the infiltrate is composed almost entirely of lymphocytes, whereas established lesions exhibit an admixture of lymphocytes and histiocytes with occasional multinucleated giant cells and melanophages. The overlying epidermis is slightly thinned and flattened with basal vacuolization and rare necrotic keratinocytes. Parakeratotic scale often overlies these epidermal changes. Lichen nitidus represents one of the classic

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of patches of skin with variable melanin content, imparting a mottled hyper- and hypopigmented appearance. The epidermis is thin and may be shiny with fine wrinkles. Ectatic papillary dermal vessels are responsible for a faint erythema or distinct telangiectasis. The minimum criteria for the histologic diagnosis of poikiloderma include epidermal atrophy with loss of the normal pattern of rete ridges, variable epidermal melanin content, dilated upper dermal vessels, and melanophages with some element of interface change. Determining hyper- and hypopigmentation in a given skin biopsy specimen generally is not possible unless the clinician includes or identifies skin with normal pigmentation for comparison. Mild papillary dermal fibrosis often accompanies these changes. The degree of inflammation is highly variable and depends, in part, on the stage of evolution of the lesion sampled. This section will discuss entities characterized by poikiloderma. The clinical and pathologic features making these diseases distinctive will be emphasized together because the histopathology alone often is not specific.

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HISTOPATHOLOGIC FEATURES The histopathologic features of lichen striatus are variable. Findings of a lichenoid dermatitis indistinguishable from lichen planus, lichen nitidus, or a combination may occur (Fig. 3-29). Para-keratosis may be seen. Lichen striatus also may present as a spongiotic dermatitis that typically exhibits prominent necrosis of keratinocytes. Another typical feature of lichen striatus is involvement of the eccrine coil by the infiltrate of lymphocytes (Fig 3-30). Occasional cases are reported with involvement of the deep vascular plexus.92

 FIGURE 3-28 Lichen nitidus. There is a circumscribed nodular lymphoid infiltrate filling the papillary dermis. The infiltrate contains some multinucleate giant cells.

idiopathic eruptions associated with a lichenoid and granulomatous form of inflammation.93 DIFFERENTIAL DIAGNOSIS The fully evolved lesion is quite characteristic. Serial sectioning of a sample submitted for the diagnosis of lichen nitidus may be necessary because the diagnostic area may be missed in initial cuts. Some lesions of lichen striatus may resemble lichen nitidus (Table 3-7) but are distinguished by additional features similar to lichen planus, some spongiosis with necrotic keratinocytes, and eccrine coil involvement. The clinical appearance of lichen striatus is as a linear patch.

Lichen Striatus CLINICAL FEATURES Lichen striatus may affect individuals of any age but most commonly occurs in children as a linear array of closely set skin-colored to erythematous papules with little or no scale. Almost any skin site may be affected; however, a common presentation is a progressively lengthening collection of erythematous papules beginning on the proximal portion of an extremity with progressive growth over several months to acral skin, commonly a digit. No associated systemic abnormalities occur. As mysteriously as lichen striatus begins, it involutes, leaving variable dyspigmentation.

Table 3-7 Lichen Nitidus versus Lichen Striatus LICHEN NITIDUS

LICHEN STRIATUS

Clinical Features 1-2-mm flesh-colored papules, often genital and acral

Grouped erythematous papules in linear array

Histopathologic Features Discrete aggregate of lymphocytes, histiocytes, and occasional multinucleated giant cells expanding a dermal papilla Epidermal collarette

Variable findings resembling lichen planus with deep perivascular and perieccrine inflammation at times May resemble lichen nitidus May display spongiosis and dyskeratosis

Differential Diagnosis

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Lichen planus

ILVEN Lichen planus

DIFFERENTIAL DIAGNOSIS While many cutaneous diseases assume a linear patterning, lichen striatus most closely resembles linear lichen planus and inflammatory linear verrucous epidermal nevus (ILVEN). Linear lichen planus displays the same histopathology as conventional lichen planus with its typical epidermal change and band of lymphocytes in the upper dermis. Lichen striatus may show fully evolved features of lichen planus but often also demonstrates parakeratosis, features of lichen nitidus, and deep dermal extension of the infiltrate. Another manifestation of lichen striatus is spongiotic dermatitis, as mentioned earlier. The epidermal changes in ILVEN usually more closely resemble psoriasis than interface dermatitis. The significant acanthosis and hyperkeratosis that impart the verrucous appearance to ILVEN are absent in lichen striatus.

Lichenoid Pigmented Purpuric Eruption of Gougerot and Blum As a group, pigmented purpuric dermatitis is discussed in more detail in Chap. 9. The lichenoid variant displays the typical erythematous/hemorrhagic patches and bronze discoloration characteristic of pigmented purpuric dermatitis. Skin samples reveal a perivascular and interstitial infiltrate of lymphocytes in the upper dermis with overlying interface change. This interstitial inflammation and the accompanying epidermal findings separate lichenoid pigmented purpuric eruption from other forms of pigmented purpuric dermatitis. Pericapillary hemorrhage is similar to that in pityriasis lichenoides chronica. In fact, these two entities are best distinguished on clinical grounds. Vasculitis with fibrin deposition and thrombosis are uncommon. Idiopathic pigmented purpuric dermatosis especially the lichenoid variant is held to represent a form of cutaneous lymphoid dyscrasia, hence lymphoid atypia, some loss of CD7, and clonality may be observed.93,94

erythematous rim show a mild-to-moderately dense perivascular and interstitial infiltrate of lymphocytes with lymphocyte apposition to degenerating melanocytes. The local cytokine milieu, such as the elaboration of soluble cytotoxic mediators, may result in the keratinocyte being injured as an innocent bystander.

Morbilliform Drug Eruption (See also Chap. 12)

Morbilliform Viral Exanthem (See also Chap. 22) Viral exanthems manifest as variably distributed erythematous macules often concentrated on the trunk. Skin biopsy samples display an upper dermal perivascular and interstitial infiltrate of lymphocytes with overlying basal vacuolization and variable numbers of necrotic keratinocytes. Typically only a few necrotic keratinocytes are noted. It is common to see erythrocyte extravasation and mild papillary dermal edema. Spongiosis and parakeratosis may be present.

 FIGURE 3-30 Lichen striatus. There is inflammation of the eccrine coils.

Macular and Lichen Amyloidosus (See also Chap. 16) Macular amyloidosus typically presents as hyperpigmented macules, often on the upper back, whereas the clinical appearance of lichen amyloidosus consists of verrucous plaques that are quite pruritic, usually on the shins. In both entities there is an accumulation of amorphous eosinophilic material to variable extent in the upper dermis. In general, greater amounts of amyloid are present in lichen amyloidosus than in macular amyloidosus. In both instances, the amyloid is derived from keratin. This fact explains the frequent finding of damage to the epidermal-dermal interface with basal

vacuolization, scattered necrotic keratinocytes, and melanophages in the upper dermis admixed with the amyloid. Acanthosis, hyperkeratosis, and papillomatosis further characterize lichen amyloidosus. These changes may reflect the sequela of chronic rubbing of the skin.

Vitiligo (See also Chap. 15) Progressive hypopigmentation leading to depigmentation of the skin correlates with the histologic findings of progressive loss of melanin content and melanocytes from the epidermis. Sampling of a chronic lesion reveals minimal inflammation with mild interface changes consisting mainly of basal vacuolization. Samples of the

CHAPTER 3 ■ INTERFACE DERMATITIS

 FIGURE 3-29 Lichen striatus. The lesion exhibits a bandlike infiltrate expanding the papillary dermis in a pattern resembling both lichen planus and lichen nitidus.

Exanthematous drug eruptions present as variably distributed pruritic erythematous macules and papules, often with a generalized distribution. The histopathology is not specific, consisting of an upper dermal perivascular and interstitial infiltrate of lymphocytes and eosinophils. Typically, these eruptions have basal vacuolization as the primary manifestation of interface change. At times, this finding may become pronounced, with rare necrotic keratinocytes. Any significant number of necrotic keratinocytes should prompt consideration of erythema multiforme.

Paraneoplastic Pemphigus (See also Chap. 7) The clinical and histologic features in paraneoplastic pemphigus (PNP) are protean. Marked mucositis is a nearly constant finding, whereas skin lesions range from erythema multiforme–like to overt blisters. The most characteristic skin biopsy specimens demonstrate interface dermatitis and suprabasal acantholysis. Many, possibly most, specimens will show only interface change. Such lesions exhibit a moderately dense upper dermal infiltrate of lymphocytes and features closely resembling erythema multiforme. Occasional eosinophils may be observed. As a rule, the degree of inflammation is heavier in PNP than in typical erythema multiforme.95 Acantholysis may be entirely absent or minimal in these specimens. Confirmation of the diagnosis through direct and indirect immunofluorescence is necessary.95

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MISCELLANEOUS DISEASES WITH SOME FEATURES OF INTERFACE DERMATITIS Although many diseases of the skin display some elements of interface dermatitis as part of the overall histopathology, such as, for example, spongiotic dermatitis, a few entities deserve special mention. The patch and plaques stages of mycosis fungoides often are characterized by basal vacuolization and migration of lymphocytes into the epidermis. Necrotic keratinocytes may be observed, but not in significant numbers. Even in that scenario one invariably sees areas of passive lymphocyte migration into the epidermis unaccompanied by significant destructive epithelial alterations. Other clues include the narrow grenz zone separating areas of band-like infiltration in the superficial dermis from the overlying epidermis and the extent of lymphocyte atypia. Under oil examination (1000×) excessive gyrate nuclear convolutions oftentimes transecting the nucleus is characteristic. Ultimately, the extent and degree of atypia, the architectural disposition of the lymphocytes in both the epidermis and dermis, and the epithelial and dermal response discriminate mycosis fungoides from other interface dermatitides. Lichenoid contact dermatitis is characterized by a perivascular and interstitial infiltrate composed of lymphocytes and eosinophils with variable overlying spongiosis and features of interface dermatitis. Most cases of contact dermatitis lack the features of interface dermatitis. Occasional immunologic reactions to the foreign materials in a tattoo will exhibit features of interface dermatitis, with the moderately heavy inflammatory infiltrate admixed among the exogenous pigments. This pattern is more common in response to mercury implantation.

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of cutaneous lesions of dermatomyositis. Hum Pathol. 1996;27:15-19. Magro CM, Dyrsen M, Kerns MJ. Cutaneous lesions of dermatomyositis with supervening fibrosis. J Cutan Pathol. 2008;35:31-39. Hinchliffe SA, Ciftci AO, Khine MM, et al. Composition of the inflammatory infiltrate in pediatric penile lichen sclerosus et atrophicus (balanitis xerotica obliterans): a prospective, comparative immunophenotyping study. Pediatr Pathol. 1994;14: 223-233. Tan SH, Derrick E, McKee PH, et al. Altered p53 expression and epidermal cell proliferation is seen in vulval lichen sclerosus. J Cutan Pathol. 1994;21: 316-323. Dillon WI, Saed GM, Fivenson DP. Borrelia burgdorferi DNA is undetectable by polymerase chain reaction in skin lesions of morphea, scleroderma, or lichen sclerosus et atrophicus of patients from North America. J Am Acad Dermatol. 1995;33:617-620. Clay FE, Cork MJ, Tarlow JK, et al. Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus. Hum Genet. 1994;94:407-410. Mihara Y, Mihara M, Hagani Y, Shimao S. Lichen sclerosus et atrophicus: a histological, immunohistochemical, and electron microscopic study. Arch Dermatol Res. 1994;286:434-442. Farrell AM, Dean D, Millard PR, et al. Alterations in fibirillin as well as collagens I and III and elastin occur in vulva lichen sclerosus. J Eur Acad Dermatol Venereol. 2001;15(3):212-217. Glockenberg A, Cohen-Sobel E, Caselli M, Chico G. Rare case of lichen sclerosus et atrophicus associated with morphea. J Am Podiatr Med Assoc. 1994;84:622-624. Scurry J, Whitehead J, Healey M. Histology of lichen sclerosus varies according to site and proximity to carcinoma. Am J Dermatopathol. 2001;23(5): 413-418. Lubbe J, Schlupen EM, Fierz W, et al. Identification of Borrelia afzelii in a juxtaarticular fibroid nodule from a human immunodeficiency virus-positive patient with acrodermatitis chronica atrophicans. Arch Dermatol. 1995;131:1341-1342. Balmelli T, Piffaretti JC. Association between different clinical manifestations of Lyme disease and different species of Borrelia burgdorferi sensu lato. Res Microbiol. 1995;146:329-340. deKoning J, Tazelaar DJ, HoogkampKorstanje JA, Elema JD. Acrodermatitis chronica atrophicans: a light and electron microscopic study. J Cutan Pathol. 1995; 22:23-32. Fink-Puches R, Soyer HP, Kerl H. Febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta. J Am Acad Dermatol. 1994;30: 261-263. Magro CM, Crowson AN, Morrison C, Li J. Pityriasis lichenoides chronica: stratification by molecular and phenotypic profile. Hum Pathol. 2007 Mar;38(3):479490. Epub 2007 Jan 19. PMID: 17239929 [PubMed—Indexed for MEDLINE]. Black MM. Lymphomatoid papulosis and pityriasis lichenoides: are they related? Br J Dermatol. 1982;106:717-721. Muhlbauer JE, Bhan AK, Harrist TJ, et al. Immunopathology of pityriasis lichenoides

76.

77. 78.

79. 80. 81.

82. 83. 84.

85. 86.

87. 88. 89. 90. 91.

92.

93.

94.

95.

acuta. J Am Acad Dermatol. 1984;10:783795. Wood GS, Strickler JG, Abel EA. Immunohistology of pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronia. Evidence for their interrelationship with lymphomatoid papulosis. J Am Acad Dermatol. 1987;16: 559-570. Terhune MH, Cooper KD. Gene rearrangements and T-cell lymphomas. Arch Dermatol. 1993;129:1484-1490. Alaibac M, Morris J, Yu R, Chu AC. T-lymphocytes bearing the gamma delta T-cell receptor: a study in normal human skin and pathologic skin conditions. Br J Dermatol. 1992;127:458-462. Weinberg JM, Kristal L, Chooback L, et al. The clonal nature of pityriasis lichenoides. Arch Dermatol. 2002;138:1063-1067. Takahashi K, Atsumi M. Pityriasis lichenoides chronica resolving after tonsillectomy. Br J Dermatol. 1993;129:353-354. Magro C, Crowson AN, Kovatich A, Burns F. Pityriasis lichenoides: a clonal T-cell lymphoproliferative disorder. Hum Pathol. 2002;33(8):788-795. Abell E, Marks R, Wilson-Jones E. Secondary syphilis: a clinicopathological review. Br J Dermatol. 1975;93:53-61. Jeerapaet P, Ackerman AB. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373-377. Vennos EN, Collins M, James WD. Rothmund-Thomson syndrome: review of the world literature. J Am Acad Dermatol. 1992;27:750-762. Online Medelian Inheritance in Man. http://www.ncb.inlm.nih.gov/sites/entrex? db=omn. Weksberg R. Low-sister-chromatidexchange Bloom syndrome cell lines: an important new tool for mapping the basic genetic defect in Bloom syndrome and for unraveling the biology of human tumor development. Am J Hum Genet. 1995;57:994-997. Drachtman RA, Alter BP. Dyskeratosis congenita. Dermatol Clin. 1995;13:33-39. Laxmisha C, Thappa DM. Generalized lichen nitidus with Down syndrome. J Eur Acad Dermatol Venereol. 2006;20:1156-1157. AL-Mutairi N, Hassanein A, Nour-Eldin O, et al. Generalized lichen nitidus. Pediatr Dermatol. 2005;22:158-160. Arizaga AT, Gaughan MD, Bang RH. Generalized lichen nitidus. Clin Exp Dermatol. 2002;27:115-117. Smoller BR, Flynn TC. Immunohistochemical examination of lichen nitidus suggests that it is not a localized papular variant of lichen planus. J Am Acad Dermatol. 1992;27:232-236. Gianotti R, Restano L, Grimalt R, et al. Lichen striatus—a chameleon: an histopathological and immunohistological study of forty-one cases. J Cutan Pathol. 1995;22: 18-22. Guitart J, Magro C. Cutaneous T-cell lymphoid dyscrasia: a unifying term for idiopathic chronic dermatoses with persistent T-cell clones. Arch Dermatol. 2007 Jul;143(7):921-932. Magro CM, Schaefer JT, Crowson AN, Li J, Morrison C. Pigmented purpuric dermatosis: classification by phenotypic and molecular profiles. Am J Clin Pathol. 2007 Aug;128(2):218-229. Horn TD, Anhalt GJ. Histologic features of paraneoplastic pemphigus. Arch Dermatol 1991;128:1091-1095.

CHAPTER 3 ■ INTERFACE DERMATITIS

46.

and histopathologic indicators of the development of progressive acute graftversus-host disease. J Invest Dermatol. 1992;99:397-402. LeBoit PE. Subacute radiation dermatitis: a histologic imitator of acute cutaneous graft-versus-host disease. J Am Acad Dermatol. 1989;20:236-241. Janin A, Socie G, Devergie A, et al. Fasciitis in chronic graft-versus-host disease: a clincopathologic study of 14 cases. Ann Intern Med. 1994;120:993-998. Bielsa I, Herrero C, Collado A, et al. Histopathologic findings in cutaneous lupus erythematosus. Arch Dermatol. 1994;130:54-58. Jerdan MS, Hood AF, Moore GW, et al. Histologic comparisons of subsets of lupus erythmatosus. Arch Dermatol. 1990;126:52-55. Crowson AN, Magro C. The cutaneous pathology of lupus erythematosus: a review. J Cutan Pathol. 2001;28(1):1-23. Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic and granulomatous dermatitis in patients with collagen vascular disease. Arch Dermatol. 1994;130:1278-1283. Kawashima T, Zappi EG, Lieu TS, Sontheimer RD. Impact of ultraviolet radiation on expression of SSA/Ro autoantigenic polypeptides in transformed human epidermal keratinocytes. Lupus. 1994;3:493-500. Perniciario C, Randle HW, Perry HO. Hypertrophic discoid lupus erythematosus resembling squamous cell carcinoma. Dermatol Surg. 1995;21:255-257.. Cheong WK, Hughes GR, Norris PG, Hawk JL. Cutaneous photosensitivity in dermatomyositis. Br J Dermatol. 1994;131: 205-208. Whitmore SE, Rosenschein NB, Provost TT. Ovarian cancer in patients with dermatomyositis. Medicine. 1994;73:153-160. Horowitz HW, Sanghera K, Goldberg N, et al. Dermatomyositis associated with Lyme disease: case report and review of Lyme myositis. Clin Infec Dis. 1994;18: 166-171. Cosnes A, Amaudric F, Gherardi R, et al. Dermatomyositis without muscle weakness: long-term follow-up of 12 patients without systemic corticosteroids. Arch Dermatol. 1995;131:1381-1385. Sigurgeirsson B, Lindelof B, Edhag O, et al. Risk of cancer in patients with dermatomyositis or polymositis: a populationbased study. New Engl J Med. 1992;326: 363-367. Magro CM, Schaefer JT, Waldman J, et al. Terbinafine-induced dermatomyositis: a case report and review of drug-induced dermatomyositis. J Cutan Pathol. 2007;35: 74-81. Hanno R, Callen JP. Histopathology of Gottron’s papules. J Cutan Pathol. 1985; 12:389-394. Mascaro JM, Jr, Hausman G, Herrero C, et al. Membrane attack complex deposits in cutaneous lesions of dermatomyositis. Arch Dermatol. 1995;131:1386-1392. Magro CM, Crowson AN. The immunoflourescent profile of dermatomyositis: a comparative study with lupus erythematosus. J Cutan Pathol. 1997;24(9): 543-552. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis

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CHAPTER 4 Psoriasiform Dermatitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Timothy T. Chang Loren E. Golitz

Inflammatory dermatoses may be categorized based on the pattern of inflammation1 and epidermal changes.2 With psoriasis as the prototype, the psoriasiform dermatitides are characterized by regular elongation of rete ridges.3 This may result from increased keratinocyte proliferation due to more rapid turnover of stem cells or an increased pool of proliferating cells. Epidermal thickening may affect any or all of the layers of the epidermis. The stratum corneum may be thickened (hyperkeratosis) and may retain nuclear remnants (parakeratosis). Thickening of the granular layer or spinous layer is termed hypergranulosis or acanthosis, respectively. In psoriasis, there is prominent parakeratosis associated with a thin to absent granular layer. Rete ridges show clubbing, are uniformly elongated, expanded at the tips, and fused. The epidermis shows thinning of the suprapapillary plates. Neutrophils migrate from dilated capillaries in the papillary dermis and extend into the stratum corneum to form Munro microabscesses. A number of inflammatory dermatoses share these features, including psoriasis, Reiter syndrome, pityriasis rubra pilaris, and neurodermatitis (lichen simplex chronicus).4 However, just as there are differences in the clinical appearance and pathogenesis, there are histologic differences in quality of scale and distribution or composition of inflammation that allow these dermatoses to be distinguished from each other.

MAJOR PSORIASIFORM DERMATOSES

Psoriasis

64

Psoriasis is a chronic papulosquamous disease affecting about 1% to 2% of the US population. There is considerable geographic and ethnic variation in incidence. For example, psoriasis is rare in native Americans. The onset is typically in the third decade, with a second peak in

the sixth.5 Certain areas of the skin are preferentially involved, including the scalp, groin, elbows, knees, umbilicus, and lumbar spine.6 The disease follows a chronic relapsing course characterized by remission and exacerbation. Psoriasis is characterized by an increased epidermal turnover rate7 leading to thickening of the epidermis and accumulation of scale. There is evidence for an inherited component in psoriasis. There is high concordance for disease in monozygotic twins8 and a linkage disequilibrium with certain human lymphocyte antigen (HLA) types, especially HLA-Cw6.9 There is evidence for genomic imprinting in the inheritance of psoriasis, in that children of males with psoriasis are more often affected than children of females with psoriasis. This and other genetic phenomena in psoriasis can be explained by the “allelic instability in mitosis” model of dominantly inherited disease, the subject of recent reviews.10,11 Evidence supporting a genetic susceptibility locus (PSORS1) within the major histocompatability (MHC) complex is presented by Capon and colleagues.12 A total of nine chromosomal loci (PSORS1-PSORS9) have now been linked to psoriasis susceptibility, with PSORS1 being the most important genetic determinant for heritability.13 An elegant experiment has demonstrated that psoriasis is not a primary defect of keratinocytes. Human psoriatic skin was grafted onto mice with severe combined immunodeficiency. Over time, mouse epidermis grew over the human dermis, but the epidermis retained psoriasiform architecture, indicating that the defect more likely lay in the dermis.14 The pathogenesis of psoriasis involves the interaction between inflammatory cells and keratinocytes. T-cell activation and cytokines are involved in epidermal proliferation,15 and cytokines produced by activated keratinocytes are thought to induce keratinocyte proliferation and lymphocyte migration.16 Psoriasis has been classified as a Th1 disease characterized by an increased production of cytokines of the Th1 pathway (IL-2, IFN-γ, and IL-12/23).17 One hypothesis is that genetic susceptibility coupled with an inflammatory process that may be triggered by activation of T cells by bacterial superantigens leads to the development of psoriasis.18,19 CLINICAL FEATURES The most common clinical presentation is chronic stationary psoriasis (psoriasis vulgaris). Individual lesions are sharply demarcated, erythematous, and covered with a thick,

silvery scale (Fig. 4-1A) (Table 4-1). They may show the Auspitz sign, in which forcible removal of scale produces pinpoint areas of bleeding. The tendency to involve the extensors has been attributed to the Koebner (isomorphic) phenomenon, in which typical lesions arise at sites of trauma. Inverse psoriasis is characterized by involvement of the flexures. Here, lesions may show less scale and exhibit a shiny erythema. Fingernails are involved in 50% and toenails in 35% of patients with psoriasis.20 Involvement of the proximal nail fold overlying the nail matrix produces pitting of the nail plate. Psoriasis of the nail bed produces yellow-brown discoloration under the nail plate (“oil spots”). Inflammation of the nail matrix causes a deformed, thickened nail plate termed onychodystrophy that can result in distal onycholysis and subungual hyperkeratosis. Mucosal lesions are rare, except on the glans penis, especially in uncircumcised men. Abrupt onset of small (guttate) lesions, especially on the trunk and proximal extremities, may follow a streptococcal infection.21,22 This phenomenon is more common in children. It may be related to cross-reactive antibodies between streptococcal M protein and human skin.23 Psoriasis may be pustular. A generalized form of pustular psoriasis with systemic symptoms is termed pustular psoriasis of von Zumbusch, which may be precipitated by systemic corticosteroids.24 When pustules are localized to the palms and soles, the process is termed pustular psoriasis of Barber. Erythrodermic psoriasis is characterized by generalized erythema and shedding of large amounts of scale. In this setting, marked dilatation of cutaneous blood vessels adversely affects body temperature regulation. Verrucous psoriasis is a recent variant of psoriasis that has been described by Khalil et al.25 Patients present with flesh-toned to white mammilated plaques and coalesced plaques primarily on the extensor surfaces of the upper and lower extremities. HISTOPATHOLOGIC FEATURES Just as the clinical picture varies with the age of the lesions, so do the histopathologic findings.26 Biopsies of fully developed plaques reflect the hyperproliferative and intermittent nature of psoriasis, showing extensive hyperkeratosis with horizontally confluent but vertically intermittent parakeratosis (Figs. 4-1 through 4-5). In areas of parakeratosis, the granular layer is thinned or absent. Parakeratosis may alternate with orthokeratosis, reflecting the episodic nature

B

 FIGURE 4-1 Psoriasis. (A) Individual lesions are sharply demarcated, erythematous, and covered with a thick, silvery scale. (B) The epidermis shows regular elongation of the epidermal rete ridges.

of the disease. Mitoses are more frequent than in uninvolved skin and may appear one or two layers above the basal layer. There is uniform elongation of rete ridges with thinning of the suprapapillary epidermis. The tips of the rete ridges are often clubbed or fused with adjacent ones. The dermal papillae are

Table 4-1 Psoriasis

Clinical Features Sharply circumscribed plaques with silvery scale Auspitz sign, Koebner phenomenon Predilection for scalp, groin, extensor surfaces (especially elbows and knees), nails Inherited component Histopathologic Features Hyperkeratosis with confluent parakeratosis Uniform elongation of rete ridges Papillary dermal edema with dilated tortuous capillaries Thinned suprapapillary plates Neutrophils within the stratum corneum (Munro microabscesses) Neutrophils within the spinous layer (spongiform pustule of Kogoj) Superficial perivascular lymphocytic infiltrate Differential Diagnosis Chronic spongiotic (eczematous) dermatitis Superficial cutaneous fungal infections Secondary syphilis Reiter syndrome Lichen simplex chronicus

edematous and contain dilated, tortuous capillaries. Despite the dermal edema, spongiosis is mild or absent. The granular and spinous layers are thinned over the edematous dermal papillae, and exocytosis of neutrophils frequently occurs in these areas. It is the thinned suprapapillary plates and the proximity of dilated dermal capillaries to the skin surface that produce the Auspitz sign. Collections of neutrophils with pyknotic nuclei in the parakeratotic stratum corneum, Munro microabscesses, are

found in approximately 75% of cases.27 Neutrophils are found less commonly in the spinous layer, where they may aggregate to form spongiform pustules of Kogoj. The underlying dermis is characterized by a superficial perivascular infiltrate of lymphocytes. Eosinophils generally are absent, and plasma cells are unusual except in mucosal biopsies or in association with HIV infection. This classic picture is seen in only a small percentage of lesions.28 Earlier or eruptive lesions may show initially a

 FIGURE 4-2 Psoriasis. The cornified layer shows horizontally confluent parakeratosis with exocytosis of neutrophils.

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

A

65

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

(see Fig. 4-4). The migration of neutrophils from dermal papillae into the overlying epidermis has been referred to as squirting papillae.30 Neutrophils are more numerous in eruptive psoriasis than in psoriasis vulgaris31 (see Fig. 4-5). Verrucous psoriasis shows many of the classical features of psoriasis including regular psoriasiform epidermal hyperplasia, hyperkeratosis, Munro microabscesses, and spongiform pustules. However, there is prominent papillomatosis and pointing of the rete ridges toward the center of the lesion that is suggestive of a verruca vulgaris. Importantly, hypergranulosis and koilocytic change are not identifed in these lesions.25

 FIGURE 4-3 Psoriasis. The granular layer is absent, and there is prominent exocytosis of neutrophils.

DIFFERENTIAL DIAGNOSIS Seborrheic dermatitis may show neutrophils within parakeratotic scale but typically situated about follicular ostia rather than diffuse and confluent. The presence of marked spongiosis within the rete ridges suggests the diagnosis of a spongiotic (eczematous) process such as nummular dermatitis or contact dermatitis. Lichen simplex chronicus shows papillary dermal fibrosis, whereas psoriasis shows papillary dermal edema and dilated, tortuous capillaries. Neutrophils in the stratum corneum may be seen in candidiasis or dermatophytosis. In these conditions, a fungal stain, such as a periodic acidSchiff (PAS) stain with diastase predigestion, may reveal hyphae, pseudohyphae, or budding yeast. Secondary syphilis may show psoriasiform epidermal hyperplasia, but may have a deeper dermal infiltrate containing plasma cells. Psoriasiform drug eruptions often show features of both psoriasis vulgaris and lichen simplex chronicus, but can be histologically identical to psoriasis. Some medications, such as lithium, induce psoriasis while other medications, such as betablockers and nonsteroidal anti-inflammatory drugs (NSAIDs), either exacerbate psoriasis or induce psoriasiform eruptions.32

Pustular Psoriasis  FIGURE 4-4 Guttate psoriasis. Note prominent focal parakeratotic scale.

66

nonspecific pattern of changes confined to the dermis.29 There is a superficial perivascular lymphocytic infiltrate with extravasation of erythrocytes associated with papillary dermal edema and dilated,

tortuous capillaries. Only later are the suprapapillary plates thinned in association with elongation of rete ridges. In early lesions, parakeratosis is typically mounded or spotty rather than confluent

Pustules in psoriasis may occur in several settings. Occasionally, pustules may be found at the periphery of typical plaquetype lesions. Sterile pustules may be localized to the palms and soles (Barber), to the paronychial tissues (acrodermatitis continua of Hallopeau), or may be generalized with associated constitutional symptoms (von Zumbusch). Impetigo herpetiformis is pustular psoriasis in association with pregnancy. Patients

Other changes are the same as those in psoriasis vulgaris, namely, diffuse parakeratosis, hypogranulosis, regular elongation of rete ridges, papillary dermal edema, and capillary dilatation in association with a superficial perivascular infiltrate of lymphocytes and neutrophils. These findings are less well developed in eruptive lesions. On acral skin, as in palmoplantar pustular psoriasis of Barber or acrodermatitis continua of Hallopeau, pustules are large and unilocular, with the typical spongiform pattern seen primarily at the periphery of the pustule (Fig. 4-9).

with impetigo herpetiformis usually have typical lesions of psoriasis elsewhere. CLINICAL FEATURES Pustular psoriasis of von Zumbusch33 presents as a sudden eruption of 2- to 3-mm sterile pustules tending toward confluence and a distribution over the trunk and extremities. The underlying skin shows a fiery erythema. The face is usually spared, but oral lesions are common.34 This process is episodic and may be accompanied by fever, leukocytosis, and arthralgias lasting several days. Nails may be shed. The average age of onset is 50 years, with males and females affected equally.35 Hypocalcemia may be present,24 possibly related to hypoalbuminemia. Pustular psoriasis of von Zumbusch has been precipitated by numerous medications, including systemic corticosteroids, iodides, salicylates, and progesterone.36 The clinical differential diagnosis includes acute generalized exanthematous pustulosis. Palmoplantar pustulosis describes psoriasis in which lesions are confined to the palms and soles. Some authors separate clinical variants, such as pustular psoriasis of Barber, acrodermatitis continua of Hallopeau, and pustular bacterid of Andrews. We will consider these entities together because they show identical histopathologic features, although the clinical presentation and/or clinical associations may allow their discrimination. HISTOPATHOLOGIC FEATURES The constant histologic feature of pustular psoriasis

is the spongiform pustule of Kogoj. Neutrophils migrate from dilated, tortuous papillary dermal capillaries and collect between residual plasma membranes, accompanied by intercellular edema, producing a spongelike appearance within the Malpighian layer37 (Figs. 4-6 through 4-9). Keratinocytes in the center of the spongiotic areas degenerate, leaving large unilocular pustules. With time, neutrophils arrive in the parakeratotic stratum corneum as Munro microabscesses.

 FIGURE 4-6 Pustular psoriasis. This lesion shows prominent parakeratotic scale, an intraepidermal neutrophilic pustule, and prominent subepidermal edema.

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

 FIGURE 4-5 Guttate psoriasis. There is focal exocytosis of neutrophils.

DIFFERENTIAL DIAGNOSIS A number of processes can present with spongiform or subcorneal pustules. Identification of the primary pathologic process is important in differentiating these disorders. Dyshidrotic eczema may show intraepidermal pustules but is more spongiotic and often has eosinophils in the dermal infiltrate. Eosinophils also may indicate a pustular drug eruption.38 Superficial fungal infections such as candidiasis and dermatophytosis may show pustules in the stratum corneum. Fungal elements cannot be reliably excluded without the use of special stains. Impetigo, pustular drug eruptions, and subcorneal pustular dermatosis of Sneddon-Wilkinson all may show subcorneal pustules. In these conditions, parakeratosis and epidermal hyperplasia are less developed. Pustular miliaria, pustular lupus erythematosus, pustular syphillis, pemphigus foliaceus, IgA pemphigus, and necrolytic migratory

67

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Approximately 80% of patients have mucocutaneous lesions.40 There is a wellestablished genetic component demonstrated by the strong association with HLA B27.41 In addition to genitourinary infections, enteric infections may trigger the reactive disease in genetically predisposed individuals. There is evidence that microbial antigens persist in patients with reactive arthritis.42 Although organisms are rarely cultured, nucleic acid sequences of Chlamydia subspecies have been found in the synovium of affected patients.43 Comprehensive reviews of the pathogenesis of reactive arthritis (Reiter syndrome) are available.44,45

 FIGURE 4-7 Pustular psoriasis. Higher magnification showing intraepidermal neutrophilic pustule.

HISTOPATHOLOGIC FEATURES The histopathologic features of keratoderma blenorrhagicum and balanitis circinata are essentially identical to those of pustular psoriasis (Fig. 4-10). Broad hyperkeratosis and parakeratosis with a thinned granular layer and elongated rete ridges are seen. Within the parakeratotic stratum corneum are collections of neutrophils with pyknotic nuclei (Munro microabscesses). Geographic tongue shows prominent spongiform pustules with less hyperkeratosis than in cutaneous lesions.47

 FIGURE 4-8 Pustular psoriasis. There are spongiform pustules in the upper part of the Malpighian layer of the epidermis.

erythema can all show spongiform or subcorneal pusutles.

Reactive Arthritis (Reiter Syndrome) 68

CLINICAL FEATURES Patients with reactive arthritis tend to be young males in whom arthritis follows urethritis and conjunctivitis by several days or weeks. Urethral cultures are usually negative. One-third of patients manifest the complete triad, and 40% have arthritis only.46 Mucocutaneous lesions include a psoriasiform eruption of the palms and soles (keratoderma blenorrhagicum), a pustular or psoriasiform eruption on the glans penis (balanitis circinata), erosive or ulcerative oral lesions (geographic tongue), and subungual pustules associated with onycholysis.

Reactive arthritis is characterized by the triad of urethritis, arthritis, and conjunc-

tivitis (Table 4-2). However, only onethird of patients manifest the classic triad. A more recent definition by the American Rheumatism Association requires “an episode of peripheral arthritis of more than 1 month’s duration occurring in association with urethritis and/or cervicitis.”39

DIFFERENTIAL DIAGNOSIS Both the keratoderma of reactive arthritis and pustular psoriasis have large, unilocular spongiform pustules. Striking hyperkeratosis favors reactive arthritis, as does a more intense perivascular inflammatory infiltrate, especially if neutrophils are prominent. Mucosal lesions are more common in Reiter syndrome. Clinical correlation may be necessary to distinguish Reiter syndrome from pustular psoriasis because the histologic changes may be identical.

Pityriasis Rubra Pilaris Pitryriasis rubra pilaris (PRP) is a rare, idiopathic, chronic papulosquamous disease with a bimodal age of onset.48

 FIGURE 4-9 Palmoplantar pustulosis. Note large intraepidermal pustule.

There is an equal sex ratio. Some cases are familial and are transmitted as an autosomal dominant trait49 with expression of keratins not normally found in

epidermis.50 As in psoriasis, the epidermal turnover rate is increased.51 CLINICAL FEATURES PRP usually begins as asymptomatic scaling and erythema of the scalp resembling seborrheic dermatitis.49 Later, truncal lesions develop as small,

HISTOPATHOLOGIC FEATURES In PRP, discrete foci of lamellar hyperkeratosis and parakeratosis alternate with orthokeratosis both perpendicular to and parallel to the skin surface (Figs. 4-11 through 4-13). Parakeratotic mounds at the edges of follicular ostia are termed shoulder parakeratosis. Keratotic plugs fill the follicular ostia and extend above the level of the adjacent epidermis. The epidermis, including the suprapapillary plates, shows hyperplasia and hypergranulosis55 and occasional acantholysis.56 Rete ridges are irregularly elongated and thickened but less so than in psoriasis. There is a mild

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

orange-red, accuminate follicular papules with perifollicular erythema (Table 4-3). These coalesce into large plaques with fine scale and distinct borders, expanding to leave islands of uninvolved skin. The disease may progress to generalized erythroderma. There is a yellow-red keratoderma of the palms and soles (Fig. 4-11A). Follicular papules on the dorsa of fingers are said to resemble a “nutmeg grater.” Nail changes include thickening of the nail plate and subungual hyperkeratosis.52 Oral lesions are infrequent. In the classic adult form (type I) the disease may undergo spontaneous remission within 3 years in approximately 80% of the cases, but the childhood form (type II) tends to be chronic.48,53 HIV-associated PRP may have coexisting acne conglobata or hidradenitis suppurativa.54

Table 4-2 Reiter Syndrome

Clinical Features Triad of urethritis (negative urethral cultures), arthritis, and conjunctivitis Predominantly young males, HLA-B27 Palms and soles (keratoderma blenorrhagicum) Penile lesions (balanitis circinata) Histopathologic Features (identical to psoriasis) Hyperkeratosis with confluent parakeratosis Uniform elongation of rete ridges Papillary dermal edema with dilated tortuous capillaries Thinned suprapapillary plates Neutrophils within the stratum corneum (Munro microabscesses) Neutrophils within the spinous layer (spongiform pustule of Kogoj) Superficial perivascular lymphocytic infiltrate Differential Diagnosis Psoriasis Chronic spongiotic (eczematous) dermatitis Superficial cutaneous fungal infections Secondary syphilis

 FIGURE 4-10 Reiter syndrome. This lesion shows a parakeratotic stratum corneum containing neutrophils that overlies psoriasiform epidermal hyperplasia.

69

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 4-3 Pityriasis Rubra Pilaris

Clinical Features Inherited (autosomal dominant) and sporadic forms Scalp involvement resembling seborrheic dermatitis Accuminate follicular papules Erythroderma with islands of sparing Palmoplantar keratoderma Histopathologic Features Vertical and horizontal foci of orthokeratosis alternate with parakeratosis Parakeratotic mounds at follicular ostia (shoulder parakeratosis) Follicular plugging Rete ridges irregularly elongated and thickened Thickened suprapapillary plates Superficial perivascular lymphocytic inflammation Differential Diagnosis Psoriasis Seborrheic dermatitis Keratosis pilaris

A

B superficial perivascular lymphocytic infiltrate, sometimes containing eosinophils or plasma cells.56 The neutrophils and Munro microabscesses of psoriasis are usually absent. Spongiosis is minimal.

 FIGURE 4-11 Pityriasis rubra pilaris. (A) There is a yellow-red keratoderma of the palms with diffuse scaling. (B) The epidermis shows psoriasiform epidermal hyperplasia with a hyperkeratotic stratum corneum.

DIFFERENTIAL DIAGNOSIS An objective histologic diagnosis of PRP can be made in about 50% of cases. The most distinctive features are follicular hyperkeratosis, hypergranulosis, and shoulder parakeratosis. In psoriasis the hyperkeratosis and parakeratosis tend to be confluent, whereas in PRP the changes are focal. The presence of neutrophils and spongiform pustules in association with dilated, tortuous capillaries argues against the diagnosis of PRP. Chronic eczematous dermatitis usually shows some degree of spongiosis. Follicular plugging may be seen in discoid lupus erythematosus, keratosis pilaris, and lesions of vitamin A deficiency (phrynoderma). In discoid lupus, the pattern of inflammation is lichenoid or deep and periappendageal. Keratosis pilaris and phrynoderma do not show significant epidermal hyperplasia.

Lichen Simplex Chronicus

70

Lichen simplex chronicus (LSC) is produced by repetitive mechanical trauma to the skin. A number of stimuli produce pruritus and provoke scratching. When

 FIGURE 4-12 Pityriasis rubra pilaris. High magnification showing alternating ortho- and parakeratosis.

DIFFERENTIAL DIAGNOSIS LSC may show residual intercellular edema and hypergranulosis, which are mild or absent in psoriasis. Both conditions show vascular ectasia, but vessels are more tortuous in psoriasis. Seborrheic dermatitis, psoriasis, and chronic fungal infections are more likely to show neutrophils within the stratum corneum. Psoriasis shows more prominent parakeratosis and an edematous rather than fibrotic papillary dermis. Benign keratoses and other epidermal neoplasms tend to be more sharply circumscribed. Chronic lesions of spongiotic dermatitis may show a superimposed pattern of LSC.

 FIGURE 4-13 Pityriasis rubra pilaris. There is follicular hyperkeratosis with parakeratosis involving the shoulders of the follicular infundibulum.

the sensation and scratching are localized, papular and nodular lesions are produced (prurigo nodularis, “picker’s nodule”). Psychogenic factors may be involved. Over time, the behavior may become subconscious. Identical lesions can be induced in normal skin by a minimum of 140,000 scratches.57 Any pruritic or eczematous dermatosis can develop secondary lichenification. We reserve the term LSC (localized neurodermatitis) for those cases in which a primary dermatosis is not apparent. CLINICAL FEATURES Lesions of LSC are always pruritic and often solitary. They are chronic and most commonly involve the lower lateral legs, dorsal feet, extensor forearms, genital region, and posterior neck. Lesions of LSC are thickened, well-demarcated, scaly papules, nodules, or plaques with excoriation and lichenification. Hyperpigmentation is common and persistent. The prurigo nodularis pattern is usually multiple and symmetrically distributed on the extremities with evidence of chronicity including dyschromia and scarring. HISTOPATHOLOGIC FEATURES A biopsy of LSC shows thickening of all layers of the skin above the reticular dermis, imparting some resemblance to acral skin (Table 4-4 and Figs. 4-14 and 4-15). Hyperkeratosis, hypergranulosis, and acanthosis are seen. When present, parakeratosis is discontinuous. The rete ridges are irregularly elongated and thickened. The epidermis may

Table 4-4 Lichen Simplex Chronicus

Clinical Features Prominent pruritus Changes produced by repetitive scratching Chronic well-demarcated plaques Lichenification/excoriation/hyperpigmentation Lateral legs, posterior neck, flexures Histopathologic Features Thickening of all layers of the skin above the reticular dermis Hyperkeratosis/hypergranulosis/acanthosis Papillary dermal fibroplasia Stellate/multinucleated fibroblasts Superficial perivascular lymphocytic infiltrate Pointed rete ridges rather than club shaped Differential Diagnosis Psoriasis Chronic spongiotic (eczematous) dermatitis Superficial cutaneous fungal infections

be papillomatous, and the superficial Malpighian layer may be pale as the result of glycogen accumulation.58 There is usually some spongiosis in the acute stage, but vesicles are rare. The papillary dermis shows thickened collagen fibers oriented perpendicular to the skin surface. There may be stellate or multinucleated fibroblasts in the superficial dermis. The superficial dermis shows vascular ectasia and a perivascular lymphocytic infiltrate with minimal exocytosis.

Parapsoriasis is not a disease but a group of diseases that includes pityriasis lichenoides, large-plaque parapsoriasis (LPP), and small-plaque parapsoriasis (SPP). This group of diseases was first proposed by Brocq in an attempt to organize the inflammatory dermatoses.59 The diseases are essentially unrelated, except that all are idiopathic, asymptomatic (although pruritus can be a variable feature), chronic, and relatively unresponsive to therapy. A review of the nosology of these diseases is available.60 In addition to a confusing nomenclature and to difficulties in defining parapsoriasis in a reproducible fashion, considerable controversy surrounds the relationship between LPP and mycosis fungoides. Many authors consider LPP to be an inflammatory process that may progress to mycosis fungoides.61 Others consider LPP to be part of the spectrum of cutaneous T-cell lymphoma or mycosis fungoides from the outset,62,63 a low-grade malignancy that smolders in the majority of cases and follows a more aggressive course in a few. In either case, both processes may show similar abnormalities of T-cell antigen expression64 and monoclonal T-cell proliferation.65,66 CLINICAL FEATURES Large-plaque parapsoriasis (LPP) is a chronic disease of middle age. It is characterized by large (>10 cm), slightly scaly, erythematous patches and plaques with irregular outlines (Table 4-5). The eruption is asymmetrical and affects predominantly the buttocks, flexures, and female breasts. Mucosal disease, nail changes, and acral involvement are rare. Lesions are usually asymptomatic but may be pruritic. Plaques often show epidermal atrophy manifested as fine wrinkling of the skin. The skin lesions may resemble poikiloderma atrophicans

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

Parapsoriasis (Parapsoriasis en Plaques)

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 4-5 Parapsoriasis en Plaques

Clinical Features Chronic disease of middle age Scaly erythematous patches and plaques Predilection for buttocks, flexures, and breasts Unresponsive to treatment Histopathologic Features Mild irregular acanthosis Mounding parakeratosis Papillary dermal fibrosis Focal vacuolar change Superficial perivascular lymphocytic infiltrate Differential Diagnosis Guttate (eruptive) psoriasis Mild chronic dermatitis Mycosis fungoides (see text)  FIGURE 4-14 Lichen simplex chronicus. There is prominent irregular psoriasiform epidermal hyperplasia with pointed rete ridges. is unusual. With chronicity, the infiltrate may become more dense and bandlike with associated papillary dermal fibrosis. Lymphocytes may be seen along the basal layer in association with vacuolar change and pigment incontinence. DIFFERENTIAL DIAGNOSIS In early lesions, the differential diagnosis includes a mild chronic dermatitis or superficial perivascular dermatitis. Clinically, the eruption may be unresponsive to standard therapy. When lymphocytes infiltrate the deeper layers of the epidermis, the histologic features resemble those seen in the earliest or patch stage of mycosis fungoides.67 Lymphocyte atypia, epidermal lymphocytes larger than dermal lymphocytes, and halos around papillary dermal lymphocytes favor mycosis fungoides. Other reactive inflammatory dermatoses usually do not show monoclonal T-cell proliferation.65,66

OTHER PSORIASIFORM DERMATOSES

Subacute and Chronic Spongiotic Dermatitides  FIGURE 4-15 Prurigo nodularis. Note the irregular psoriasiform epidermal hyperplasia as in lichen simplex chronicus.

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vasculare, which is characterized by epidermal atrophy, dyschromia, and telangiectasia. Progression to overt mycosis fungoides may be heralded by thickening of the plaques.

HISTOPATHOLOGIC FEATURES The earliest lesions show only a superficial perivascular lymphocytic infiltrate. The epidermis initially shows mild, irregular acanthosis and mounding parakeratosis. Spongiosis

Spongiotic dermatitis represents a cutaneous reaction to a variety of endogenous or exogenous stimuli. This pattern clinically has been termed eczema or eczematous dermatitis. However, some authors have argued that the term eczema lacks a specific meaning and should be avoided.68 The acute phase of this reaction pattern is considered in detail in Chap. 2. The chronic phase is included

here because it may show psoriasiform epidermal hyperplasia.

HISTOPATHOLOGIC FEATURES The histologic picture of chronic and subacute spongiotic dermatitis is dominated by the changes produced by chronic rubbing and scratching, as seen in lichen simplex chronicus. All layers of the epidermis and papillary dermis are thickened, manifesting as compact hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, and papillary dermal fibrosis. These changes correspond to the clinical finding of lichenification. The prominent spongiosis and exocytosis of lymphocytes of acute lesions are diminished in chronic ones. Dried plasma is present as crust, and there may be superficial ulceration due to excoriation. DIFFERENTIAL DIAGNOSIS Different clinical forms of spongiotic dermatitis may show distinctive histologic features. Stasis dermatitis shows clusters of tortuous capillaries and siderophages within a fibrotic papillary dermis. Nummular dermatitis shows focal, mounding parakeratosis and spongiosis associated with a superficial perivascular infiltrate of lymphocytes and a variable number of eosinophils.

Erythroderma Erythroderma is a clinical term referring to generalized redness of the skin. Exfoliative dermatitis refers to those cases with extensive scaling. This reaction pattern may result from a number of mechanisms.69 Generalization of preexisting papulosquamous disease or spongiotic dermatitis accounts for 25% to 62.5% of cases. Psoriasis, pityriasis rubra pilaris, atopic dermatitis, and seborrheic dermatitis are common causes. Drugs are another major cause of erythroderma (14%-42%). Lymphoma, especially Sézary syndrome, accounts for 8% to 21% of cases. Many cases are idiopathic. CLINICAL FEATURES Erythema, scaling, and desquamation may involve the entire body. High blood flow to the skin may disrupt temperature regulation or lead to high-output cardiac failure. Nails or hair may be shed. There may be a history of a drug eruption or a preexisting dermatosis. A careful examination may reveal typical lesions of psoriasis, stigmata of atopy, or “islands of sparing,” as seen in pityriasis rubra pilaris. Many cases show no distinguishing features. HISTOPATHOLOGIC FEATURES The histologic pattern varies with the underlying etiology. In those cases resulting from chronic or subacute spongiotic dermatitis, the histologic picture is nonspecific. A biopsy may show intercellular and

intracellular edema with exocytosis of mononuclear cells. Crusting may be present. The superficial dermis contains perivascular lymphocytic iniltrates and edema. Chronic changes are inversely related to the preceding. They consist of hyperkeratosis, parakeratosis, acanthosis, and papillary dermal fibrosis. In cases related to a primary inflammatory dermatosis, such as psoriasis or pityriasis rubra pilaris, the histologic pattern may still be recognizable70 but is usually less typical than in the primary disease. Cases of Sézary syndrome may show atypical, cerebriform lymphocytes in the epidermis with minimal associated spongiosis; however, fully developed Pautrier microabscesses are less common than in the plaque stage of mycosis fungoides. Drug eruptions may show atypical lymphocytes along the interface and within the epidermis, leading to confusion with mycosis fungoides. In a blinded retrospective study of erythrodermic patients, histologic impression correlated with final diagnosis in up to 66% of cases. The authors suggest that multiple biopsies taken simultaneously may improve diagnostic accuracy.71

Pityriasis Rosea Pityriasis rosea (PR) is a self-limited exanthematous eruption of unknown etiology. However, there is some evidence that it is infectious. Recent work has shown an association with human herpesvirus (HHV)-7 and to a lesser extent, HHV-6 infection.72 There is a seasonal variation, with an increased incidence in the fall.73 Cases are often clustered,74 recurrence is unusual, and passive transfer of immunity has been demonstrated.75 Patients are usually in the first to fourth decades of life, and there is a slight female preponderance. Drugs may induce a similar eruption, particularly captopril76 and gold.77 Although PR is clinically a papulosquamous eruption, the histologic appearance is fundamentally that of spongiotic dermatitis, reviewed in Chap. 2. CLINICAL FEATURES The classic presentation is that of a single larger initial lesion known as the herald patch or mother patch. There may be a prodrome consisting of coryza, fever, and malaise. A secondary, more diffuse eruption appears 1 to 3 weeks after the initial lesion. Both the primary and the secondary lesions are oval orange-brown- or salmon-colored patches distributed on the upper trunk and proximal extremities. Individual lesions show a collarette of trailing scale. The long axis of lesions follows the lines of skin cleavage

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

CLINICAL FEATURES Lesions of the spongiotic reaction pattern have a similar clinical appearance regardless of etiology. Acute lesions show poorly defined pruitic, erythematous, edematous patches studded with vesicles. Subacute lesions show secondary changes of excoriation and crust formation, often with impetiginization. In chronic lesions, the edema and vesiculation are replaced by lichenification, scaling, and dyschromia. The clinical distribution of spongiotic dermatitis may offer clues to the specific etiology. Briefly, allergic contact dermatitis occurs at the site of antigen contact and may be patterned. It is uncommon on the thick skin of the palms and soles but may affect the dorsa of the hands and feet. Atopic dermatitis typically involves the flexures and occurs in people with a personal or family history of asthma or allergic rhinitis. Spongiotic systemic drug eruptions are unusual, but when they do occur, they are typically diffuse or photodistributed. Seborrheic dermatitis involves the central face, scalp, ears, upper chest, axillae, and groin. Lesions of nummular dermatitis are symmetrically distributed on the extremities as small, round plaques. Dyshidrotic dermatitis is characterized by vesicles along the margins of the digits and on the palms and soles.

In chronic atopic dermatitis, one sees a pattern indistinguishable from lichen simplex chronicus except that eosinophils are more common in the former. Dyshidrotic dermatitis shows spongiotic vesicles on acral skin. Neutrophils may be present in older vesicles. Allergic contact dermatitis may show intraepidermal spongiotic vesicles containing Langerhans cells and lymphocytes. Eosinophils are uncommon in allergic contact dermatitis. Seborrheic dermatitis shows follicular plugging, focal spongiosis, hemorrhage, and neutrophils within perifollicular parakeratotic scale/ crust. Vesicular dermatophyte infections show small collections of neutrophils within the stratum corneum. Hyphae may be recognized in hematoxylin and eosin (H&E)-stained sections as small holes in the stratum corneum. Fungal stains confirm the diagnosis. Dyshidrotic dermatitis may be pustular but can be distinguished from pustular psoriasis of the palms and soles by the presence of more extensive spongiosis and the absence of intracorneal collections of neutrophils (Munro microabscesses) in the former.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

(Langer lines) such that the pattern on the back has been compared with a Christmas tree. Less common patterns include flexural (inverse), papular, and purpuric PR. The clinical differential diagnosis includes secondary syphilis, nummular eczema, dermatophytosis, guttate psoriasis, and drug eruptions.

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HISTOPATHOLOGIC FEATURES Lesional skin shows mounding parakeratosis with underlying hypogranulosis, spongiosis, lymphocytic exocytosis, and extravasation of erythrocytes, sometimes extending into the epidermis (Fig. 4-16). There may be spongiotic microvesicles and irregular acanthosis. The superficial dermis contains a patchy, predominantly lymphocytic infiltrate, and the epidermis may contain dyskeratotic cells.78 DIFFERENTIAL DIAGNOSIS In PR, dermal papillae are not as elongated as in psoriasis, and neutrophils are not usually present. Spongiosis and lymphocytic exocytosis are more focal than in chronic spongiotic dermatitis, sometimes resembling Pautrier microabscesses. The eosinophils found in nummular dermatitis are usually absent in PR. Large-plaque parapsoriasis shows less spongiosis and a tendency for lymphocytes to line the dermal-epidermal junction. Plasma cells and endothelial swelling suggest syphilis. The superficial form of erythema annulare centrifugum is indistinguishable from PR.

Chronic Candidiasis and Dermatophytosis Dermatophytosis and candidiasis represent superficial fungal infections of the skin and its appendages. Infection is limited to the nonviable cornified components, including the hair, nails, and stratum corneum. Host factors are important in the development of clinical infection and the subsequent course of disease. Atopic patients,79 in whom IgE-mediated type I hypersensitivity response may inhibit delayed-type hypersensitivity, are susceptible to dermatophytosis. These infections are considered in greater detail in Chap. 21. CLINICAL FEATURES Chronic dermatophytosis may involve the glabrous skin (tinea corporis), palms and soles (tinea manuum and pedis), or nails (tinea unguium, onychomycosis). Tinea corporis is characterized by annular, scaly, erythematous plaques with central clearing. Lesions may be psoriasiform with abundant scale. On the feet or hands, chronic infection presents as thick, hyperkeratotic scale with minimal inflammation. Involvement of the thick stratum corneum of the hands or feet produces a glove- or moccasin-like pattern. Some patients may have involvement of both feet and one hand. Although candidiasis in otherwise healthy individuals is restricted to the intertriginous areas,

 FIGURE 4-16 Pityriasis rosea. The lesion exhibits focal parakeratosis and psoriasiform epidermal hyperplasia.

chronic mucocutaneous candidiasis may be more extensive, involving the scalp and acral skin. Lesions are often hyperkeratotic or granulomatous rather than the more typical erosive, erythematous, or pustular lesions seen in acute infection. Patients with chronic mucocutaneous candidiasis have an immune deficiency. HISTOPATHOLOGIC FEATURES In acute infections with dermatophytes or Candida species, the epidermis is spongiotic with focal parakeratosis. With chronicity, the epidermis becomes acanthotic with elongation of rete ridges. There may be aggregates of neutrophils within the parakeratotic scale or in subcorneal pustules resembling the spongiform pustules of Kogoj. Demonstration of organisms within the stratum corneum is diagnostic. The organisms are found in the nonviable, cornified components of the epidermis and its appendages, but they are sparse and may not be visible on routinely stained sections. Fungi may be visualized better in sections stained with PAS stain following diastase predigestion or with the methenamine silver stain. Typically, organisms may be found between an orthokeratotic layer and a parakeratotic layer (“sandwich sign”).80

Mycosis Fungoides (Cutaneous T-Cell Lymphoma) Mycosis fungoides (MF) is a T-cell lymphoma that primarily affects the skin.81 It is considered in detail in Chap. 34 but is included here because it may mimic nearly all patterns of inflammatory dermatoses, including psoriasiform dermatitis.82,83 CLINICAL FEATURES Classically, mycosis fungoides evolves through several stages. The patch stage is characterized by large, erythematous, scaly patches usually located on the trunk and proximal extremities. Lesions tend to be chronic, asymptomatic, and unresponsive to treatment. There may be dyschromia, epidermal atrophy, and telangiectasia (poikiloderma). The patch stage may persist for years, with an average of 6.1 years between the onset of disease and the ultimate diagnosis.84 Thickened plaques may develop from existing lesions or arise on previously unaffected skin. Plaques may be arcuate or annular as the result of coalescence or central clearing. They may have abundant scale resembling psoriasis. The development of cutaneous tumors is correlated with a poor prognosis, with a mean survival of 2.5 years.84 Plaques and tumors have a tendency to ulcerate and may become secondarily infected.

Sézary syndrome represents the leukemic phase of the disease, presenting as erythroderma with constitutional symptoms. Sézary syndrome must be distinguished clinically from other causes of erythroderma, such as pityriasis rubra pilaris, psoriasis, drug eruptions, and widespread spongiotic dermatitis.

DIFFERENTIAL DIAGNOSIS Because the earliest changes of MF are subtle and may mimic inflammatory dermatoses, multiple specimens taken over time may be necessary to establish the diagnosis. MF and psoriasis both show epidermal

A

Scabies Scabies infestation is a pruritic communicable disease caused by infestation by the human scabies mite, Sarcoptes scabiei var. hominis. The itch results from sensitization to the mite or its products and subsequent cell-mediated immune response. The mite is usually transmitted by direct contact with infested individuals or, less commonly, by fomites. Mites may survive away from the human host for several days.89 After mating, the female mite burrows into the superficial layers of the skin and lays her eggs. The female dies after about 5 weeks; the eggs hatch, and the cycle repeats.90 Typically, a patient is infested with only 10 to 15 adult mites,91 making demonstration and diagnosis occasionally difficult. In crusted scabies, however, mites are much more numerous.92 This clinical pattern is seen

in incapacitated, immunosuppressed, or institutionalized patients. CLINICAL FEATURES Scabies infestation is pruritic, particularly at night. Sites of predilection include the web spaces of fingers and toes, wrists, flexures, elbows, and male genitals. The diagnostic lesion is a linear burrow with a tiny vesicle at the blind end. Although there are typically few mites, intense pruritus and scratching may produce widespread secondary lesions. Areas of excoriation, irritant dermatitis, lichenification, or secondary infection are common.93 In crusted scabies, one sees hyperkeratotic or psoriasiform papules and plaques. The eruption may be diffuse, presenting as erythroderma. Because mites are numerous, these patients are highly contagious. Testing for human immunodeficiency virus (HIV) may be appropriate in patients with crusted scabies.94 Nodular scabies represents a persistent hypersensitivity response, as seen in other arthropod assaults (Fig. 4-17 A). HISTOPATHOLOGIC FEATURES The epidermis shows irregular acanthosis and focal spongiosis (Fig. 4-17). There may be a space within or just underneath the stratum corneum corresponding to the clinical burrow. The end of the burrow extends into the superficial stratum malpighii.95 Step sections may reveal the female mite or its products, including eggs or fecal material (scabala). The dermis contains a superficial and deep perivascular or nodular infiltrate composed of lymphocytes and variable numbers of eosinophils (sometimes producing flame figures). The infiltrate in

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

HISTOPATHOLOGIC FEATURES The histologic findings of mycosis fungoides vary with the clinical stage of the disease. Biopsies of infiltrated plaques show epidermal hyperplasia with elongation of the rete ridges resembling psoriasis. However, there are atypical lymphocytes in both the epidermis and the dermis. The epidermotropic lymphocytes may be single, in small aggregates (Pautrier microabscesses), or in a diffuse pattern resembling Paget disease. Adnexal epithelium may be similarly involved,62 and the pattern of epidermotropism may be limited to follicular epithelium85 or eccrine glands.86 These lymphocytes may show hyperchromatic, cerebriform nuclei and may be surrounded by clear halos. Similar cells may line the dermal-epidermal junction with vacuolar change of basal keratinocytes, the so-called “sentinel sign.” The papillary dermis shows random irregular fibrosis. Lymphocytes in the superficial dermis are also surrounded by clear halos.

hyperplasia and a superficial infiltrate composed of lymphocytes. Features favoring MF include irregular papillary dermal fibrosis and epidermotropism of atypical lymphocytes. Features favoring psoriasis include papillary dermal edema with dilated, tortuous capillaries and neutrophils within the stratum corneum. MF also may resemble chronic dermatitis. Inflammatory dermatoses may show some atypical cells, but the irregularity of nuclear contour, as determined by image analysis, is not as great as in MF.87 Although spongiosis may be seen in MF, it is mild compared with the number of lymphocytes within the epidermis. Drug eruptions, particularly those due to anticonvulsants, may simulate MF.88

B

 FIGURE 4-17 Scabies. (A) Nodular scabies. Erythematous firm nodules indistinguishable from chronic arthropod bite reactions. (B) Crusted scabies. The epidermis shows psoriasiform epidermal hyperplasia. The exoskeleton of two mites can be observed in the lower stratum corneum.

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nodular lesions may have the picture of lymphocytoma cutis and may contain atypical lymphocytes suggesting lymphoma.96 In crusted (Norwegian) scabies, mites are usually numerous and easily identified within a greatly thickened stratum corneum.97 Mites or their products are diagnostic. A nodular dermal infiltrate with eosinophils is not seen in other psoriasiform dermatitides.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Inflammatory Linear Verrucose (Verrucous) Epidermal Nevus Epidermal nevi are hamartomas of the epidermis or its appendages and are considered in detail in Chap. 26. Briefly, epidermal nevi may represent a mosaic state of disorders of cornification. For example, the acantholytic dyskeratotic variant may represent a localized form of Darier disease (keratosis follicularis), and the epidermolytic variant may represent localized epidermolytic hyperkeratosis, a disorder of keratins 1 or 10.98 Inflammatory linear verrucose epidermal nevus (ILVEN) was described as a distinct entity in 1971.99 Most cases are sporadic, but familial cases have been described.100 CLINICAL FEATURES ILVEN consists of grouped or coalescent lichenoid, psoriasiform, or verrucous papules in a linear arrangement, most commonly on the lower extremities. Fifty percent are

present by 6 months of age and seventyfive percent by 5 years of age.99 Lesions follow the lines of Blaschko,98 are pruritic, and may wax and wane in intensity. Associated skeletal malformations occur in some cases.101 HISTOPATHOLOGIC FEATURES The classic histopathologic finding of ILVEN consists of broad columns of parakeratosis without an underlying granular layer, alternating in the horizontal direction with columns of compact hyperkeratosis with underlying hypergranulosis102 (Fig. 4-18). Rete ridges are thickened and elongated with occasional slight spongiosis.99 Exocytosis of neutrophils as in psoriasis may occur. The superficial dermis contains a predominantly perivascular lymphocytic infiltrate. DIFFERENTIAL DIAGNOSIS The clinical differential diagnosis includes other linear papulosquamous lesions, such as linear psoriasis, linear Darier disease, linear porokeratosis, lichen striatus, and noninflammatory linear epidermal nevi. At the histological level, suprapapillary plates are thickened in ILVEN, whereas they are usually thinned in psoriasis. Parakeratosis in psoriasis is diffuse rather than arrayed in the broad columns of ILVEN. Linear Darier disease shows acantholysis and dyskeratosis. Porokeratosis is characterized by cornoid lamellae. Ordinary epidermal nevi show papillomatosis and are not inflammatory.

Bazex Syndrome Bazex syndrome (acrokeratosis neoplastica) is a paraneoplastic syndrome characterized by psoriasiform skin lesions in association with internal malignancy. Bullous lesions are also reported.103 A review of 113 cases found the most common neoplasm to be squamous cell carcinoma of the upper aerodigestive tract. Patients had a mean age of 61 years with a striking male predominance (108 of 113 patients).104 The pathogenesis may be related to a shared antigen between the neoplasm and normal skin or to tumor production of keratinocyte growth factors. An unrelated X-linked disorder showing follicular atrophoderma on the dorsal hands and feet, hypotrichosis, hypohidrosis, and basal cell carcinomas also carries the eponym Bazex syndrome (Bazex-Dupre-Christol syndrome).105 CLINICAL FEATURES Acrokeratosis neoplastica is a symmetrical psoriasiform eruption affecting acral areas, including hands and feet, ears, and nose. Nail involvement is common, with periungual and subungual hyperkeratosis and shedding of the nail plate. Lesions are distinctly violaceous and often resistant to treatment. Commonly the skin changes precede the diagnosis of internal malignancy. Treatment of the underlying malignancy reverses the skin changes but not the nail changes. Relapse of skin lesions may herald tumor recurrence.104 HISTOPATHOLOGIC FEATURES The histopathologic pattern is nonspecific. In addition to psoriasiform epidermal hyperplasia, keratinocytes may show vacuolar change and nuclear pyknosis.106

Pellagra

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 FIGURE 4-18 Inflammatory linear verrucose epidermal nevus. The epidermis shows psoriasiform epidermal hyperplasia with alternating hyperkeratosis and parakeratosis.

Pellagra results from a systemic deficiency of niacin (nicotinic acid) or its precursor, the essential amino acid tryptophan. The disease is characterized by the three D’s—diarrhea, dementia, and dermatitis. It was thought to be infectious until the remarkable work of Joseph Golberger.107 One hypothesis holds that the clinical manifestations may be caused by increased extracellular matrix viscosity.108 In this model, cutaneous lesions are localized to areas of sun exposure and trauma because “mediators” cannot diffuse from the site. Increased viscosity in the gastrointestinal tract may limit absorption leading to diarrhea.

Niacin deficiency also may occur in the carcinoid syndrome, where tryptophan is converted in quantity into serotonin (5-OH tryptophan). Hartnup disease is an autosomal recessive disorder characterized by an impairment of neutral amino acid transport. Tryptophan is not absorbed from the diet and is lost in the urine, leading to a deficiency of niacin.109 Regardless of the cause of niacin deficiency, the signs and symptoms respond promptly to replacement therapy.

HISTOPATHOLOGIC FEATURES The histopathologic features of pellagra are essentially identical to those seen in acrodermatitis enteropathica, necrolytic migratory erythema, essential fatty acid deficiency, and various nutritional disorders. They consist of extensive parakeratosis with underlying irregular epidermal hyperplasia. There is a pallor of the upper epidermis representing diffuse superficial keratinocyte necrosis. There may be a superficial perivascular lymphocytic infiltrate. A rash produced by a topical anesthetic demonstrated similar histology.110

CLINICAL FEATURES The hereditary form of zinc deficiency (ie, acrodermatitis enteropathica) develops earlier in bottlefed as opposed to breast-fed infants. As the name implies, the eruption typically starts as eczematous, scaly plaques on acral skin, including the scalp, paronychial folds, and perineum. Lesions may be erosive, pustular, or bullous, and secondary infection with Candida or bacteria is common. There may be failure to thrive. There may be alopecia or alternating light and dark banding of hair, which may be observed with polarizing light microscopy.114 HISTOPATHOLOGIC FEATURES Early lesions show continuous parakeratotic scale overlying a zone of normal stratum corneum. The epidermis is verrucous with pallor of the superficial malpighian layer and extensive necrosis of individual keratinocytes. Chronic lesions show psoriasiform epidermal hyperplasia with overlying hyperkeratosis and parakeratosis (Fig. 4-19). The superficial dermis contains a mild perivascular lymphocytic infiltrate. Bullous lesions show intraepidermal vacuolar change and ballooning degeneration associated with

extensive epidermal necrosis without acantholysis.115

Glucagonoma Syndrome Glucagon-producing islet cell (alpha cell) tumors of the pancreas are associated with necrolytic migratory erythema.116 The cutaneous manifestations may be related to a hypoaminoacidemia or to the high levels of glucagon itself. Diagnosis is made by demonstrating increased levels of glucagon in patients with the typical syndrome. Removal of the pancreatic tumor is curative. Necrolytic migratory erythema also may occur without glucagonoma117 in association with hepatocellular dysfunction and hypoalbuminemia.118 CLINICAL FEATURES The eruption is periorificial, acral, and flexural, often with severe glossitis. Lesions begin as erythematous papules. Later there are superficial vesicular lesions, erosions, crusting, and fissuring. Older lesions may be psoriasiform.119 Secondary infection with Candida and bacteria is common. Noncutaneous findings include stomatitis, weight loss, glucose intolerance, and diarrhea. HISTOPATHOLOGIC FEATURES Specimens are characterized by psoriasiform epidermal hyperplasia with confluent parakeratosis. There is pallor of the superficial epidermis with dyskeratotic keratinocytes. The pallor may result from intracellular edema.120 In more acute lesions, necrosis may be extensive, producing an intraepidermal

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

CLINICAL FEATURES In addition to the gastrointestinal symptoms (diarrhea) and neurologic disease, there is a characteristic skin eruption. Lesions are symmetrical and involve sun-exposed skin and areas of pressure. There are first erythema and burning or itching. Early lesions may be bullous. Later the eruption is characterized by hyperpigmentation, scaling, and fissuring. Facial involvement may simulate the “butterfly” eruption of lupus erythematosus. The limitation to sun-exposed sites may be striking, with extremity involvement showing a glove or stocking distribution. Involvement of the neck by a sharply demarcated photoinduced rash has been termed Casal necklace.

infants.111 As with the inherited form, dietary deficiency is quickly and completely reversed by supplementation with oral or parenteral zinc salts. The defective gene, SLC39A4, which encodes a zinc transporter named Zip4 has recently been described.112,113

Acrodermatitis Enteropathica Acrodermatitis enteropathica is an autosomal recessive disease caused by a defect in dietary zinc absorption. The defect is not complete, in that the disease may be reversed by zinc supplementation. Identical symptoms also may be produced by a diet deficient in zinc. Causes of noninherited zinc deficiency are numerous and include chronic diarrhea of any etiology, inadequate dietary content as in alcoholism or crash dieting, or renal loss as in dialysis. Also, chronic diseases with an increased catabolic rate may lead to zinc deficiency. Breast milk may have a low concentration of zinc, leading to zinc deficiency in breast-fed

 FIGURE 4-19 Acrodermatitis enteropathica.This well-developed lesion displays confluent parakeratosis, absence of the granular layer, and psoriasiform epidermal hyperplasia.

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bulla. Subcorneal pustules have been noted either in association with epidermal necrosis or as an isolated finding.121 There is a superficial perivascular lymphocytic infiltrate with papillary dermal edema. This condition also has been reported to show extensive suprabasilar acantholysis.122

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Secondary Syphilis Syphilis is a venereal disease caused by Treponema pallidum. This and other treponemal infections are considered in detail in Chap. 20. Secondary syphilis is reviewed briefly here because it may present as generalized psoriasiform lesions. As in psoriasis, the palms and soles may be involved. Mucosal lesions include condylomata lata, which are mamillated or papillomatous whitish papules or plaques. The clinical differential diagnosis of secondary syphilis includes guttate psoriasis, pityriasis rosea, tinea corporis, tinea versicolor, and nummular eczema. HISTOPATHOLOGIC FEATURES The papulosquamous lesions of secondary syphilis may show psoriasiform hyperplasia and hyperkeratosis, associated with exocytosis of neutrophils that accumulate in the scale-crust. The dermis shows a superficial and deep perivascular123 infiltrate composed of lymphocytes and plasma cells. Endothelial cells may be swollen, protruding into vascular lumina. The lichenoid pattern is more common than the psoriasiform pattern in secondary syphilis. DIFFERENTIAL DIAGNOSIS The inflammatory infiltrate of psoriasis, chronic dermatitis, and dermatophytosis is uniformly superficial rather than deep and does not contain plasma cells. Mycosis fungoides may have a superficial and deep infiltrate as well as a lichenoid pattern. However, the presence of atypical lymphocytes,124 Pautrier microabscesses, and a variable number of eosinophils distinguishes it from syphilis. Serological testing allows definitive diagnosis in syphilis.

Bowen Disease

78

Bowen disease, originally described in 1912,125 is a squamous cell carcinoma in situ. Although not a dermatitis, Bowen disease is included here because it may show psoriasiform epidermal thickening. Lesions arise more commonly on sun-exposed than covered skin, usually in patients older than 60 years of age.126 Bowen disease presents as a long-standing, fairly well-circumscribed, scaly, erythematous plaque. Lesions are usually solitary but may be multiple. Thus, Bowen

disease clinically may resemble papulosquamous dermatoses. HISTOPATHOLOGIC FEATURES Overall, the neoplasm is poorly circumscribed and asymmetrical. The epidermis is thickened with elongated rete ridges and may be papillomatous, resembling seborrheic keratosis in silhouette. The granular layer is absent with broad, thick overlying parakeratosis, which may form a cutaneous horn. Keratinocytes show marked atypia, lack of maturation, and individual cell dyskeratosis. Large, atypical cells with ample glycogen-containing cytoplasm may be distributed singly in a pagetoid pattern or in clusters among normal keratinocytes. This pattern may involve adnexal epithelium, particularly follicular infundibula.127 The superficial dermis often shows extensive solar elastosis and a perivascular lymphocytic infiltrate. At low power, the presence of parakeratosis, a thickened epidermis, and superficial dermal inflammation may suggest psoriasis. However, the presence of full-thickness keratinocyte atypia and lack of maturation define Bowen disease as a neoplasm and exclude inflammatory causes of psoriasiform epidermal changes.

Clear Cell Acanthoma Clear cell acanthoma (CCA, Degos acanthoma, pale cell acanthoma) is included here because it may show psoriasiform epidermal changes. A study of keratin expression found a pattern similar to that seen in inflammatory dermatoses such as psoriasis, and the authors speculate that CCA is an inflammatory dermatosis rather than a neoplasm.128 Another recent study lends support to CCA being a psoriasiform reaction pattern often occuring in the setting of chronic inflammation such as stasis dermatitis or a scar.129 The process is uncommon and most often occurs in adults. CCA is usually solitary but may be multiple.130 It is located most commonly on the extensor aspect of the leg. The typical presentation is a redbrown papule with a somewhat eroded surface. Lesions share clinical features with irritated seborrheic keratoses and pyogenic granuloma.131 HISTOPATHOLOGIC FEATURES CCA has the silhouette of a benign epidermal neoplasm in that it is well circumscribed, symmetrical, and sharply demarcated from the surrounding uninvolved skin. The granular layer is absent, and the surface may show hyperkeratosis, parakeratosis, or erosion. Rete ridges are elongated and interconnected in an anastomosing pattern.

Keratinocytes contain ample pale-staining cytoplasm, except for the basal layer, acrosyringia, and acrotrichia, which are spared. The pale-staining pattern represents accumulation of glycogen, which is PAS-positive and diastase-labile. Throughout the lesion are numerous neutrophils in association with spongiosis. Neutrophils may extend into the stratum corneum, forming microabscesses132 resembling psoriasis. The papillary dermis between elongated, interconnected rete ridges often is edematous with dilated capillaries and a perivascular lymphocytic infiltrate.

Lamellar Ichthyosis Lamellar ichthyosis (LI) is an autosomal recessive disorder of cornification distinct from nonbullous congenital ichthyosiform erythroderma.133 Affected individuals may be born encased in a colloidion membrane that is shed in the first 2 weeks of life. There is a lifelong thick scale over the entire body. This represents a retention hyperkeratosis rather than a hyperproliferative process. Palms and soles are hyperkeratotic, and the eyelids and lips are often everted (ectropion and eclabium). The disease has been attributed to a mutation in the gene for transglutaminase 1134 leading to defective cross-links required for normal cell envelope production with resulting permeability barrier abnormality.135 HISTOPATHOLOGIC FEATURES The histologic pattern of lamellar ichthyosis is nonspecific. In addition to irregular acanthosis, there is striking compact hyperkeratosis without parakeratosis.136 This pattern reflects the fact that LI is a retention hyperkeratosis rather than a hyperproliferative disorder. The granular layer may be thickened or thinned.137 Because LI is a genodermatosis rather than an inflammatory dermatosis, it is usually noninflammatory.

REFERENCES 1. Ackerman AB. Histologic Diagnosis of Inflammatory Skin Diseases. Philadelphia, PA: Lea and Febiger; 1978. 2. Farmer ER, Hood AF. Pathology of the Skin. East Norwalk, CT: Appleton and Lange; 1990. 3. Pinkus H. Psoriasiform tissue reactions. Aust J Dermatol. 1965;3:31-35. 4. Pinkus H, Mehregen AH. A Guide to Dermatohistopathology. East Norwalk, CT: Appleton Lange; 1976. 5. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Acad Dermatol. 1985;13:450-458.

27. Gordon M, Johnson WC. Histopathology and histochemistry of psoriasis: I. The active lesion and clinically normal skin. Arch Dermatol. 1967;95:402. 28. Cox AJ, Watson W. Histologic variation in lesions of psoriasis. Arch Dermatol. 1972;106:503. 29. Ragaz A, Ackerman AB. Evolution, maturation, and regression of lesions of psoriasis. Am J Dermatopathol. 1979;1:199-214. 30. Pinkus H, Mehregan AH. The primary histologic lesion of seborrheic dermatitis and psoriasis. J Invest Dermatol. 1966;46:109–116. 31. Braun-Falco O, Christophers E. Structural aspects of initial psoriatic lesions. Arch Dermatol Res. 1974;251:95. 32. Tsankov N, Angelova I, Kazandjieva J. Drug-induced psoriasis. recognition and management. Am J Clin Dermatol. 2000;1:159-165. 33. Baker H, Ryan TJ. Generalized pustular psoriasis: a clinical and epidemiological study of 104 cases. Br J Dermatol. 1968;80:771. 34. Wagner G, Luckasen JR, Goltz RW. Mucous membrane involvement in generalized psoriasis. Arch Dermatol. 1976;112:1010-1014. 35. Zelickson B, Muller S. Generalized pustular psoriasis: a review of 63 cases. Arch Dermatol. 1991;127:1339-1345. 36. Shelly WB. Generalized Pustular Psoriasis: Consultations in Dermatology. Philadelphia, PA; Saunders: 1972. 37. Rupec M. Zur ultrastruktur der spongiformen pustel. Arch Klin Exp Dermatol. 1970;239:30-49. 38. Spencer J, Silvers D, Grossman M. Pustular eruption after drug exposure: is it pustular psoriasis or a pustular drug eruption? Br J Dermatol. 1994;130:514-519. 39. Wilkins RF. Reiter’s syndrome: evaluation of preliminary criteria for definite diagnosis. Arthritis Rheum. 1981;24:844. 40. Engelman EP, Weber HM. Reiter’s syndrome. Clin Orthop. 1968;57:19. 41. Brewerton DA. Reiter’s disease and HLA 27. Lancet. 1973;2:996. 42. Granfors K. Yersinia antigens in synovial fluid cells from patients with reactive arthritis. New Engl J Med. 1989;320:216. 43. Beutler A, Whittum-Hudson J, Nanagara R, et al. Intracellular location of inapparently infecting Chlamydia in synovial tissue from patients with Reiter’s syndrome. Immunol Res. 1994;13:163-171. 44. Keat A. Reactive arthritis (review). Adv Exp Med Biol. 1999;455:201-206. 45. Petersel DL, Sigal LH. Reactive arthritis. Infect Dis Clin North Am. 2005;19:863-883. 46. Arnett FC. Incomplete Reiter’s syndrome: clinical comparison with the classical triad. Ann Rheumatol Dis. 1979;38:73. 47. Kulka JP. The lesions of Reiter’s syndrome. Arthritis Rheum. 1962;5:195. 48. Griffiths WAD. Pityriasis rubra pilaris. Clin Exp Dermatol. 1980;5:105. 49. Gross DA, Landau JW, Newcomer VD. Pityriasis rubra pilaris: report of a case and analysis of the literature. Arch Dermatol. 1969;99:710. 50. Vanderhooft SL, Francis JS, Holbrook KA, et al. Familial pityriasis rubra pilaris. Arch Dermatol. 1995;131:448-453. 51. Porter D, Shuster S. Epidermal renewal and amino acids in psoriasis and pityriasis rubra pilaris. Arch Dermatol. 1968; 98:339.

52. Sonex TS. Nail changes in adult type I pityriasis rubra pilaris. J Am Acad Dermatol. 1986;15:956. 53. Albert MR, Mackool BT. Pityriasis rubra pilaris. Int J Dermatol. 1999;38:1-11. 54. Gonzalez-Lopez A, Velasco E, Pozo T, Del Villar A. HIV-associated pityriasis rubra pilaris responsive to triple antiretroviral therapy. Br J Dermatol. 1999;140: 931-934. 55. Soeprono FF. Histologic criteria for the diagnosis of pityriasis rubra pilaris. Am J Dermatopathol. 1986;8:277-283. 56. Magro CM, Crowson AN. The clinical and histomorphological features of pityriasis rubra pilaris: a comparative analysis with psoriasis. Cutan Pathol. 1997;24:416-424. 57. Goldblum RW, Piper WN. Artificial lichenification produced by a scratching machine. J Invest Dermatol. 1957;22: 405-415. 58. Neumann E, Winter V. The character of cells with “alteration cavitaire” (Leloir). Acta Dermatol Venereol. 1965;45:272-274. 59. Brocq L. Les parapsoriasis. Ann Dermatol Syphiligr. 1902;3:433. 60. Lambert WC, Everett MA. The nosology of parapsoriasis. J Am Acad Dermatol. 1981;5:373. 61. Samman PD. The natural history of parapsoriasis en plaque (chronic superficial dermatitis) and prereticulotic poikiloderma. Br J Dermatol. 1972;87:405. 62. Sanchez JL, Ackerman AB. The patch stage of mycosis fungoides. Am J Dermatopathol. 1979;1:5-26. 63. Simon M, Flaig MJ, Kind P, et al. Large plaque parapsoriasis: clinical and genotypic correlations. J Cutan Pathol. 2000; 27:57-60. 64. Lindae ML. Poikilodermatous mycosis fungoides and atrophic large plaque psoriasis exhibit similar abnormalities of T-cell antigen expression. Arch Dermatol. 1988;124:366. 65. Staib G, Sterry W. Use of polymerase chain reaction in the detection of clones in lymphoproliferative diseases of the skin. Recent Results Cancer Res. 1995;139: 239-247. 66. Klemke CD, Dippel E, Dembinski A, et al. Clonal T cell receptor gammachain gene rearrangement by PCRbased GeneScan analysis in the skin and blood of patients with parapsoriasis and early-stage mycosis fungoides. J Pathol. 2002;197:348-354. 67. Kikuchi A, Naka W, Harada T, et al. Parapsoriasis en plaques: its potential for progression to malignant lymphoma. J Am Acad Dermatol. 1993;29: 419-422. 68. Ackerman AB, Ragaz A. A plea to expunge the word “eczema” from the lexicon of dermatology and dermatopathology. Am J Dermatopathol. 1982;4:315-326. 69. Botella-Estrada R, Sanmartin O, Oliver V, et al. Erythroderma: a clinicopathological study of 56 cases. Arch Dermatol. 1994;130:1503-1507. 70. Zip C, Murray S, Walsh NM. The specificity of histopathology in erythroderma. J Cutan Pathol. 1993;20:393-398. 71. Walsh N, Prokopetz R, Tron V, et al. Histopathology in erythroderma: review of a series of cases by multiple observers. J Cutan Pathol. 1994;21:419-423. 72. Broccolo F, Drago F, Careddu AM, et al. Additional evidence that pityriasis rosea is associated with reactivation of

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

6. Cram DL. Psoriasis: current advances in etiology and treatment. J Am Acad Dermatol. 1981;4:1-14. 7. Weinstein GD. Autoradiographic analysis of turnover times of normal and psoriatic epidermis. J Invest Dermatol. 1968;45:257. 8. Farber EM, Nall ML, Watson W. Natural history of psoriasis in 61 twin pairs. Arch Dermatol. 1974;109:207. 9. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol. 1985;13:450-456. 10. Theeuwes M, Morhenn V. Allelic instability in the mitosis model and the inheritance of psoriasis (review). Am Acad Dermatol. 1995;32:44-52. 11. Zheng G, Thomson G, Pen Y. Allelic instability in mitosis can explain “genome imprinting” and other genetic phenomena in psoriasis. J Med Genet. 1994;51: 163-164. 12. Capon F, Munro M, Barker J, Trembath R. Searching for the major histocompatibility complex psoriasis susceptibility gene. J Invest Dermatol. 2002;118: 745-751. 13. Capon F, Trembath RC, Barker JN. An update on the genetics of psoriasis. Dermatol Clin. 2004;22:339-347. 14. Boehncke W, Sterry W, Hainzl A, et al. Psoriasiform architecture of murine epidermis overlying human psoriatic dermis transplanted onto SCID mice. Arch Dermatol Res. 1994;286:325-330. 15. Bata-Csorgo Z, Hammerberg C, Voorhees J, Cooper K. Intralesional Tlymphocyte activation as a mediator of psoriatic epidermal hyperplasia (review). J Invest Dermatol. 1995;105:89s-94s. 16. Creamer J, Barker J. Vascular proliferation and angiogenic factors in psoriasis. Clin Exp Dermatol. 1995;20:6-9. 17. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370:263-271. 18. Leung D, Walsh P, Giorno R, Norris D. A potential role for superantigens in the pathogenesis of psoriasis. J Invest Dermatol. 1993;100:225-228. 19. Valdimarsson H, Baker B, Jonsdottir I, et al. Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens? (review). Immunol Today. 1995;16:145-149. 20. Farber EM, Nall ML. The natural history of psoriasis in 5600 patients. Dermatologica. 1974;148:1. 21. Whyte HJ, Baughmann RD. Acute guttate psoriasis and streptococcal infection. Arch Dermatol. 1964;89:350. 22. Telfer N, Chalmers R, Whale K, Colman G. The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol. 1992;128:39-42. 23. McFadden J, Valdimarsson H, Fry L. Cross-reactivity between streptococcal M surface antigen and human skin. Br J Dermatol. 1991;125:443-447. 24. Braverman JM, Cohen I, Black MM. Metabolic and ultrastructural studies in a patient with pustular psoriasis. Br J Dermatol. 1972;105:189. 25. Khalil FK, Keehn CA, Saeed S, et al. Verrucous psoriasis: a distinctive clinicopathologic variant of psoriasis. Am J Dermatopathol. 2005;27:204-207. 26. Ackerman AB, Ragaz A. The Lives of Lesions: Chronology in Dermatopathology. New York: Masson; 1984.

79

73.

74

75.

76.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

77.

78.

79. 80. 81. 82.

83. 84.

85. 86.

87.

88.

89.

90. 91. 92.

80

human herpesvirus-6 and -7. J Invest Dermatol. 2005;124:1234-1240. Chuang T. Pityriasis rosea in Rochester, Minnesota, 1969 to 1978: a 10-year epidemiologic study. J Am Acad Dermatol. 1982;7:80. Bjornberg A, Hellgren L. Pityriasis rosea: a statistical, clinical, and laboratory investigation of 826 patients and matched healthy controls. Acta Dermatol Venereol. 1962;42(suppl 50):1. Salin RW. The treatment of pityriasis rosea with convalescent plasma, gamma globulin, and pooled plasma. Arch Dermatol. 1957;76:659. Wilkin JK, Kirkendall WM. Pityriasis rosea-like rash from Captopril. Arch Dermatol. 1982;118:186. Wilkinson SM, Smith AG, Davis MJ, et al. Pityriasis rosea and discoid eczema: doserelated reactions to treatment with gold. Ann Rheumatol Dis. 1992;51:881-884. Okamato H, Imamura S, Aoskima T. Dyskeratotic degeneration of epidermal cells in pityriasis rosea. Br J Dermatol. 1982;107:189-194. Jones HE. The atopic-chronic-dermatophytosis syndrome. Acta Dermatol Venereol. 1980;92(suppl):81. Gottlieb GJ, Ackerman AB. The “sandwich sign” of dermatophytosis. Am J Dermatopathol. 1986;8:347-350. Willemze R, Jaffe ES, Burg G, et al. WHOEORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785. Shapiro P, Pinto F. The histologic spectrum of mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma): a review of 222 biopsies, including newly described patterns and the earliest pathologic changes. Am J Surg Pathol. 1994;18:645-667. Reddy K, Bhawan J. Histologic mimickers of mycosis fungoides: a review. J Cutan Pathol. 2007;34:519-525. Epstein EHJ. Mycosis fungoides: survival, prognostic factors, response to therapy, and autopsy findings. Medicine. 1972;51:61. Goldenhersh M, Zlotogorski A, Rosenmann E. Follicular mycosis fungoides. Am J Dermatopathol. 1994;16:52-55. Zelger B, Sepp N, Weyrer K, et al. Syringotropic cutaneous T-cell lymphoma: a variant of mycosis fungoides? Br J Dermatol. 1994;130:756-769. McNutt NS, Crain WR. Quantitative electron microscopic comparison of lymphocyte nuclear contours in mycosis fungoides and benign infiltrates in the skin. Cancer. 1981;47:698. Rijlaarsdam U, Scheffer E, Meijer CJ, et al. Mycosis fungoides-like lesions associated with phenytoin and carbamazepine therapy. J Am Acad Dermatol. 1991;24:216-220. Arlian LG. Prevalence of Sarcoptes scabiei in the homes and nursing homes of scabietic patients. J Am Acad Dermatol. 1988;19:806. Molinaro MJ, Schwartz RA, Janniger CK. Scabies. Cutis. 1995;56:317-321. Commons CA. We can get rid of scabies: new treatment available soon. Med J Aust. 1994;160:317-318. Sierra G, Ruis F, Romeu J. Hospital outbreak of scabies stemming from two AIDS patients with Norwegian scabies. Lancet. 1990;335:1227.

93. O’Donnell BF, O’Loughlin S, Powell FC. Management of crusted scabies. Int J Dermatol 1990;29:258-266. 94. Schlesinger I, Oelrich DM, Tyring SK. Crusted (Norwegian) scabies in patients with AIDS: the range of clinical presentations. South Med J. 1994;87:352-356. 95. Hejazi N, Mehregen AH. Histologic study of inflammatory lesions. Arch Dermatol. 1975;111:37-39. 96. Thomson J, Cochrane T, Cochran R. Histology simulating reticulosis in nodular scabies. Br J Dermatol. 1974;90: 421-429. 97. Fernandez N, Torres A, Ackerman AB. Pathological findings in human scabies. Arch Dermatol. 1977;113:320-324. 98. Bolognia JL, Orlow SJ, Glick SA. Lines of Blaschko. J Am Acad Dermatol. 1994; 31:157-190. 99. Altman L, Mehregan AH. Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1971;104:385-389. 100. Goldman K, Don PC. Adult onset of inflammatory linear verrucous epidermal nevus in a mother and her daughter. Dermatology. 1994;189:170-172. 101. Golitz LE, Weston WL. Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1979;115:1208-1212. 102. Dupre A, Christol B. Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1977;113:767-769. 103. Mutasim DF, Meiri G. Bazex syndrome mimicking a primary autoimmune bullous disorder. J Am Acad Dermatol. 1999;40:822-825. 104. Bolognia JL. Bazex syndrome: acrokeratosis paraneoplastica. Semin Dermatol. 1995;14:84-89. 105. Plosila M, Kustala R, Niemi KM. Bazex syndrome: follicular atrophoderma with multiple basal cell carcinomas, hypotrichosis, and hypohidrosis. Clin Exp Dermatol. 1981;6:31. 106. Pecora AL, Landsman L, Imgrund SP. Acrokeratosis neoplastica (Bazex syndrome). Arch Dermatol. 1983;120: 820-826. 107. Elmore JG, Feinstein AR. Joseph Goldberger: an unsung hero of American clinical epidemiology. Ann Intern Med. 1994;121:372-375. 108. Stone OJ. Pellagra: increased viscosity of extracellular matrix. Med Hypoth. 1993;40:355-359. 109. Halvorsen K, Halvorsen S. Hartnup disease. Pediatrics. 1963;31:565. 110. Dong H, Kerl H, Cerroni L. EMLA cream-induced irritant contact dermatitis. J Cutan Pathol. 2002;29:190-192. 111. Lee MG. Transient symptomatic zinc deficiency in a full term breast fed infant. J Am Acad Dermatol. 1990;23:375-379. 112. Kury S, Dreno B, Bezieau S, et al. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nature Genet. 2002;31:239-240. 113. Maverakis E, Fung MA, Lynch PJ, et al. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol. 2007;56:116-124. 114. Traupe H. Polarizing microscopy of hair in AE. Pediatr Dermatol. 1986;3:300. 115. Borroni G, Brazzelli V, Vignati G, et al. Bullous lesions in acrodermatitis enteropathica: histopathologic findings regarding two patients. Am J Dermatopathol. 1992;14:304-309.

116. Mallinson CN, Bloom SR, Warin AP, et al. A glucagonoma syndrome. Lancet. 1974; 2:1-5. 117. Thivolet J. Necrolytic migratory erythema without glucagonoma. Arch Dermatol. 1981;117:4. 118. Marinkovich MP, Botella R, Datloff J, Sangueza OP. Necrolytic migratory erythema without glucagonoma in patients with liver disease. J Am Acad Dermatol. 1995;32:604-609. 119. Kahan RS, Perez-Figaredo RA, Neimanis A. Necrolytic migratory erythema. Arch Dermatol. 1977;113:792-797. 120. Sweet R. A dermatosis specifically associated with a tumor of pancreatic alpha cells. Br J Dermatol. 1974;90:301-308. 121. Kheir SM, Omura EF, Grizzle WE, et al. Histologic variation in the skin lesions of the glucagonoma syndrome. Am J Surg Pathol. 1986;10:445-453. 122. Long CC, Laidler P, Holt P. Suprabasal acantholysis: an unusual feature of necrolytic migratory erythema. Clin Exp Dermatol. 1993;18:464-467. 123. Jeerapeet P, Ackerman A. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373-377. 124. Cochran R, Thomson J, Flemming K. Histology simulating reticulosis in secondary syphilis. Br J Dermatol. 1976;95: 251-254. 125. Bowen JT. Precancerous dermatosis. J Cutan Dis. 1912;30:241-255. 126. Thestrup-Pedersen K. Morbus Bowen: a description of the disease in 617 patients. Acta Dermatol Venereol. 1988; 68:236. 127. Brownstein MH, Raboniwitz AD. The precursors of cutaneous squamous cell carcinoma (review). Int J Dermatol. 1979; 18:1-16. 128. Ohnishi T, Watanabe S. Immunohistochemical characterization of keratin expression in clear cell acanthoma. Br J Dermatol. 1995;133:186-193. 129. Zedek DC, Langel DJ, White WL. Clear cell acanthoma acanthosis: a psoriasiform reaction pattern lacking tricholemmal differentiation. Am J Dermatopathol. 2007;29:378-384. 130. Baden TJ. Multiple clear cell acanthomas. J Am Acad Dermatol. 1987; 16:1075. 131. Fine RM, Chernosky ME. Clinical recognition of clear-cell acanthoma (Degos). Arch Dermatol. 1969;100: 559-563. 132. Jones EW, Wells GC. Dego’s acanthoma (acantome a cellules claires). Arch Dermatol. 1966;94:286-294. 133. Williams ML, Elias PM. Heterogeneity in autosomal recessive ichthyosis: clinical and biochemical differentiation of lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma. Arch Dermatol. 1985;121:477. 134. Russell LJ, DiGiovanna JJ, Rogers GR, et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nature Genet. 1995;9:279-283. 135. Elias PM, Schmuth M, Uchida Y, et al. Basis for the permeability barrier abnormality in lamellar ichthyosis. Exp Dermatol. 2002;11:248-256. 136. Williams ML, Elias PM. Heterogeneity in autosomal recessive ichthyosis. Arch Dermatol. 1985;121:477-488. 137. Vandersteen PR, Muller SA. Lamellar ichthyosis. Arch Dermatol. 1972;106: 694-701.

CHAPTER 5 Superficial and Deep Perivascular Dermatitis A. Neil Crowson

SUPERFICIAL PERIVASCULAR DERMATITIS

SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

Urticaria Perivascular lymphocytic dermatitis Toxic erythema of pregnancy Gyrate erythemas Pityriasis lichenoides Perniosis Rickettsial and viral infections Polymorphous light eruption (superficial variant)

Urticaria Superficial and deep perivascular dermatitis lymphocytic Toxic erythema of pregnancy Gyrate erythemas Pityriasis lichenoides Perniosis Rickettsial and viral infections Polymorphous light eruption (superficial and deep variant) Photosensitive eruptions Connective tissue disease Discoid lupus erythematosus

Connective tissue disease Systemic lupus erythematosus Subacute cutaneous lupus erythematosus Mixed connective tissue disease Dermatomyositis

Urticaria pigmentosa

Leprosy (indeterminate) Syphilis Borreliosis Leukemia and leukemids Urticaria pigmentosa

URTICARIA CLINICAL FEATURES The urticarias are common, transient eruptions that affect roughly 15% of the population at some time in life.1 They comprise palpable erythematous papules or wheals that lack surface alteration and wax and wane without a clinical residuum (Fig. 5-1A). Lesions of urticaria are typically “here today and gone tomorrow,” unlike urticarial rashes induced by drugs or urticarial vasculitis, in which the individual lesions superficially may resemble urticaria but last several days.2 Urticarias may be acute or chronic, the latter defined as those that last longer than 6 weeks, and may be either idiopathic or of physical, IgE-, immune-complex-, or histamine-releasing agent-mediated types (Table 5-2). The term chronic urticaria embraces idiopathic urticaria, urticarial vasculitis, and physical urticaria.3 Roughly one-third of all cases of chronic urticaria represent physical urticarias, defined by specific triggering stimuli and subclassified as adrenergic, aquagenic, cholinergic, cold, delayed pressure, localized heat, and solar urticarias; vibratory angioedema; dermographism; and exercise-induced anaphylaxis.2 The physical urticarias typically manifest within 10 minutes of exposure to the triggering stimulus and resolve within a day. The exception is delayed pressure urticaria, which often

arises several hours after an episode of sustained pressure and may last over a day. Contact urticaria often manifests 10 to 20 minutes after the stimulus and disappears within a few hours. Various forms of physical urticaria may overlap with idiopathic urticaria, and some patients manifest multiple different types of physical urticaria.4,5 Physical triggers are held to be the most common precipitating factors in children.6 It is important to attempt to separate the various triggers and forms of urticaria, as both the pathogenesis and therapy may be different. Acute urticarias, for example, typically reflect a hypersensitivity response, while chronic urticarias have a more complex pathogenesis.7 The clinical appearance of individual lesions results from vasodilation, enhanced vascular permeability, and extravasation of proteins into the dermis. There is often a surrounding flare due to an axonal reflex.2 Lesions may progress to form confluent plaques with an annular or arcuate morphology. Angioedema is an analogous physiologic process that extends to the subcutis and subjacent soft tissues and sometimes to the upper airways with potentially fatal consequences; it may relate to an absolute or relative C1 esterase-inhibitor deficiency that may be familial. The main mediators include histamine, prostaglandins, and interleukin 1 (IL-1), the liberation of

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

When approaching a skin biopsy showing a dermal inflammatory cell infiltrate, one must take note of the presence and type of epidermal alteration, vascular changes, stromal response, and the character of the infiltrate itself. With respect to the former, the presence or absence of parakeratosis and orthohyperkeratosis and concomitant acanthosis or atrophy is a clue to the chronicity of the process and the type of injury pattern; eg, a spongiotic versus a cell-poor vacuolopathic interface dermatitis, respectively, points toward a delayed-type hypersensitivity reaction versus a humorally mediated or autoimmune disease. The infiltrate may be lymphohistiocytic or may contain an admixture of granulocytes, the former usually a sign of delayed-type hypersensitivity and the latter often a clue to an immune-complex (type III) or an anaphylactic (type I) hypersensitivity reaction. Histiocyte-predominant infiltrates may be a clue to a drug, viral, or idiopathic granulomatous process. The disposition of the infiltrate, either tightly “cuffed” around the vasculature or both perivascular and interstitial in distribution, may be a clue to a gyrate erythema, on the one hand, or to urticaria, on the other. The stromal response, in the context of either a fibrosing reaction or collagen necrobiosis, may be a clue to a chronic process or a systemic disease. The presence or absence of vascular fibrin deposition is essential to definition of a vasculitis, and the presence or absence of endothelial cell necrosis, telangiectasia, and diminished vascular density of the superficial plexus, features indicative of certain of the connective tissue diseases, must be addressed, as must the type of inflammatory cells in vessel walls and lumina. Although by no means comprehensive, Table 5-1 provides a differential diagnostic approach to the superficial and the superficial and deep perivascular dermatitides. The reader is referred to other sections of this book for an in-depth consideration of many of these entities.

Table 5-1 Perivascular Inflammatory Cell Infiltrates with Minimal or No Epidermal Alteration

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A

B

 FIGURE 5-1 Urticaria. (A) Erythematous papules and plaques without surface alteration show expansion, coalescence, and central clearing. Such lesions wax and wane and usually disappear in a matter of hours without any clinical residuum. (B) The reticular dermis shows edema, consisting of separation of collagen bundles, accompanied by an interstitial granulocytic infiltrate.

Table 5-2 The Common Forms of Chronic Urticarias TYPE OF URTICARIA

PRINCIPAL CLINICAL FEATURES

HISTOPATHOLOGICAL FEATURES

Acute and chronic idiopathic

Profuse or sparse edematous papules or wheals, often annular with itching

Symptomatic dermatographism

Itchy, linear wheals with a surrounding bright red flare at sites of scratching or rubbing

Absence of epidermal alteration Dermal edema Sparse perivascular infiltrate composed of lymphocytes, eosinophils, neutrophils (variable) As above

Other physical urticarias Cold

Itchy pale or red swelling at sites of contact with cold surfaces or fluids Large painful or itchy red swelling at sites of pressure lasting 24 hours or more

As above but neutrophils may be more prominent

Solar

Itchy pale or red swelling at site of exposure to ultraviolet or visible light

As above but neutrophils may be more prominent

Cholinergic

Itchy wheals on trunk, neck, and limbs

As above but neutrophils may be more prominent

Pressure

As above but neutrophils may be more prominent

DIAGNOSTIC TEST

Light stroking of skin causes an immediate wheal with itching 10-minute application of an ice pack causes a wheal within 5 minutes of the removal of ice Application of pressure produces persisent red swelling after a latent period of 1-4 hours Irradiation by a 2.5 kW 290-690 nm source for 30-120 seconds causes wheals in 30 minutes Exercise or a hot shower elicits eruption

SOURCE: After Greaves.1

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which is provoked by type I and III immune reactions (see Chap. 22) and nonimmunologic mechanisms causing mast cell or basophil degranulation. The latter are exemplified by opiates and foods such as strawberries and shellfish.

The IgE-mediated urticarias constitute antigen-specific reactions to certain foods, drugs, pollens, insect bites, and stings. Roughly 35% of urticarias have an autoimmune basis2 and are associated with autoimmune thyroid disease,

insulin-dependent diabetes, vitiligo, pernicious anemia, and rheumatoid arthritis.8 Patients with autoantibodies tend to have more severe disease.8 There is evidence that delayed-type hypersensitivity mechanisms may play a role in cases of

urticaria, typically of acute type, implying that acute urticaria may be a risk factor for anaphylactic reactions.19 HISTOPATHOLOGIC FEATURES The histology reflects the age of the lesion biopsied and the type of provocative stimulus. One constant is edema, characterized by separation of collagen bundles (Fig. 5-1 B). Blood vessels and lymphatics usually are dilated and show endothelial swelling. The upper dermis is preferentially involved, except in angioedema, which prominently involves the deep reticular dermis and subcutis. A sparse perivascular inflammatory infiltrate consisting of a variable admixture of lymphocytes, eosinophils, and neutrophils characterizes the lesions. Mast cells and granulocytes are seen within the interstitium and granulocytes within blood vessels. Degranulated mast cells resemble lymphocytes and, when present, may suggest a mononuclear cell-predominant vascular reaction. The neutrophilic urticarias tend to have a more cellular infiltrate, often with neutrophilic packing of blood vessels (Fig. 5-2). This neutrophil-rich histology may be seen in an incipient lesion of physical urticaria, which is, in its chronic state, more likely to manifest the cell-poor morphology previously described. The autoimmune and nonautoimmune urticarias have a similar histomorphology.20 DIFFERENTIAL DIAGNOSIS The differential diagnosis of urticaria includes persistent dermal hypersensitivity reactions to drugs,

insect bite reactions, dermal contact hypersensitivity, viral exanthems, gyrate erythemas, and small-vessel vasculitides. Most of these can be distinguished from urticaria by epidermal changes such as parakeratosis, acanthosis, spongiosis, and basal layer vacuolization, by lymphocytic infiltrates that usually are heavier and manifest a more pronounced perivascular distribution, and by the absence of interstitial granulocytes or prominent reticular dermal edema. With respect to gyrate erythemas, these can be either superficial, associated with the aforementioned epidermal changes, or deep; the latter show striking perivascular cuffing of lymphocytes, accompanied in some cases by eosinophils. The absence of vascular fibrin deposition, leukocytoclastic debris, or extravasation of fragmented red blood cells enables distinction from leukocytoclastic vasculitis. More challenging is the distinction from urticarial vasculitis, which characteristically manifests only mild vascular injury, but should be suspected when urticaria-like lesions resolve clinically after more than 24 hours with a residuum of pigmentation. The histopathology of urticarial vasculitis is typified by a mild form of leukocytoclastic vasculitis comprising erythrocyte extravasation, slight leukocytoclasia, and neutrophilic infiltration of venular endothelia with minimal fibrin deposition. It is important to make this distinction, and when urticarial vasculitis is present, to explore for manifestations of systemic disease including renal involvement.3

 FIGURE 5-2 Urticaria. A sparse superficial and deep perivascular mixed-cell infiltrate is seen, including lymphocytes, neutrophils, and eosinophils. Neutrophils are present in blood vessels, and a sparse interstitial infiltrate of granulocytes is present.

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

urticaria, particularly those due to food additives and chronic infections.9 Roughly one in eight children with physical urticaria will develop respiratory symptoms and two-thirds will manifest angioedema.5 Long-term follow-up indicates that less than half will manifest complete remissions over time.5 Novel cellular basophil activation tests, including the measurement of CD203c and/or CD63 as activation markers on human basophils when incubated with patient serum, are developing as an effective screening measure,3,10 and may ultimately bear fruit from the standpoint of elucidating specific drug and other antigenic triggers in the individual patient. Physical urticarias tend to respond to H1 antihistamines, save for the exceptions of solar and delayed pressure urticaria.11 The neutrophilic urticarias usually represent the sequelae of complement activation, causes of which include C1q esterase deficiency and circulating immune complexes containing antigens of endogenous or exogenous origin, the latter often comprising drug or microbial antigens such as Epstein-Barr virus or the hepatitis viruses.12 Characteristic endogenous causes include connective tissue diseases, neoplasms, and mixed cryoglobulinemia. Neutrophilic urticaria also may characterize the physical urticarias. Chronic urticarias relate in some patients to IgG autoantibodies that crosslink the alpha subunit of the high-affinity IgE receptor (FceRIa) on basophils and mast cells, causing their degranulation with subsequent upregulation of endothelial adhesion molecules.13,14 Some patients with chronic urticaria exhibit allergies to food, acetylsalicylic acid, or other common antigens. A link to Helicobacter pylori colonization of gastric mucosa has been suggested but must be considered unproven in the absence of a controlled eradication trial.15,16 Cholinergic urticaria is caused by a rise in core temperature following exercise, overheating, or stress2; enhancement of sympathetic activity is postulated to lead to acetylcholine release at nerve endings, triggering degranulation of apposed mast cells. Schnitzler syndrome is a rare form of chronic urticaria associated with IgM-k paraproteinemia, bone pain, hyperostosis, and pyrexia.17 Even more rare are cases of autosomal dominantly inherited familial cold urticaria characterized by recurrent inflammatory crises commencing in childhood and associated with fever, arthralgia, and urticaria in response to cold exposure.18 One study of patients with idiopathic anaphylaxis showed that some 58% had a prior history of idiopathic

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Other extracutaneous manifestations include involvement of synovia, and of ophthalmologic, respiratory, central nervous, and gastrointestinal systems.9,21 The same underlying systemic diseases are as implicated in conventional leukocytoclastic vasculitis, such as malignancy or systemic connective tissue diseases.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

TOXIC ERYTHEMA OF PREGNANCY (POLYMORPHIC ERUPTION OF PREGNANCY/ PRURITIC URTICARIAL PAPULES AND PLAQUES OF PREGNANCY) CLINICAL FEATURES The most common dermatosis of the gravid state, pruritic urticarial papules and plaques of pregnancy (PUPPP), has an incidence of 1 in 20 pregnancies and manifests as pruritic papules and urticarial plaques, sometimes with superimposed vesicles, in and near striae of the abdomen and proximal thighs22 (Table 5-3). While the initial lesions are as described above, roughly half of the patients show changing morphology over time,23 developing polymorphous features including erythema, vesicles, and targetoid eczematous lesions.23 Lesions usually develop in the last few weeks of pregnancy and may spread to the extremities or become generalized. Periumbilical sparing and spontaneous resolution are characteristic. The association of this eruption with large babies, twin and triplet pregnancies, and increased

maternal weight gain raises the possibility that it relates somehow to excessive abdominal distension.24 It occurs in late pregnancy in 85% of cases and in the immediate postpartum period in 15% of cases.23 HISTOPATHOLOGIC FEATURES Superficial perivascular lymphocytic or lymphocytic and eosinophilic infiltrates with a nondescript appearance, accompanied in one-third of cases by exocytosis and spongiosis, are characteristic (Fig. 5-3). Fibroblast proliferation is an infrequent concomitant.22 Leukocyte debris may be present, but there is no vascular fibrin deposition to suggest a leukocytoclastic vasculitis. Although usually nonreactive by direct immunofluorescent testing, lesions of PUPPP may show granular IgM, IgA, or C3 deposition at the dermalepidermal junction and/or in blood vessels,25,26 suggesting a delayed-type hypersensitivity reaction or possibly an immune-complex contribution to the pathogenesis.22,25,26 Analysis of serum hormone levels in one series showed a significant drop in cortisol levels in patients with PUPPP versus normal pregnant control patients27; enhanced progesterone receptor expression in lesional as opposed to nonlesional keratinocytes also suggests the possibility that the action of hormones may play a role.28 DIFFERENTIAL DIAGNOSIS The differential diagnosis of PUPPP includes atopic dermatitis; dermal hypersensitivity reactions

to drugs, contactants, and insect bites; and herpes gestationis. Most of the hypersensitivity reactions cannot be reliably distinguished from PUPPP because of its nondescript histomorphology. Herpes gestationis can occur at any time during pregnancy and often is raised as a clinical consideration. Lesions of herpes gestationis often show subepidermal blisters accompanied by eosinophils in the epidermis, at tips of dermal papillae, and in a perivascular disposition associated with focal necrosis of basal layer keratinocytes and colloid body formation. Tissue eosinophilia is quantitatively greater in herpes gestationis than in PUPPP.29 Circulating anti-basement membrane IgG is demonstrable by indirect immunofluorescence in 25% of herpes gestationis patients, associated invariably with linear C3 deposition along the dermal-epidermal junction and, in 50% of cases, a similar pattern of IgG deposition.22,30 The linear dermal-epidermal junction deposition of C3 and IgG that characterizes herpes gestationis is not seen in PUPPP. Direct immunofluorescence testing is thus a valuable adjunct to light microscopy in making this important distinction. Herpes gestationis is associated with increased fetal morbidity and may require systemic steroid therapy, whereas PUPPP is a selflimited eruption with no associated fetal morbidity.22,30,31 A less problematic concern is that of pruritic folliculitis of pregnancy that manifests a follicular-based eruption characterized histologically by a neutrophilic folliculitis.32

Table 5-3 Pruritic Urticarial Papules and Plaques of Pregnancy

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Clinical Features Pruritic erythematous urticarial papules, vesicles, and plaques in and near abdominal striae Most common dermatosis of pregnancy Occurs classically in week 35+ Histopathologic Features Superficial perivascular lymphocytic or lymphocytic and eosinophilic dermal infiltrate Exocytosis and spongiosis in one-third of cases Differential Diagnosis Delayed-type hypersensitivity reactions of diverse causes: Drugs Contactants Insect bite reactions (including papular urticaria) Atopic dermatitis Herpes gestationis

 FIGURE 5-3 Pruritic urticarial papules and plaques of pregnancy. A nondescript superficial perivascular infiltrate of lymphocytes and eosinophils is present.

GYRATE ERYTHEMAS CLINICAL FEATURES The gyrate erythemas are characterized by annular, polycyclic, often migratory erythematous macular eruptions. Erythema annulare centrifugum (EAC) (Table 5-4) consists of one or more annular fixed or migratory large (>1 cm), erythematous, scaly, indurated plaques, often with a fine peripheral scale at the advancing edge, involving the trunk and proximal extremities (Fig. 5-4 A). A number of triggers are implicated33 (Table 5-5). Although A

Clinical Features Erythematous infiltrated papules which slowly enlarge to form annular or arciform arrays Histopathologic Features Superficial EAC Superficial perivascular lymphocytic or lymphocytic and eosinophilic dermal infiltrate Exocytosis and spongiosis with focal parakeratosis Superficial and deep EAC Superficial and deep perivascular lymphocytic or lymphocytic and eosinophilic dermal infiltrate with prominent “cuffing” around blood vessels Differential Diagnosis Superficial EAC Delayed-type hypersensitivity reactions including: Allergic contact reactions Atopy Pityriasis rosea Pityriasiform and other drug eruptions Polymorphous light eruption and other photoallergic conditions Insect bite reactions Connective tissue diseases including: Discoid lupus erythematosus Subacute lupus erythematosus Relapsing polychondritis Sjögren syndrome Mixed connective tissue disease Superficial and deep EAC Jessner lymphocytic infiltrate Connective tissue diseases including: Discoid and tumid lupus erythematosus Relapsing polychondritis Sjogren syndrome Mixed connective tissue disease Delayed-type hypersensitivity reactions including: Dermal contact hypersensitivity reactions (to nickel) Polymorphous light eruption, deep variant Insect bite reactions and papular urticaria

B  FIGURE 5-4 Erythema annulare centrifugum, superficial type. (A) Large annular erythematous, indurated plaques with central clearing involving the shoulder and trunk. A fine peripheral scale is present at the advancing edges of the plaques. (B) There is a moderately heavy superficial perivascular infiltrate of lymphocytes and eosinophils associated with exocytosis of inflammatory cells, concomitant spongiosis, and often an adherent plasma-containing scale-crust.

lesions may be seen in the neonatal period, in which they may be a sign of maternal systemic lupus erythematosus, onset is most often in early adulthood or middle age.34 The initial lesion, a pink infiltrated papule, slowly enlarges to form a ring as its center fades; some lesions reach a diameter of 8.0 cm over a 2- to 3-week period. Eccentric expansion may yield an irregular arciform pattern. Lesions may last from days to months and may be associated with purpuric or pigmented residua. The clinical differential diagnosis includes granuloma annulare (which more often has a beaded edge), fungal infections, parapsoriasis, sarcoidosis, urticaria, urticarial bullous pemphigoid, connective tissue disease, atypical forms of pityriasis rosea (particularly the pityriasis marginatum et circinatum of Vidal variant), and necrolytic migratory erythema associated with pancreatic islet cell neoplasms. The nature of the factors that trigger EAC implicate delayed-type hypersensitivity

as the pathogenetic basis; internal disease and superficial fungal infection are thought to be highly associated.35 Lymphoma, chronic lymphocytic leukemia, autoimmune disease, sarcoidosis, drug intake, and bacterial and viral infections have been reported variably in association with EAC.35-46 The disorder tends to be a chronic and recurrent one despite treatment. Erythema gyratum repens manifests as broad polycyclic patches that resemble the rings on the cut surface of a tree. This eruption is associated in over 80% of cases with malignancies of parenchymal organs such as lung or kidney,47-49 tuberculosis, ichthyotic states, pityriasis rubra pilaris, hematologic dyscrasias including hypereosinophilic syndrome,50 and CREST syndrome.51 Clinical mimics include atypical cases of autoimmune bullous dermatoses, such as bullous pemphigoid or linear IgA disease, and subacute cutaneous lupus erythematosus.51 The pathophysiologic

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

Table 5-4 Erythema Annulare Centrifugum

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Table 5-5 Possible Trigger Factors for Erythema Annulare Centrifugum

86

Infective and Nondrug Hypersensitivity States Tinea Candida infection Ascaris infection Viral infection Ingested molds Autoimmune Diseases Sjögren syndrome Hyperthyroidism Liver disease Immunologic disturbances Drug-Related Cimetidine Salicylates Diazides Antimalarials Neoplastic Liver disease Carcinoma Dysproteinemia Blood dyscrasias

basis is held to reflect an autoimmune basis, although the antigen is not well characterized.52,53 Erythema marginatum is associated with rheumatic fever in less than 10% of cases and consists of erythematous macules with a raised edge and a pale center. Rheumatic fever is a multisystem inflammatory disease associated with group A streptococcal pharyngitis. By consensus, one establishes the diagnosis clinically through the system described by T. Duckett Jones, requiring the expression of two major or one major and two minor criteria. The major criteria are carditis, migratory large joint polyarthritis, chorea, erythema marginatum, and subcutaneous nodules, whereas the minor criteria include fever, arthralgia, an elevated erythrocyte sedimentation rate or C-reactive protein level, and an elongated P-R interval on an electrocardiogram.54,55 None of 44 patients with rheumatic fever in one study manifested erythema marginatum.56 Erythema chronicum migrans, the distinctive cutaneous manifestation of stage I Lyme disease, is discussed in Chap. 20. HISTOPATHOLOGIC FEATURES There are two discrete forms of gyrate or figurate erythema. The superficial variant (the most common form, usually termed erythema annulare centrifugum) shows epidermal spongiosis and parakeratosis with papillary dermal edema, which may be considerable (Fig. 5-4 B). There are superficial

 FIGURE 5-5 Erythema annulare centrifugum, superficial and deep type. A moderately heavy superficial and deep perivascular lymphocyte-predominant infiltrate manifests “cuffing” around blood vessels without exocytosis of inflammatory cells into the epidermis, which shows no appreciable pathology.

perivascular lymphocytic infiltrates that typically exhibit some degree of cuffing about blood vessels in addition to a loose scattering of lymphocytes in the papillary dermis. The second form is a superficial and deep one in which a sharply demarcated perivascular lymphoid infiltrate spares the overlying epidermis57 (Fig. 5-5). In one series, 80% of patients had superficial EAC, and 20% had the deep form.34 Endothelial swelling may be seen in both types and may be accompanied by hemorrhage, but fibrin deposition is absent. Eosinophils are seen in roughly 10% to 20% of cases (personal observation) (Fig. 5-6). The histopathology of erythema gyratum repens comprises spongiosis with parakeratosis, focal mild perivascular lymphoid infiltrates, and variable edema or eosinophilia of the dermis. Skin biopsies in erythema marginatum show perivascular neutrophilic, lymphocytic, and eosinophilic infiltrates with perivascular debris but absent vascular fibrin deposition.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of the superficial variant of gyrate erythema (erythema annulare centrifugum) includes allergic contact reactions, atopy, pityriasis rosea and pityriasiform drug eruptions, polymorphous light eruption and other photoallergic conditions, insect bite reactions, and occasional cases of lupus erythematosus. With respect to the superficial

and deep forms of gyrate erythema, differential diagnostic considerations include Jessner lymphocytic infiltrate, connective tissue diseases such as discoid and tumid lupus erythematosus, relapsing polychondritis, Sjögren syndrome, and lesions of mixed connective tissue disease and subacute cutaneous lupus erythematosus that have been treated with topical steroids, all of which may manifest perivascular lymphocytic infiltrates without epidermal alterations, and those hypersensitivity reactions whose expression is principally confined to the dermis. With respect to Jessner lymphocytic infiltrate and the aforementioned connective tissue diseases, eosinophils are most unusual, whereas in tumid lupus erythematosus, massive mucin deposition is characteristic, and the lymphocytic infiltrate usually is sparse. The dermal contact hypersensitivity reactions, such as those owing to nickel, manifest perivascular lymphocytic and eosinophilic infiltrates in the absence of epidermal changes. With respect to erythema marginatum, other conditions that combine perivascular lymphocytic infiltrates with a neutrophilic and eosinophilic component in the presence of perivascular leukocytoclasia but absent or minimal fibrin deposition include urticaria, urticarial vasculitis, rheumatoid neutrophilic dermatosis, and some cases of Henoch-Schönlein purpura.58 With respect to the latter, although a mononuclear cellpredominant vascular injury pattern may be seen, most cases manifest a distinctive pustular vasculitis.58,59

Table 5-6 Pityriasis Lichenoides

PITYRIASIS LICHENOIDES CLINICAL FEATURES Pityriasis lichenoides is a self-limited dermatosis that usually presents in the first to third decades of life and shows a predilection for males60 (Table 5-6). The onset ranges from an acute eruption termed pityriasis lichenoides et varioliformis acuta (PLEVA), consisting of hemorrhagic papules (thus pityriasis lichenoides), pustules or vesicles that heal with scars mimicking smallpox (thus varioliformis), and a chronic eruption termed pityriasis lichenoides chronica. The latter may heal with postinflammatory hyperpigmentation. Lesions number from dozens to hundreds and frequently affect the anterior trunk and flexor aspects of the proximal extremities preferentially.61 Although occasional cases of pityriasis lichenoides are seen in patients with autoimmune diseases such as autoimmune hepatitis,62 the etiologic basis has long been postulated to be viral in nature, based in part on the clinical behavior, in part on phenotypic studies that show a characteristic infiltrate comprising CD8+ lymphocytes admixed with a minor populace of Langerhans cells or indeterminate cells, and in light of case reports of the detection of Cytomegalovirus in

endothelia in cases of PLEVA.63 However, larger series in the modern era have shown clonal restriction of T-cell populations in lesions of PLEVA64-69 and PLC.64-69 T-cell populations in both forms of pityriasis lichenoides show deletion of pan-Tcell markers indicating that the process represents a true lymphoid dyscrasia.67 Recently, defects in activity of the CD4+/CD25+ T-regulatory cell population have been described.65 HISTOPATHOLOGIC FEATURES In PLEVA, the dermal-epidermal junction often is obscured by a pure population of lymphocytes associated with basal layer vacuolopathy, colloid body formation, and variable but sometimes confluent epidermal necrosis (see Chap. 3). As a reflection of the underlying T-cell dyscrasia, small lymphoid forms percolate the epidermis in a fashion that often mimics patch or early plaque stage mycosis fungoides. Intraepidermal hemorrhage, endothelial swelling, papillary dermal edema, bleeding, and wedge-shaped superficial and deep dermal lymphoid infiltrates are classical.60 The parakeratotic scale often contains neutrophils. A rare extreme expression of the disease is the ulceronecrotic variant, in which necrotizing

lymphocytic vasculitis produces confluent epidermal necrosis.70 Parakeratosis is often confluent and epidermal injury less striking in pityriasis lichenoides chronica.71 The epidermis may show superficial pallor, and melanophages often are present in the papillary dermis, reflecting basal layer injury. Since PLEVA and pityriasis lichenoides chronica represent opposite poles of a spectrum of injury, not all cases can be reliably classified as one or the other; some authorities sign out most cases simply as pityriasis lichenoides without further qualification. Incidental IgM and C3 deposition may be seen along the basement membrane zone and in blood vessels by direct immunofluorescence. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes pityriasis rosea, in which discrete mounds of parakeratin overlie foci of epidermal spongiosis, and small-plaque parapsoriasis, where the

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

 FIGURE 5-6 Erythema annulare centrifugum, superficial and deep type. The dermal lymphocyte-predominant infiltrate is associated with scattered eosinophils and mural and endothelial swelling but no fibrin deposition within blood vessel walls or lumina.

Clinical Features Self-limited dermatosis comprising 10s to 100s of hemorrhagic papules, pustules, or vesicles that heal with scars Onset in first to third decades with male predominance Spectrum ranging from acute (pityriasis lichenoides et varioliformis acuta, or PLEVA) to chronic (pityriasis lichenoides chronica, or PLC) eruptions Histopathologic Features PLEVA Lymphocytic infiltrate obscures dermoepidermal junction Erythrocyte extravasation into degenerating epidermis Papillary dermal edema Wedge-shaped superficial and deep, purely lymphocytic dermal infiltrate Sometimes atypical transformed lymphocytes PLC Confluent parakeratotic scale, often containing neutrophils More sparse lymphocytic interface injury pattern Less conspicuous epidermal injury and hemorrhage Melanophages in papillary dermis Differential Diagnosis Pityriasis rosea Small plaque parapsoriasis Viral exanthemata Lymphomatoid papulosis Secondary syphilis Connective tissue disease

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degree of epithelial injury generally is less and the infiltrate more sparse.71 The common viral exanthem pattern may mimic PLEVA by virtue of a perivascular and interface lymphocytic infiltrate accompanied by basilar vacuolopathy with scattered cytoid bodies and streak dyskeratosis, but the epidermis usually is surmounted by a basket-weave pattern of orthokeratinization, and the lymphocytic infiltrate is usually superficial only. Similar features also typify evolving lesions of erythema multiforme, which may show scattered eosinophils in the dermal inflammatory populace, enabling distinction. Secondary syphilis merits consideration but usually has a significant plasma cell component, at variance with the pure lymphoid populace of pityriasis lichenoides. Connective tissue diseases with pronounced keratinocyte degeneration, such as subacute cutaneous lupus erythematosus, can be problematic if a superfical shave biopsy is submitted, and the deep infiltrates of pityriasis lichenoides, which would enable distinction, cannot be assessed. The atypical pigmentary purpuras and purpuric forms of mycosis fungoides merit consideration but generally show little or no epidermal necrosis despite epidermotropism of transformed lymphocytes and intraepithelial hemorrhage.72 These lesions also show horizontal wiry sclerosis of collagen in the fashion of lesions of large-plaque parapsoriasis, a finding typically absent in lesions of PLEVA but common in lesions of PLC.

Table 5-7 Perniosis (Chilblains)

Clinical Features Cold-induced purplish macules, papules, and nodules involving acral, thigh, or buttock skin Occurs in humid climates Histopathologic Features Dense superficial and deep lymphocytic infiltrates with preferential migration to epidermal retia and acrosyringia Occasional fibrin thrombi in dermal papillae capillaries Transmural lymphocytic migration through blood vessel walls Marked papillary dermal edema Mucinosis around eccrine coil Differential Diagnosis Connective tissue diseases, especially: Chilblains lupus erythematosus Mixed connective tissue disease Behçet disease Erythema multiforme Viral exanthems

resulting ischemia of vessel walls is the proposed etiology, with humidity playing a role through enhanced air conductivity of temperature. Lesions clear dramatically

with warming.73-75 An association with anorexia nervosa has been reported; it appears that anxiety states and the ingestion of antidepressant medications with immune dysregulating properties may play a role.76,77 HISTOPATHOLOGIC FEATURES Biopsies show a dense superficial or superficial and deep perivascular lymphocytic infiltrate with exocytosis to retia and acrosyringia (Fig. 5-7). Epithelial necrosis is observed occasionally. Edema of blood vessel walls accompanied by transmural lymphocytic infiltrates is characteristic (the so-called fluffy edema of microvessels), and thrombi may be observed in dermal papillae capillaries. Pronounced papillary dermal edema is often present.74 Mucinosis around the eccrine coil and luminal fibrin thrombi localized to dermal papillae capillaries may be seen, but pandermal mucin deposition or reticular dermal vascular thrombosis is unusual.75 DIFFERENTIAL DIAGNOSIS Other causes of acral purpuric papulonodular lesions include rare childhood lesions of leukemiacutis,76 of zoophilic mycoses in farm workers,77 celiac disease,78 hyperviscosity and procoagulant states, namely,

PIGMENTED PURPURIC DERMATOSES The pigmented purpuric dermatoses, a group of idiopathic disorders having in common a lymphocytic vascular reaction associated with endothelial swelling and perivascular hemorrhage, are discussed in detail in Chap. 9.

PERNIOSIS

88

CLINICAL FEATURES Perniosis (chilblains) is a form of cold-induced injury that manifests as inflammatory red to purple macules, nodules, papules, or plaques, at times accompanied by overlying blisters, erosions, or ulcers characteristically distributed symmetrically on acral skin, thighs, or buttocks (Table 5-7). It is common in the humid climate of northwest Europe but is decreasing in frequency with modern home heating methods.73-75 A vasospastic response to cold with

 FIGURE 5-7 Perniosis (chilblains). There is a dense superficial and deep perivascular lymphocytic infiltrate associated with marked papillary dermal edema and migration of lymphocytes into retia and acrosyringia.

RICKETTSIAL AND VIRAL INFECTIONS Rickettsial and viral infections produce a lymphocytic interface injury pattern mimicking the common viral exanthem pattern, often in concert with vascular injury, and are discussed in detail in Chap. 20.

Table 5-8 Polymorphous Light Eruption

Clinical Features Erythematous, pruritic papules or papulovesicles and urticarial plaques Eruption occurs 30 minutes to 3 days after sun exposure, and resolves in 7-10 days Predilection for sun-exposed sites: hands, forearms, head, and neck area Histopathologic Features Perivascular infiltrates of lymphocytes, eosinophils, and neutrophils Exocytosis, spongiosis, vesiculation, acanthosis, and focal parakeratosis common Some cases show vacuolopathic interface injury pattern or no epidermal changes Marked papillary dermal edema classically Blood vessels show ectasia and endothelial swelling which preferentially affects superficial vasculature Differential Diagnosis Delayed-type hypersensitivity reactions including: Allergic contact reactions Rosacea Other photoallergic/phototoxic eruptions Insect bite reactions Connective tissue diseases including: Discoid lupus erythematosus Subacute cutaneous lupus erythematosus Jessner lymphocytic infiltrate

3 days after UV exposure and characteristically resolve in 7 to 10 days.90 Lesions may appear eczematous or may resemble pemphigus, prurigo nodularis, erythema multiforme, or insect bite reactions. There is a predilection for the hands, forearms, upper arms, and the head and neck region. Females are preferentially affected and there is a small statistical predilection for African Americans91; onset is classically in the third to fourth decade of life.92 Roughly 50% of patients show decreasing photosensitivity over time. Polymorphous light eruption can be a clue to underlying seropositivity for antibodies to Ro.93 HISTOPATHOLOGIC FEATURES Characteristic findings include papillary dermal edema accompanied in early lesions by a superficial perivascular lymphoid infiltrate (Fig. 5-8) and in late lesions by a moderate-to-intense superficial and deep lymphocytic infiltrate, which often manifests perivascular “cuffing.” Eosinophils, neutrophils, hemorrhage, and vesiculation owing to marked papillary dermal edema may be seen (Fig. 5-9). The epidermis may be normal or may show basal layer vacuolization, acanthosis, parakeratosis, spongiosis, vesiculation, and uncommonly, necrosis.94 Vascular changes consisting of mural and endothelial swelling and edema diminish in the depths of the biopsy. By direct immunofluorescence examination, perivascular IgM and C3 deposition is seen in the setting of a negative lupus band test. On occasion, patients with apparently robust clinical findings may manifest only minimal histologic changes.95

POLYMORPHOUS LIGHT ERUPTION CLINICAL FEATURES AND PATHOGENESIS Polymorphous light eruption is an idiopathic photoinduced eruption (Table 5-8). It likely represents the combined effects of phototoxicity and a delayed-type hypersensitivity reaction to ultraviolet (UV) light of both UVA and UVB spectra.88 Early lesions are dominated by CD4+ lymphocytes, whereas late lesions manifest a predominant CD8+ populace. Patients with polymorphous light eruption fail to manifest the UV-induced downregulation of function of epidermal CD1a+ Langerhans cells seen in normal individuals; this deviant response may be a clue to pathogenesis as well as to diagnosis.89 Lesions manifest as pruritic erythematous papules, papulovesicles, or urticarial plaques that erupt 30 minutes to

 FIGURE 5-8 Polymorphous light eruption. A superficial perivascular lymphocytic infiltrate is associated with papillary dermal edema in the absence of an interface dermatitis or eczematous epithelial alterations.

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

hypergammaglobulinemia, essential cryofibrinogenemia, antiphospholipid antibody syndrome, rheumatoid arthritis, Crohn disease, Behçet disease, and systemic lupus erythematosus.81-83 The latter lesions are termed chilblains lupus erythematosus and resemble Behçet disease by virtue of the distribution of the infiltrate and the presence of a vacuolopathic lymphocytic interface dermatitis.83,84 All the aforementioned differential diagnostic considerations are associated with reticular dermal endovascular thrombi. The perniosis-like lesions in Crohn disease characteristically manifest an interstitial histiocytopathy mimicking granuloma annulare and accompanied at times by granulomatous vasculitis.85,86 When seen in concert with pulp atrophy and “parrotbeaked” clawing of the nails, perniosis constitutes a component of a pseudo sclerodermatous triad that may indicate chronic crack cocaine use.87 Pandermal mucinosis should prompt consideration of a systemic connective tissue disease.75,83 Erythema multiforme merits consideration but rarely shows vasculopathy. Polymorphous light eruption demonstrates many of the same findings but is usually more photodistributed.

89

Table 5-9 Causes of a Cell-Poor Interface Dermatitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Connective tissue disease syndromes Systemic lupus erythematosus Subacute cutaneous lupus erythematosus Dermatomyositis Mixed connective tissue disease Hypersensitivity reactions Erythema multiforme Drug reaction Viral exanthem Graft-versus-host disease

90

 FIGURE 5-9 Polymorphous light eruption. In addition to a superficial perivascular mononuclear cell infiltrate there is often, but not invariably, striking papillary dermal edema.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of polymorphous light eruption includes the other photoallergic and phototoxic dermatoses (including those that are drug-related; see Chap. 22), lupus erythematosus, Jessner lymphocytic infiltrate, the gyrate erythemas (particularly superficial erythema annulare centrifugum), granuloma faciale, and other delayed-type hypersensitivity reactions such as rosacea, atopy, insect bite, and contact reactions. Whereas distinction from photoallergic eruptions may be impossible, epidermal changes tend to be more pronounced than in polymorphous light eruption. Purely phototoxic eruptions show a greater degree of epidermal necrosis. The pattern of epithelial injury in lupus erythematosus is one of vacuolopathic basal layer degeneration usually associated with atrophy, whereas Jessner lymphocytic infiltrate typically spares the epidermis altogether. The superficial gyrate erythemas show eczematous epithelial changes such as may be seen in polymorphous light eruption, accompanied by a similar pattern of dermal inflammation, but generally lack a neutrophilic component. Granuloma faciale manifests a dermal inflammatory infiltrate of a similarly polymorphous composition, but the infiltrate usually is much more dense, is associated with a grenz zone of papillary dermal sparing, and is accompanied by vasculitic alterations and eosinophilic dermal trabeculation, features not seen in polymorphous light eruption. Acne rosacea frequently manifests eczematous alterations, but demodectic mites

commonly are present in hair follicles, and the dermal infiltrate usually is folliculocentric. The dermal neutrophilia seen in some examples of polymorphous light eruption would not be a feature of most other types of hypersensitivity reaction. Patients with polymorphous light eruption may have an increased incidence of underlying autoimmune diseases, including lupus erythematosus and autoimmune thyroid disorders.96,97 Two other forms of photodermatosis deserve mention: actinic prurigo and hydroa vacciniforme. The former is a form of chronic photosensitivity dermatitis that combines phototoxic, photoadaptive, and photoallergic features to produce a chronic, typically psoriasiform dermatitis that is more prevalent in native Americans.98 Hydroa vacciniforme consists of crops of discrete erythematous macules that evolve into blisters within a few days of sun exposure.99

CONNECTIVE TISSUE DISEASES The manifestations of connective tissue disease in the skin encompass vasculopathy and vasculitis of leukocytoclastic, granulomatous, and lymphocytic subtypes; panniculitis; and dermal and epidermal infiltrates. The vasculitides and panniculitides are addressed elsewhere. With respect to the epidermal and dermal findings, the characteristic morphology seen in most skin lesions of lupus erythematosus, dermatomyositis, relapsing polychondritis (personal observation), Sjögren syndrome, and mixed connective tissue disease consists of a

variable superficial or superficial and deep lymphocytic infiltrate in concert with a lymphocytic interface dermatitis ranging from a subtle cell-poor vacuolopathic injury pattern to a lichenoid infiltrate (see Chap. 3).83,100-103 The hallmark of the cell-poor interface dermatitis, the causes of which are listed in Table 5-9, is a sparse number of lymphocytes scattered along the dermal-epidermal junction with concomitant degenerative epithelial changes manifested by basilar vacuolopathy and dyskeratosis.104 Relatively specific to the connective tissue diseases are hyperkeratosis with follicular and acrosyringeal plugging, epidermal atrophy, basement membrane zone thickening, and prominent dermal mucinosis. In cases of cell-poor interface dermatitis owing to hypersensitivity reactions, where the insult is acute, no alteration of the stratum corneum or of the basement membrane zone is seen, nor is dermal mucinosis conspicuous. With respect to the subclassification of connective tissue disease, a skin biopsy processed for both routine microscopy and immunofluorescence analysis can provide information of essential value in support of the clinical diagnosis. However, knowledge of the clinical findings, including in the context of extracutaneous disease and serology (Table 5-10), must be integrated carefully to arrive at a correct diagnosis. The pathologist is in a powerful position to positively influence this process.

Lupus Erythematosus CLINICAL FEATURES Lupus erythematosus (LE) is an autoimmune disorder affecting skin, hematopoietic and lymphoreticular organs, joints, kidneys, lungs, serosa, and cardiovascular structures in concert or in isolation (see Chap. 3). Lupus erythematosus is subdivided clinically into systemic (SLE), subacute cutaneous (SCLE),

Table 5-10 Seropositivitya by Connective Tissue Disease Classification ANA SLE SCLE DLE CRST PSS MCTD

C

95-100 70 20-30 90 70 95-100

0-10 0 90 10 0

ss-DNA 70 10-20 10-20 0 10-20 30

ds-DNA 70 0 10-20 0 0 0

Sm b

<30 0 0 0 0 0-5

SSA/R O

SSB/La

nRNP

HISTONE

40 60-80 10-20 0 10 0

10-20 10 10 0 10 0

40-50 0 0 0 20 100

30 0 0 0 0 0

Scl70 0 0 0 0 30 0

and discoid (DLE) forms, each with its own characteristic skin findings100,105-108 (Table 5-11). A diagnosis of SLE is based on the presence of four or more of the criteria of the American College of Rheumatology105 (Table 5-12). Patients with SCLE manifest photodistributed, annular papulosquamous eruptions accompanied by extracutaneous manifestations that, if present, are mild in nature, such as microhematuria or arthralgia.83,100 In DLE, disease is restricted to a cutaneous expression as one or more scaling plaques in photodistributed areas, typically involving the head and neck region. HISTOPATHOLOGIC FEATURES Some authors aver that light microscopy has limitations in the subclassification of LE107 and that the differences between subtypes reflect

lesional age (Table 5-13). However, although it is true that a sparse lymphocytic interface infiltrate in the incipient lesion of DLE may mimic the more ominous systemic form and that discoid lesions may be seen in SLE patients, the pattern of disease progression, seen in some 5% of patients, is from DLE to SLE and not vice versa.83,100,109 Certain features prove particularly helpful in subclassification.83,100 Lesions of SLE, for example, show a pauci-inflammatory interface dermatitis with subtle basal layer vacuolopathy and none of basement membrane zone thickening, keratotic follicular plugging, or acanthosis. Skin biopsies from patients with SCLE demonstrate suprabasilar exocytosis of lymphocytes with satellitosis to necrotic keratinocytes, slight or absent thickening

Table 5-11 Lupus Erythematosus: Comparison of Clinical and Direct Immunofluorescence Manifestations by Subtype FEATURE

Lesion character Scale Follicular atrophy Photodistribution Scarring Atrophy Pigmentary alteration Telangiectasia ≥4ACR criteria for SLE (incidence) Positive Lupus Band Test Lesional skin Nonlesional sunprotected skin

SLE

SCLE

DLE

Fine, easily detached Absent Present Absent Usually absent Slight Present 100%

Fine, easily detached Absent Marked Absent Usually absent Slight Present 40%

Thick, adherent Present Present Present Present—often marked Often Marked Present 10%

>90% Active disease 90% Inactive disease 30%

60% 30%

90% 0-10%

Abbreviations: SLE, systemic lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; DLE, discoid lupus erythematosus, ACR, America College of Rheumatology SOURCE: After Crowson and Magro.83

of the basement membrane zone or follicular plugging, and no significant deep perivascular or periadnexal infiltrate. Atrophy is variable but usually is present in lesions of SLE and SCLE. Lesions of DLE generally manifest a heavier superficial and deep perivascular and periappendageal lymphocytic infiltrate, basement membrane zone thickening, keratotic follicular plugging, and variable acanthosis and atrophy.83,100 DIFFERENTIAL DIAGNOSIS The differential diagnosis is that of lymphocytic interface dermatitis and embraces dermatomyositis, Sjögren syndrome, drug-related lupus erythematosus-like eruptions, polymorphous light eruption, Jessner lymphocytic infiltrate, and certain delayed-type hypersensitivity reactions and viral exanthemata.101,102,108,110,111 Kikuchi necrotizing lymphadenitis can produce skin lesions with a lymphocytic vasculopathy and cell-poor interface dermatitis identical to that seen in SLE.112 The idiopathic lichenoid eruptions lichen planus, lichen nitidus, and lichen striatus can be problematic if parakeratosis and atrophy are seen.113 Another pitfall is the distinction of lichen planus-like keratoses and lichenoid actinic keratoses from lesions of DLE in sun-damaged skin. Correlation with clinical, serologic, and immunofluorescence findings is imperative.

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

Abbreviations: ANA, antinuclear antibody; C, centromere; CRST, CREST syndrome; DLE, discoid lupus erythematosus; ds-DNA, double-stranded DNA; MCTD, mixed connective tissue disease; nRNP, nuclear ribonucleoprotein; PSS, progressive systemic sclerosis/scleroderma; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; Sm, Smith; ss-DNA, single-stranded DNA. a Expressed as percentage of cases. b Dependent on ethnicity. SOURCE: After Crowson and Magro.83

Direct Immunofluorescence: The Lupus Band Test and Its Implications for Pathogenesis of Connective Tissue Diseases The examination by fluorescence microscopy of frozen sections cut from lesional or nonlesional sun-exposed or nonsun-exposed skin received fresh, in saline

91

Table 5-12 Revised Criteria of the American College of Rheumatology for the Classification of Systemic Lupus Erythematosus

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

1. 2. 3. 4. 5. 6. 7. 8. 9.

Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis: (a) pleuritis or (b) pericarditis Renal disorder: (a) proteinuria >0.5 g/24 h or 3+ , persistently, or (b) cellular casts Neurological disorder: (a) seizures or (b) psychosis (having excluded other causes, eg, drugs) Hematologic disorders: Hemolytic anemia Leukopenia <4.0 × 109/L on two or more occasions Lymphopenia <1.5 × 109/L on two or more occasions Thrombocytopenia <100 × 109/L 10. Immunologic disorders: Positive LE cell Raised anti-native DNA antibody binding Anti-Sm antibody False-positive serologic test for syphilis, present for at least 6 months 11. Antinuclear antibody in raised titer Sm, Smith antigen. SOURCE: Data from Tan et al.105

or transport medium, and incubated with fluorescein-conjugated antibodies monospecific for IgG, IgA, IgM, and complement constitutes the lupus band test (LBT).83,114 The definition of a positive LBT is controversial, with differences in applicable criteria in part explaining the disparate results from various series. To be

considered a positive LBT, deposition of IgM in sun-exposed skin should assume a continuous band over at least 50% of the width of the biopsy specimen and be at least moderate in intensity.83,114 Weak IgM decoration along the dermal-epidermal junction is common in sun-exposed skin of patients who do not have LE, including

Table 5-13 Histopathologic Criteria for Subtypes of Lupus Erythematosus I. Systemic lupus erythematosus Pauci-inflammatory interface dermatitis Slight to absent epidermal atrophy Basement membrane zone of normal thickness No follicular plugging Prominent papillary dermal edema and reticular dermal mucin accumulation II. Subacute cutaneous lupus erythematosus Prominent suprabasilar exocytosis of lymphocytes and dyskeratosis extending into upper spinous layers Prominent epidermal atrophy Follicular plugging or basement membrane zone thickening minimal or absent Mild to moderate mononuclear cell infiltrate confined to the superficial dermis III. Discoid lupus erythematosus Lymphocyte-rich interface dermatitis Less epidermal atrophy than SCLE; sometimes acanthosis Prominent basement membrane zone thickening Prominent follicular hyperkeratosis Dense superficial and deep perivascular and periadnexal infiltrates with prominent follicular degeneration Dermal fibrosis

92

SOURCE: After Magro et al.100

in the context of normal skin specimens from healthy young adults; one study showed weak interrupted linear and granular IgM and C1q deposition along the dermal-epidermal junction in 25% of such samples,115,116 whereas deposition of IgG, IgA, and C3 were seen in less than 5%.83,114 In sun-protected skin, an interrupted band of IgM of at least moderate intensity is sufficient for designation as a positive LBT. The deposition of IgG is usually less intense than that of IgM, but false-positive results are rare. Thus even an interrupted weak band of IgG deposition in sun-exposed skin83,100,114 is considered a positive LBT by some authorities. Concomitant IgA deposition enhances the specificity of the assay. Sun-exposed lesional skin should be used to substantiate an initial diagnosis of LE so as to avoid a false-negative result due to reduced sensitivity in sunprotected skin. After the diagnosis of LE is made, a biopsy of nonlesional skin may be performed to further assist in subclassification and prognostication; a positive LBT in sun-protected skin is predictive of systemic disease in the context of renal and other organ involvement. Although a skin lesion less than 2 months old may give negative direct immunofluorescence results, a positive LBT is seen in 90% of lesional skin biopsies from DLE and SLE patients. A negative LBT is almost invariably seen in nonlesional skin of DLE patients, whereas over 80% of nonlesional skin biopsies show a positive LBT in SLE patients.117 The LBT is positive in over 90% of sun-exposed nonlesional skin biopsies from SLE patients with active disease versus only one-third of patients with inactive disease.117 Patients with SCLE manifest a positive LBT in only 30% to 50% of cases.100 The LBT functions as well as an in-vivo test for antibodies to nuclear antigens; a homogenous flourescent pattern can indicate antibodies to dsDNA in SLE. In vivo, the binding of DNA by anti-DNA antibodies can trigger complement cascades to generate clinical disease. Anti-DNA antibodies can bind, for example, to cell surface antigens or components of renal tubules and glomerular basement membranes to generate lupus nephritis.118

Indirect Immunofluorescence: The Membrane Attack Complex of Complement and its Putative Pathogenetic Role An indirect immunofluorescence methodology to detect the presence of the membrane attack complex of complement

skin, suggests its pathogenic role.100,125 The surface binding of anti-Ro antibodies may allow adherence of C5b-9, the latter forming plasmalemmal pores that, in concert with antibody-dependent cellular cytotoxicity, may be an important mechanism of keratinocyte injury.100,125,126 In part, the accumulation of necrotic keratinocytes in the epidermis may reflect delayed clearance.127 Vascular deposition of C5b-9 is seen in dermatomyositis, in mixed connective tissue disease (MCTD), and in SLE patients who possess the lupus anticoagulant, antibodies to Ro, or biopsy-proven lymphocytic vasculitis.99,100,103,120,128 Vasculitis has been shown in skeletal muscle biopsy specimens of LE patients with anti-Ro and anti-La antibodies, perhaps reflecting localization of the Ro antigen to endothelia, as has been shown in vitro.120,122,129 In addition to myositis, SLE patients with anti-Ro antibodies manifest cutaneous lesions virtually identical to those seen in dermatomyositis.120

Dermatomyositis CLINICAL FEATURES Dermatomyositis combines an inflammatory myopathy with characteristic skin lesions: the often subtle heliotrope rash, the Gottron papule, a violaceous or hypopigmented

 FIGURE 5-10 Subacute cutaneous lupus erythematosus. Positive staining of keratinocyte nuclei with C5b-9 correlates strongly with antibodies to extractable nuclear antigens Ro, La, Smith, or as in this case, RNP. A similar pattern may be seen in MCTD, Sjögren syndrome, dermatomyositis, SLE, and very rare cases of DLE associated with antibodies to extractable nuclear antigens.

Table 5-14 Criteria for Myopathic Dermatomyositis Proximal symmetric muscle weakness Elevated serum levels of muscle-derived enzymes Abnormal electromyogram Abnormal muscle biopsy Cutaneous disease compatible with dermatomyositis SOURCE: Data from Bohan and Peter.132

papule over the joints of the fingers, erythema of the upper back (the “shawl sign”), extensive erythema of the extensor surfaces of the arms, scaly alopecia, and cuticular overgrowth with periungual telangiectasias.100,130,131 Myopathic dermatomyositis is defined by the criteria listed in Table 5-14.132 Although myositis usually eventuates, skin involvement may be unaccompanied initially by objective evidence of muscle disease; such cases are referred to as amyopathic dermatomyositis or dermatomyositis sine myositis.133 In adult populations, roughly one-third of patients have an underlying malignancy, with statistical correlation demonstrated to lymphoma and to carcinomas of ovary, lung, pancreas, nasopharynx, colon, and stomach.130,134 High-dose intravenous immunoglobulin therapy has proven efficacious in patients refractory to other forms of therapy.135 Treatment of the underlying malignancy can dramatically alter the course of disease.136 Other manifestations include arthritis, myocarditis, and esophageal and pulmonary disease. Dermatomyositis appears to represent an aberrant immune response directed principally at endothelia in an immunogenetically predisposed individual following antigenic stimuli such as neoplasms, drugs, or infections. Drug triggers include terbenafine and lipid-lowering agents.137 With respect to infectious triggers, it has been demonstrated that symptomatology in some cases of dermatomyositis reflects the presence of endotheliotropic viruses such as parvovirus B19 that may alter endothelial antigenicity.138-140 As a postulated sequel of endothelial cell dysfunction,141 endotheliopathy of dermatomyositis is associated with increased levels of certain chemokines.142 Downregulation of chemokine activity may in part explain the efficacy of intravenous immunoglobulin therapy. Ischemic injury may also be a trigger for skin and soft tissue calcification which occurs in patients with severe disease, and, in a minority of cases of juvenile dermatomyositis, precedes the diagnosis of the systemic disease.143

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

(C5b-9) in frozen sections may be a helpful adjunct to the LBT.100 Keratinocyte fluorescence for C5b-9 correlates with seropositivity for antibodies to extractable nuclear antigens Smith, Ro/SSA, La/SSB, or RNP (Fig. 5-10). Patients with such antibodies often manifest distinctive clinical features and may be seronegative for antinuclear antibody.100 Antibodies to La correlate with SICCA syndrome and, in the setting of SCLE, may be predictive of a higher incidence of pulmonary disease, whereas patients with SLE who have antibodies to Ro are at greater risk for photosensitive skin eruptions, interstitial pneumonitis, myositis, myocarditis, and complete heart block.119,120 Patients with antibodies to RNP frequently have Raynaud disease, sclerodactyly, and myopathy.121 The Ro, La, Sm, and RNP antigens are small ribonucleoprotein macromolecules resident in nuclei and, in the case of Ro, the cytoplasm of all eukaryotic cells.121 Binding of the Ro autoantibody may depend on relocation of nuclear and cytoplasmic Ro antigens to the cell surface, an event that follows UV exposure, viral infection, or estrogen therapy.122-124 The presence of the membrane attack complex of complement in the basement membrane zone of skin lesions of patients with SLE and DLE and of renal tubules in patients with lupus nephritis, coupled with its absence in uninvolved

93

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 94

HISTOPATHOLOGIC FEATURES Although some observers doubt that histologic criteria exist to distinguish dermatomyositis from other connective tissue diseases, such as SLE, SCLE, and MCTD, a constellation of light microscopic and immunofluorescence features, in concert with modern serology, is virtually pathognomonic for each of these entities.83,100-103 Skin lesions of dermatomyositis manifest an atrophying cell-poor lymphocytic interface dermatitis accompanied by dermal mucinosis and vascular alterations that vary according to the age of the lesion biopsied and the presence or absence of myopathy; in patients with myopathic dermatomyositis, a characteristic injury pattern consisting of a variably cell-poor thrombogenic lymphocytic vasculopathy mainly affecting the dermal papillae capillaries is seen. IMMUNOFLUORESCENCE The immunofluorescent profile of dermatomyositis consists of a negative lupus band test in conjunction with membrane attack complex (C5b-9) deposition along the dermalepidermal junction and within blood vessels.101 Similar vascular deposition is seen in the setting of SLE with antibodies to Ro and MCTD in the setting of antibodies to RNP.103,120 All three conditions manifest myopathy, interstitial lung disease, and vasculitis, perhaps reflecting the common localization of antibodies to endothelial RNA antigens, the expression of which is upregulated owing to endogenous or exogenous triggers. DIFFERENTIAL DIAGNOSIS The differentiating points of dermatomyositis from most cases of LE include active vascular injury characterized by endothelial cell necrosis and intraluminal fibrin deposition along with the end sequela of vasculopathy, namely, reduction of vascular density and vascular ectasia. Hypovascularity is more conspicuous in cases of myopathic versus amyopathic dermatomyositis, implying that cutaneous vascular changes mirror those in muscle, whereby a critical reduction in vascular density is necessary to generate objective evidence of myopathy.101,144,145 In MCTD, a lymphocytic interface injury pattern in concert with a lymphocytic vasculopathy can closely mimic dermatomyositis. Sclerodermoid tissue alterations are fairly common in the former but rare in the latter. Eosinophils are observed in biopsies of dermatomyositis in approximately 10% to 20% of cases (personal observation) but are rare in idiopathic LE and MCTD, possibly reflecting a pathogenic role for aberrant delayed-type hypersensitivity in a minority of cases. The

other causes of cell-poor vacuolopathic interface dermatitis, such as certain viral exanthems and hypersensitivity reactions, do not typically produce the same vascular injury patterns.

Mixed Connective Tissue Disease CLINICAL FEATURES Mixed connective tissue disease (MCTD) was first defined by Sharp as a distinct rheumatic disease syndrome associated with high titers of antibody to an extractable nuclear antigen (nRNP).146 The typical features (Table 5-15) include Raynaud phenomenon, polyarthritis, polyserositis, myositis, sclerodactyly, restrictive lung disease, lymphadenopathy, and esophageal dysfunction. The cutaneous manifestations include SLE-like malar erythema, discoid plaques, an SCLE-like photodistributed eruption, swollen hands, sclerodactyly, and vasculitis. HISTOPATHOLOGIC FEATURES Biopsies of the photodistributed eruptions show a cell-poor or lichenoid interface dermatitis with suprabasilar exocytosis around necrotic keratinocytes in the absence of deep periadnexal or perivascular extension or conspicuous follicular plugging.103 IMMUNOFLUORESCENCE Nuclear keratinocyte immunoreactivity with IgG and

C5b-9 is demonstrated in all cases studied (Fig. 5-10), accompanied by a positive LBT in roughly one-half of cases. The in vivo speckled nuclear staining for IgG observed within keratinocytes of lesional and nonlesional skin correlates with antibodies to nRNP, the serologic hallmark of MCTD. Granular vascular deposition of immunoreactants including C5b-9 is also is seen.103 DIFFERENTIAL DIAGNOSIS The histopathology of MCTD mimics SCLE by virtue of the lymphocytic interface dermatitis but differs by showing vasculopathic alterations consisting of ectasia, hypovascularity, and luminal thrombosis confined to the superficial vascular plexus and sometimes by a concomitant sclerodermoid tissue reaction.103 As mentioned earlier, distinction from dermatomyositis can be problematic. Perniosis can demonstrate a similar pattern of interface injury with associated lymphocytic vasculopathy, but the exocytosis of lymphocytes in perniosis tends to be directed to retia and acrosyringia.75 The interface dermatitis of erythema multiforme often is accompanied by pronounced papillary dermal edema, tissue eosinophilia, and epidermal colloid body formation in the absence of atrophy, vascular density reduction, or alterations of the stratum corneum.

Table 5-15 Diagnostic Criteria for Mixed Connective Tissue Disease A diagnosis of mixed connective tissue disease (MCTD) is based on the presence of one criterion from category I, plus the criterion from category II, plus one or more criteria from category III. I. Common symptoms: Raynaud phenomenon Swollen fingers or hands II. Anti-nRNP antibody III. Mixed findings: SLE-like findings: Polyarthritis Lymphadenopathy Facial erythema Pericarditis or pleuritis Leukocytopenia or thrombocytopenia PSS-like findings: Sclerodactyly Pulmonary fibrosis, restrictive changes of the lung, or reduced diffusion capacity Hypomotility or dilatation of the esophagus DM-like findings: Muscle weakness Increased serum level of myogenic enzymes (CPK) Myogenic pattern at electromyography SOURCE: After Doria et al.147

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1. Greaves MW. Current Concepts: Chronic urticaria. New Engl J Med. 1995;332: 1767-1772. 2. Grattan CEH, Sabroe RA, Greaves MW. Chronic urticaria. J Am Acad Dermatol. 2002;46:645-657. 3. Greaves MW, Tan KT. Chronic urticaria: recent advances. Clin Rev Allergy Immunol. 2007;33:134-143. 4. Barlow RJ, Warburton F, Watson F, et al. Diagnosis and incidence of delayed pressure urticaria in patients with chronic urticaria. J Am Acad Dermatol. 1993;29:954-958. 5. Torchia D, Francalanci S, Bellandi S, Fabbri P. Multiple physical urticarias. Postgrad Med J. 2008;84:el-e2. 6. Khakoo G, Sofianou-Katsoulis A, Perkin MR, Lack G. Clinical features and natural history of physical urticaria in children. Pediatr Allergy Immunol. 2008;19(4): 363-366. 7. Amar SM, Dreskin SC. Urticaria. Prim Care. 2008;35:141-157. 8. Sabroe RA, Seed PT, Francis DM, et al. Chronic idiopathic urticaria: comparison of the clinical features of patients with and without anti-FceRI or anti-IgE autoantibodies. J Am Acad Dermatol. 1999;40:443-450. 9. Kobza Black A, Greaves MW, Champion RH, Pye RJ. The urticarias 1990. Br J Dermatol. 1991;124:100-108. 10. de Weck AL, Sanz ML, Gamboa PM, et al. Diagnostic tests based on human basophils: more potentials and perspectives than pitfalls. Int Arch Allergy Immunol. 2008;146:177-189. 11. Jáuregui I, Ferrer M, Montoro J, et al. Antihistamines in the treatment of chronic Urticaria. J Investig Allergol Clin Immunol. 2007;17(suppl 2):41-52. 12. Doeglas HMG, Rijnten WJ, Schroder FP, Schirm J. Cold urticaria and virus infections: a clinical and serological study in 39 patients. Br J Dermatol. 1986;114:311-318. 13. Hide M, Francis DM, Grattan CEH, et al. Autoantibodies against the high affinity IgE receptor as a cause of histamine release in chronic urticaria. New Engl J Med. 1993;328:1599-1604. 14. Lee KH, Kim JY, Kang DS, et al. Incereased expression of endothelial cell adhesion molecules due to mediator release from human foreskin mast cells stimulated by autoantibodies in chronic urticaria sera. J Invest Dermatol. 2002;118:658-663. 15. Schnyder B, Heibling A, Pichler WJ. Chronic idiopathic urticaria: natural course and association with Helicobacter pylori infection. Int Arch Allergy Immuol. 1999;119:60-63. 16. Greaves MW. Chronic idiopathic urticaria (CIU) and Helicobacter pylori: not directly causative, but could there be a link? Allergy Clin Immunol Int. 2001; 13:23-26. 17. Baty V, Hoen B, Hudziak H, et al. Schnitzler’s syndrome: two case reports and review of the literature. Mayo Clin Proc. 1995;70:570-572. 18. Dode C, Le Du N, Cuisset L, et al. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet. 2002;70:1498-1506.

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CHAPTER 6 Nodular and Diffuse Cutaneous Infiltrates

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Jeff D. Harvell Raymond L. Barnhill

Nodular and diffuse dermal infiltrates encompass a wide spectrum of infectious and noninfectious dermatitides, noninflammatory dermatoses, and neoplasms. Nodular infiltrates produce discrete cellular aggregations that are separated by relatively normal dermis. Diffuse infiltrates tend to involve the entire breadth of a biopsy. They may be relegated to either the upper, middle, or lower portion of a specimen or can be confluent. This chapter will focus on inflammatory diseases, dermatoses, and

cannot be overemphasized, especially in the case of granulomatous infiltrates (whether tuberculoid, sarcoidal, palisaded, or diffuse “histiocytic”). This same rule holds true for neutrophilic and sometimes lymphocytic-plasma cellular infiltrates seen in the setting of immunodeficiency, which often have unexpected histologic appearances. Since cutaneous infections are considered in detail elsewhere, they are presented only in tabular form here.

GRANULOMATOUS INFILTRATES In general, all granulomatous infiltrates require the exclusion of infectious agents and foreign material through the judicious use of special stains for microorganisms and polarization microscopy. Rarely, more sophisticated techniques will be required, such as spectrophotometric or x-ray analysis. Table 6-1 lists infectious diseases whose histologic pattern is typically, but not exclusively, granulomatous. Granulomatous infiltrates in

Table 6-1 Infectious Causes of Granulomatous Infiltrates ORGANISM

TISSUE MORPHOLOGY

HISTOPATHOLOGIC FEATURES

Mycobacterium tuberculosis M tuberculosis M tuberculosis Hypersensitivity reaction to M tuberculosis M leprae

Ziehl-Neelsen-positive AFB Ziehl-Neelsen-positive AFB Ziehl-Neelsen-positive AFB AFB not seen

Caseation usually, but not always present Caseation usually, but not always present Pseudocarcinomatous hyperplasia Vasculitis; granuloma annulare-like

Acid-fast (Fite-positive)

Chronic mucocutaneous candidiasis

Candida albicans

Aspergillosis

Late cryptococcosis

Aspergillus flavus A fumigatus A niger Cryptococcus neoformans

Pseudohyphae and yeasts in stratum corneum and hair follicle (PAS-positive) 2-4μ septate hyphae; 45° angle branching; no yeasts

Elongated, sausage-shaped granulomas; perineural Presence of yeasts distinguishes from dermatophyte

Lobomycosis

Loboa loboi

Mucormycosis

Secondary and tertiary syphilis Brucellosis

Rhizopus Mucor Absidia Treponema pallidum Brucella sp.

Chronic leishmaniasis

Leishmania sp.

Tularemia

Francisella tularensis

Protothecosis

P wickerhamii

Primary cutaneous tuberculosis Lupus vulgaris Tuberculosis verrucosa cutis Tuberculids Tuberculoid leprosy

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some entities in which the true nature of the infiltrate is not precisely defined (inflammatory vs neoplastic). Although many neoplasms display these patterns, they will be treated mainly as differential diagnoses that are discussed in depth in other sections of this book. The conditions to be discussed are organized according to the predominant type of cutaneous inflammation seen histologically and include the following eight categories: granulomatous infiltrates, palisaded granulomatous infiltrates, suppurative granulomatous infiltrates, diffuse histiocytic infiltrates, neutrophilic infiltrates, lymphocytic-plasma cellular infiltrates, mast cell infiltrates, and eosinophilic infiltrates. Each category thus represents a fairly extensive differential diagnostic list that is further subdivided into infectious and noninfectious conditions. Key histologic/clinical features that differentiate one condition from another are provided. A low threshold for use of special stains to demonstrate microorganisms

5-l5μ yeasts with thick capsule; no hyphae 10-μ yeast; form short linear chains, no hyphae Large (30-μ) nonseptate hyphae; 90° angle branching; no yeasts Spirochete (Warthin-Starry-positive) Gram-negative, intracellular coccobacilli 2-4μ round-oval protozoa with nucleus and kinetoplast (Giemsa-positive) Gram-negative coccobacillus 5-10μ round spores; morulalike sporangia

Present in blood vessel walls

Mucicarmine stains capsule red Mucicarmine-negative Easily seen in H&E

Plasma cells; lichenoid granulomatous Perivascular and periadnexal with plasma cells Oranisms within macrophages;nucleus and kinetoplast stain red with Giemsa Not seen in H&E; may be visualized by immunomicroscopy

 FIGURE 6-1 Acne rosacea. A perivascular and perifollicular granulomatous infiltrate. Note dilated, telangiectatic blood vessels.

Acne Rosacea (See also Chap. 10) Synonyms: Rosacea, adult-onset acne. The pathogenesis of acne rosacea is unknown. A disorder of abnormal dermal vessel regulation and vasodilatory responses has been proposed.1-3 Others consider it a sebaceous gland disorder or a folliculitis. CLINICAL FEATURES Patients present with erythematous papules, pustules, and/or telangiectases on the central face. Long-standing cases may eventuate into rhinophyma or phymas involving of portions of the face such as the chin, forehead, or cheeks. An advanced granulomatous form (Lewandowsky rosacea) presents as yellow-brown nodules. Patients may give a history of blushing or flushing with consumption of hot liquids, alcohol, or spicy foods, or exposure to cold or wind. HISTOPATHOLOGIC FEATURES The pathology of acne rosacea depends on the stage of the disease that is biopsied. Nonpustular lesions reveal a mixed perivascular and perifollicular inflammation with lymphocytes, plasma cells, macrophages (some multinucleated), and fewer scattered neutrophils and eosinophils.2 In pustular lesions, the numbers of neutrophils increase, and in a variant referred to as pyoderma faciale (or rosacea fulminans), perifollicular neutrophils are prominent. There is usually spongiosis of the infundibular epithelium. Pronounced granulomatous

inflammation often results from rupture of involved hair follicles (Fig. 6-1). In this instance, central necrosis may be present, producing caseation indistinguishable from that seen in mycobacterial infections. Although marked telangiectasia is a component of acne rosacea, histologically this feature often is difficult to assess objectively. DIFFERENTIAL DIAGNOSIS Lupus miliaris disseminatus faciei is probably best classified as a variant of granulomatous acne rosacea with extensive caseation necrosis. Folliculocentric plasmacytic or granulomatous inflammation should suggest acne rosacea or perioral dermatitis. The differential diagnosis of oral-facial granulomas includes perioral dermatitis, cheilitis granulomatosa, Crohn disease, sarcoidosis, lupus vulgaris, and chronic granulomatous disease. In general, the histologic features of perioral dermatitis and rosacea are identical. Cheilitis granulomatosa is characterized by discrete granulomas that impinge on dilated lymphatics. In Crohn disease, the granulomas lack a perifollicular distribution, typically involve the deep dermis, and may be associated with a granulomatous vasculitis. In sarcoidosis, the granulomas are “naked,” lacking a well-developed peripheral cuff of lymphocytes. Lupus vulgaris is a form of cutaneous tuberculosis and exhibits acid-fast mycobacteria. Chronic granulomatous disease is a rare immunodeficiency syndrome seen in the

pediatric population, and it is associated with clinical signs of an immunodeficiency state. Cutaneous T-cell lymphomas sometimes can demonstrate an accompanying reactive granulomatous infiltrate. On head and neck sites, the lesions of natural killer (NK)/T-cell lymphoma (previously known as lethal midline granuloma) can feature large numbers of reactive histiocytes and NK cells that can cause misinterpretation as a reactive process.4 On the scalp, the whorled configurations of meningocytes seen in cutaneous meningioma and meningothelial hamartoma may bear a superficial resemblance to multinucleated giant cells. When present, psammoma bodies are a useful histologic clue.5

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

the skin can be broadly classified as conditions in which the tissue monocytesmacrophages, that is, histiocytes, are the predominating inflammatory cell. Because of their abundant cytoplasm, granulomatous infiltrates may have a pale appearance on scanning magnification, a clue to the granulomatous nature. In some granulomatous infiltrates, especially in early disease, the aggregations of tissue macrophages are not well-defined, so it is difficult to identify a discrete granuloma. Traditionally, granulomas have been subdivided into aggregations of tissue macrophages having no or few surrounding lymphocytes (“naked” or sarcoidal granulomas), those rimmed by lymphocytes (tuberculoid granulomas), palisading granulomas in which the infiltrate forms around a central area of degeneration and/or necrosis, and foreign-body granulomas. These divisions have utility in defining a differential diagnosis, but there may be considerable overlap in any given patient among these particular types.

Perioral Dermatitis Perioral dermatitis is seen most commonly in young women. The underlying etiology is not understood, but potent fluorinated topical steroids were implicated in the past. Some consider perioral dermatitis a distinct entity; others, a form of acne rosacea.6,7 CLINICAL FEATURES Patients present with relatively symmetric erythematous papules or pustules in a perioral distribution. Involvement of the nasolabial folds is fairly characteristic. Similar lesions may occur exclusively in a periocular distribution (periocular dermatitis).

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HISTOPATHOLOGIC FEATURES Histology is identical to acne rosacea (see “Acne Rosacea” above). Early lesions may show follicular spongiosis with infundibular hyperkeratosis. These changes are similar to topical steroid-induced rosacea and are indistinguishable from those of systemic steroid acne.8

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Cheilitis Granulomatosa (MiescherMelkersson-Rosenthal Syndrome) Synonyms: Orofacial granulomatosis, granulomatous cheilitis. Cheilitis granulomatosa and MiescherMelkersson-Rosenthal syndrome are overlapping clinical conditions with identical histology. The etiology is unclear. CLINICAL FEATURES In MiescherMelkersson-Rosenthal syndrome, patients present with a triad of lip swelling, unilateral facial paralysis, and furrowed tongue.9 In some cases there is more extensive facial swelling involving the eyelids. Similar swelling may affect the penis and vulva. Mono- and oligosymptomatic disease is the rule.10 Patients with cheilitis granulomatosa have lip swelling alone. HISTOPATHOLOGIC FEATURES There is prominent dermal edema and noncaseating, poorly formed, “naked” granulomas adjacent to, and sometimes impinging on, dilated lymphatic channels (Fig. 6-2). A perivascular lymphocytic and plasma cell infiltrate also is present (Table 6-2). DIFFERENTIAL DIAGNOSIS The hallmarks of cheilitis granulomatosa are paralymphatic granulomas and dermal edema. The differential diagnosis of granulomas

A

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at oral-facial sites includes the same processes discussed under acne rosacea (see “Acne Rosacea” above).

Cutaneous Crohn Disease Crohn disease is a form of intrinsic inflammatory bowel disease. The pathogenesis is not understood, but it may be immunologically mediated. Unlike ulcerative colitis, all parts of the gastrointestinal tract are potentially affected, including oral and perianal areas. CLINICAL FEATURES Oral involvement presents as cobblestoning, facial/lip swelling, or linear ulcers and may precede gastrointestinal involvement by many years. Perianal involvement presents as fistulas, sinus tracts, or ulcers.11,12 Cutaneous involvement at sites distant from the anus or mouth has been termed metastatic Crohn disease, a designation that should be avoided because it implies a malignancy. These disseminated lesions present as nodules or plaques in the flexural areas and tend to ulcerate. Lesions on the lower extremities (mimicking erythema nodosum) and the penis are common, and vulvar disease also has been reported. 13 Finally, in patients with colostomies, peristomal lesions may be seen.11,12 Rarely, patients may have quiescent bowel disease but active cutaneous lesions as the sole manifestation of persistent disease, even developing during sulfasalazine treatment. The cutaneous disease in these settings is very refractory to therapy.13 HISTOPATHOLOGIC FEATURES Regardless of site, histology reveals noncaseating

granulomatous inflammation with lymphocytes and plasma cells (Fig. 6-3), often extending deeply into the subcutaneous tissue, where it may produce an extensive septolobular panniculitis (Table 6-3). Palisaded granulomatous areas may be present as well as granulomatous vasculitis.13 On genitalia, marked edema may accompany the granulomatous changes. DIFFERENTIAL DIAGNOSIS Granulomas in the deep dermis or subcutis, especially with granulomatous vasculitis, should suggest Crohn disease.12,13 In oral and perioral sites, the differential diagnosis includes cheilitis granulomatosa, which is typified by granulomas adjacent to dilated lymphatic vessels, and sarcoidosis, which features “naked” granulomas. In the perianal or vulvar areas, hidradenitis suppurativa enters the differential diagnosis. The granulomas of hidradenitis suppurativa are folliculocentric and usually are accompanied by suppuration. Cutaneous T-cell lymphomas can exhibit granulomatous inflammation, and this is particularly true of granulomatous mycosis fungoides and granulomatous slack skin. Granulomatous mycosis fungoides is a histologic variant of mycosis fungoides that features noncaseating granulomatous inflammation in addition to typical papillary dermal and epidermal changes of mycosis fungoides.14 Granulomatous slack skin is a T-cell lymphoma and is probably a variant of granulomatous mycosis fungoides that presents clinically as large, pendulous folds of the skin in the axillae, groin, and elsewhere. Histology reveals noncaseating granulomatous inflammation with papillary dermal and epidermal changes

B

 FIGURE 6-2 Cheilitis granulomatosa (Miescher-Melkersson-Rosenthal syndrome). (A) Marked edema of the dermis is accompanied by (B) discrete granulomata that impinge upon dilated lymphatics.

Table 6-2 Cheilitis Granulomatosa (MiescherMelkersson-Rosenthal Syndrome)

Sarcoidosis Sarcoidosis is a systemic disease of unknown etiology that affects multiple organ systems, typically the lungs, lymph nodes, skin, and eyes. Black females are the most commonly affected patient population. Approximately 25% of patients with systemic involvement have cutaneous involvement, and rarely, the skin may be involved alone.17 CLINICAL FEATURES The clinical presentation of sarcoidosis may be extremely diverse. Smooth-surfaced, violaceous nodules that develop on the nose, cheeks, or earlobes characterize lupus pernio. Other sites may show brown-purple indurated papules, nodules, or plaques with annular or serpiginous configurations. A diffuse maculopapular form also is recognized. Lesions may develop in scars or tattoos. Scalp involvement causes a secondary scarring alopecia.17

caseation necrosis when the panniculus is involved.18 Asteroid bodies, Schaumann bodies, and Hamazaki-Wasserman bodies may be present but are nonspecific. One may see a number of cytoplasmic positively birefringent crystals on polarization, which probably are calcium oxalate and calcium carbonate degradation products of cell metabolism.19 Although their appearance should make one consider a diagnosis of foreign-body reaction, such crystals are a well-established phenomenon in both pulmonary and cutaneous sarcoidosis.19-21 DIFFERENTIAL DIAGNOSIS Lesions of lupus pernio on the face need to be distinguished from other forms of oral-facial granulomas, as discussed in the preceding section, especially acne rosacea. Especially when polarizable crystals are present, the differential diagnosis includes foreign-body giant cell reactions. Clinically, foreign-body reactions are usually solitary lesions, often with a history of prior trauma, and histologically, the foreign material is relatively abundant. If the clinical picture is typical, the presence of a rare crystal by polarization microscopy should not negate a diagnosis of sarcoidosis20,21 (Table 6-4). An intermediate-grade soft tissue neoplasm known as plexiform fibrohistiocytic tumor can simulate a granulomatous process due to the presence of osteoclast-like multinucleated giant cells. It is usually encountered in children and young adults and is characterized by a biphasic appearance with fascicles of spindle cells merging with and surrounding small nodules composed of

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Clinical Features Miescher-Melkersson-Rosenthal syndrome Lip swelling Unilateral facial paralysis Furrowed tongue Cheilitis granulomatosa Lip swelling, alone Histopathologic Features Noncaseating granulomas adjacent to and impinging on dilated lymphatics Dermal edema Perivascular lymphocytes and plasma cells Differential Diagnosis Oral-facial granulomas Acne rosacea Perioral dermatitis Crohn disease Sarcoidosis Lupus vulgaris and other infections Chronic granulomatous disease

can resemble a reactive granulomatous infiltrate.15,16

 FIGURE 6-3 Crohn disease. ( A) A deep dermal granulomatous infiltrate extends into the subcutaneous fat producing a mixed septal and lobular panniculitis. ( B ) Note noncaseating granuloma with surrounding lymphocytes.

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suggesting mycosis fungoides. The multinucleated giant cells in the infiltrate are characteristic, containing large numbers of nuclei (up to 50) per cell. Elastic tissue stains reveal almost complete loss of connective tissue elastic fibers. 14 Angiomatoid fibrous histiocytoma is a soft tissue neoplasm of intermediate malignancy usually seen in childhood. Due to the combination of epithelioid and spindle-shaped cells that resemble histiocytes and accompanying lymphoid aggregates, this neoplasm superficially

A

HISTOPATHOLOGIC FEATURES Typically, noncaseating epithelioid granulomas are scattered throughout the dermis without any relation to nerves, hair follicles, or blood vessels. The granulomas are usually “naked,” having no or only a sparse surrounding lymphocytic infiltrate (Fig. 6-4). Although not frequently described, sarcoid granulomas may fill the papillary dermis and about the epidermis, producing spongiosis, crusting, and irregular hyperplasia. The centers of some granulomas may demonstrate fibrinoid degeneration and even frank

B

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 6-3 Cutaneous Crohn Disease

Clinical Features Facial or lip swelling Oral mucosa cobblestoning/linear ulcers Perianal ulcers, sinus tracts, fistulas Ulcerating nodules/plaques in flexural areas, genitalia, or peri-colostomy sites Erythema nodosum–like lesion Histopathologic Features Noncaseating granulomas with deep dermal and subcutaneous extension Granulomatous panniculitis, often Differential Diagnosis Oral-facial granulomas Acne rosacea Perioral dermatitis Cheilitis granulomatosa Sarcoidosis Lupus vulgaris and other infections Chronic granulomatous disease Hidradenitis suppurativa

A

histiocytic cells and multinucleate osteoclast-like giant cells.22

Chalazion

B

Chalazia are eyelid lesions that are the result of a foreign-body inflammatory reaction to lipid released from ruptured sebaceous glands (meibomian glands). CLINICAL FEATURES Chalazia present as nodules of the eyelid, and they are usually painless and solitary. HISTOPATHOLOGIC FEATURES There is a nodular infiltrate consisting of lymphocytes, plasma cells, sometimes neutrophils, and noncaseating granulomas centered around lipid vacuoles and/or meibomian glands (Fig. 6-5).

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DIFFERENTIAL DIAGNOSIS Granulomatous inflammation of the eyelid is highly suggestive of chalazion, and the presence of distinct vacuoles that represent lipid dissolved during specimen processing is distinctive. Acne rosacea may involve the lids but usually does not present as a solitary lesion. Some cases of MiescherMelkersson-Rosenthal syndrome may involve primarily the eyelid, but dilated lymphatics and edema are characteristic of that condition. Recurrent chalazia should arouse suspicion for sebaceous carcinoma, but histologically, chalazia lack the cytologic atypia seen in sebaceous carcinoma.23

C  FIGURE 6-4 Sarcoidosis. ( A ) Specific cutaneous lesion of sarcoidosis. Smooth-surfaced red to yellowish-brown somewhat tranlucent nodule surmounts a plaque on the upper lip. Telangiectasias involve the nodule as well. ( B ) Confluent granulomata involve the entire reticular dermis and are accompanied by only scattered lymphocytes. No caseation necrosis is identified. ( C ) Note naked granulomata with very sparse accompanying lymphocytic inflammation.

Lupus Miliaris Disseminatus Faciei Synonyms: Acnitis, acne agminata. Lupus miliaris disseminatus faciei most likely represents a dramatic form of the granulomatous stage of acne rosacea.

CLINICAL FEATURES As with granulomatous acne rosacea, patients present with yellow-brown papules on the central face. Eyelid involvement is characteristic.

Table 6-4 Sarcoidosis

 FIGURE 6-5 Chalazion. Granulomatous inflammation surrounds spherical aggregates of lipid.

inflammatory response. Regardless of the origin, multinucleated giant cells, usually with nuclei conglomerated centrally or at one edge of the cell, form around the structure in an attempt to phagocytize and destroy the substance (Fig. 6-6). Table 6-5 lists both endogenous and exogenous foreign materials commonly encountered in skin specimens.

DIFFERENTIAL DIAGNOSIS For granulomatous infiltrates in which the etiology is not readily apparent, it is always good practice to consider the possibility of foreign-body giant cell reaction, especially if the lesion is solitary or associated with a prior history of trauma. Polarization microscopy is helpful in this regard. Sarcoidosis can feature polarizable

HISTOPATHOLOGIC FEATURES Histology is identical to granulomatous acne rosacea in which caseation necrosis may be prominent (see “Acne Rosacea” above).

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Clinical Features Systemic disease with lung, eye, lymph node, and skin involvement Lupus pemio Violaceous nodules on nose, cheeks, earlobes Brown-purple papules, nodules, plaques Diffuse maculopapular form, rarely Scarring alopecia Development of lesions in scars, tattoos Histopathologic Features “Naked” epithelioid granulomas, lacking well-developed lymphocyte cuff Asteroid bodies Schaumann bodies Hamazaki-Wasserman bodies Differential Diagnosis Oral-facial granulomas Acne rosacea Perioral dermatitis Cheilitis granulomatosa Crohn disease Chronic granulomatous disease Foreign body granulomas Tattoo pigments Silicates Zirconium Beryllium Infectious agents Tuberculosis Tuberculoid leprosy Secondary and tertiary syphilis Leishmaniasis Lymphoproliferative disorders

Foreign-Body Granulomas Granulomatous inflammation frequently forms around either endogenous or exogenous material that comes in direct contact with the dermis, where it is perceived as foreign. This occurs commonly when cornified cells or hair, devoid of epithelial cloaks, are extruded into the dermis. A foreign-body granulomatous infiltrate, frequently with suppuration, forms around these structures (see “Ruptured Follicles and Follicular Cysts and Sinuses” below). Injected carbon, such as in carbon tattoos, is inert, and if one sees granulomatous inflammation associated with a carbon tattoo, there are additional substances present (eg, silica) that are responsible for the

 FIGURE 6-6 Foreign-body granulomas. This reaction is to the foreign material from a cosmetic filler. Multinucleate giant cells contain fragments of the filler material.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 6-5 Foreign-Body Granulomas MATERIAL

H&E FEATURES

ADJUNCTIVE TECHNIQUES

CLINICAL/SOURCE

Suture material Tattoo pigments

Basophilic-yellow fibers Black pigment granules

Polarizable

Starch

l0-20 μm oval, particles

Talc (magnesium silicate)

l0-20 μm particles

Oils (mineral oil, paraffin, cottenseed, sesame, camphor) Silicone

Round-ovoid clear spaces; “Swiss cheese” appearance Round-ovoid clear spaces; “Swiss cheese” appearance Hair shaft

Polarizable; PAS-, GMS-positive; maltese cross birefringence Polarizable, white particles; x-ray diffraction Sudan IV, oil red O stains reveal lipid on frozen tissue

Prior surgery Chrome green; carbon; cobalt blue; cinnabar Surgical glove powder; IV drug abuse

Hair Silica (Silicon dioxide) Zirconium Aluminum (adjuvant in vaccines) Beryllium Injectable steroid

Gout (sodium urate)

Injectable collagen Mercury

Sarcoidal granulomas; crystalline particles Sarcoidal granulomas Central basophilic granular material Sarcoidal with hyalinized central necrosis Amphophilic granular/ amorphous material, sometimes with crystalline material Amorphous amphophilic material; needle-shaped urate crystals seen in specimens fixed in alcohol May be sarcoidal or palisaded granulomatous Spherical black globules with foreign body reaction, refractile brown-black granules in macrophages (up to 300 μm)

crystalline material, which represents calcium oxalate or calcium carbonate. Provided that additional clinical and histologic features are characteristic of sarcoidosis, the presence of polarizable crystalline material should not be erroneously interpreted as a foreign-body giant cell reaction.20,21

PALISADED GRANULOMATOUS INFILTRATES

Granuloma Annulare

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The etiology and pathogenesis underlying granuloma annulare is unknown; however, the following mechanisms have been suggested: cell-mediated immunity, immune complex–mediated vasculitis, abnormalities of macrophage function, and primary collagen degeneration.24 It is

Polarizable; spectrographic analysis Nonpolarizable; spectrographic analysis, only X-ray microanalysis Nonpolarizable; spectrographic analysis, only Weakly PAS-positive

Alcohol fixation preserves crystals better than formalin; under polarized light, crystals are negatively birefringent Electron microscopy

important to emphasize that an incomplete, early, or interstitial granuloma annulare–type histologic pattern—defined as a superficial and deep perivascular lymphocytic infiltrate with histiocytes splayed between collagen bundles—is a dermal reaction pattern that can characterize interstital granuloma annulare or simply represent an epiphenomenon associated with other processes (see “Palisaded Granulomatous Dermatitis” below). For example, one can see this interstitial granuloma annulare–type reaction in resolving neutrophilic dermatitides, drug reactions, and even insect bites with no clinical evidence of granuloma annulare. On the other hand, typical clinical lesions of granuloma annulare have been seen following herpesvirus infections, in the acquired immunodeficiency syndrome (AIDS),25,26 and in

Male genitalia (sclerosing lipogranuloma) Breast augmentation mammoplasty Interdigital web space; barbers; dog groomers Contamination of wound from soil or glass Deodorant sticks Site of vaccinations Fluorescent light bulbs Intralesional corticosteroids Big toe, helix of ear

History of bovine collagen injection Self-injection, thermometer accidents, topical mercurial preparations

pityriasis lichenoides et varioliformis acuta–like lesions. It is possible that granuloma annulare is a nonspecific reaction pattern that may follow any number of diverse processes in the skin. CLINICAL FEATURES Children and young adults are mainly affected, although the disease can occur at any age. Women are affected more often than men. Granuloma annulare presents as localized erythematous, skin-colored, and occasionally violaceous discrete and coalescent papules in annular and polycyclic configurations, mainly on the dorsal surfaces of the hands, feet, arms, and legs (Fig. 6-7A). The lesions often enlarge centrifugally anywhere from 1 to 5 cm and usually are not associated with pruritus or other symptoms. On occasion, large geographic patches and plaques are encountered. Generalized or

Palisaded Granulomatous Form

A

B

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

HISTOPATHOLOGIC FEATURES The fully developed lesion of granuloma annulare (GA) displays a palisaded granulomatous dermatitis surrounding an area of degenerated collagen (Fig. 6-7A). Such palisading granulomas are usually focal and discrete phenomena in the dermis with intervening normal collagen. The granulomas may extend along the fibrous trabeculae of the subcutaneous fat and thus constitute a septal panniculitis (that is later also lobular). Connective tissue mucin deposition within the central degenerated collagen is a near-constant finding but may require special stains (ie, alcian blue or colloidal iron) to demonstrate the same. In hematoxylin and eosin (H&E)-stained sections, mucin appears as stringy and/or granular basophilic material. Uncommonly, the collagen degeneration is characterized by fully developed fibrinoid necrosis. Away from the central palisade, there is a superficial and deep perivascular inflammatory cell infiltrate of lymphocytes and macrophages. On occasion one may observe a so-called sarcoidal variant of GA based on the finding of aggregates of epithelioid histiocytes that mimic sarcoidosis. Lesions with overlapping feature of both GA and sarcoidosis have been described. In some instances, particularly in sun-damaged skin, the macrophages and multinucleate giant cells comprising the palisaded infiltrates are noted to contain phagocytosed elastic fibers (elastophagocytosis). The latter finding is nonspecific, and the demonstration of collagen degeneration with mucin deposition provides confirmatory evidence for GA. Eosinophils occur in approximately 40% of cases and may be so numerous as to suggest an arthropod bite reaction.

Interstitial or Incomplete Form C  FIGURE 6-7 Granuloma annulare. (A) Pink to erythematous coalescent papules in annular and polycyclic configurations on the dorsal surface of the hand. The lesions exhibit slightly depressed central areas in some instances with a return to normal skin color. ( B ) Early or so-called interstitial granuloma annulare consists of tissue macrophages (histiocytes) splayed between collagen bundles with an increase in connective tissue mucin. (C ) A fully developed lesion of granuloma annulare shows well-formed palisaded granulomas containing central mucin and degenerated collagen.

widely disseminated, giant, linear, perforating, and subcutaneous forms have been described (see “Deep Granuloma Annulare” below). Umbilicated clustered lesions sim-

ulate molluscum contagiosum. A recently described clinical variant of granuloma annulare presents with subtle patches on the extremities and trunk.27

HISTOPATHOLOGIC FEATURES Some lesions of GA lack typical palisading granulomatous dermatitis but instead show macrophages splayed between individual collagen bundles, increased connective tissue mucin deposition, and little to no collagen degeneration (see Fig. 6-7B). This pattern has been labeled interstitial GA, but alternative terms include early or incomplete GA. This pattern is typical of the recently described clinical variant of granuloma annulare in which subtle patches are found predominantly on extremities.27 DIFFERENTIAL DIAGNOSIS The major differential diagnostic consideration is necrobiosis lipoidica (NL). The following

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4. The palisades in GA are round to ovoid. In NL, they are horizontally oriented tiers.

Eruptive xanthomas can mimic this pattern but are recognized by foamy macrophages, occasional neutrophils, extracellular lipid, no mucin, and rarely, urate-like crystals (see the following section). Palisaded neutrophilic and granulomatous dermatitis features greater numbers of neutrophils and/or neutrophilic nuclear dust than is seen in GA (Table 6-6). Granulomatous mycosis fungoides is a histologic variant of mycosis fungoides that features granulomatous inflammation. The pattern of granulomatous inflammation is variable and may be diffuse or palisaded, but there are usually superimposed changes of conventional mycosis fungoides in which small, atypical lymphocytes permeate the epidermis.14

5. NL features prominent plasma cells, whereas GA does not.

Deep Granuloma Annulare

features help distinguish granuloma annulare from NL. 1. In GA, the dermis surrounding the primary focus of inflammation is normal. In NL, it is often altered. 2. NL features a greater degree of central collagen degeneration. Sometimes the central collagen in GA is not yet morphologically altered.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

3. NL lacks central mucin deposition as a rule. Central mucin in GA usually is prominent but may require special stains for demonstration.

6. NL may demonstrate a granulomatous vasculitis not seen in GA.28 Central mucin accumulation and focal (as opposed to diffuse) dermal involvement are distinguishing features of GA.

CLINICAL FEATURES Deep GA affects children more often than adults. Subcutaneous nodules are found on the extensor aspects of hands, feet, lower legs, buttocks, scalp, and periorbitally. HISTOPATHOLOGIC FEATURES Except for its subcutaneous locale, the histologic features of deep GA are similar to the more superficial forms (Fig. 6-8). The deep reticular demis above the subcutaneous disease frequently shows focal involvement. The subcutaneous locale with central connective tissue mucin deposition are distinctive. DIFFERENTIAL DIAGNOSIS A subcutaneous palisaded granulomatous dermatitis with mucin deposition, especially in children,

Table 6-6 Palisaded Granulomatous Dermatitis GRANULOMA ANNULARE (GA)

NECROBIOSIS LIPOIDICA

RHEUMATOID NODULE

RHEUMATIC FEVER NODULE

PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS

Clinical Features Annular papules Hands, feet, arms, legs

Plaques Shins

Adults with rheumatoid arthritis Subcutaneous nodules Elbows, knuckles, Achilles tendon

Children with rheumatic fever

Many associated diseases

IgG paraproteinemia

Variable, according to specific infection

Subcutaneous nodules Elbows, knuckles

Umbilicated papules

Papules, nodules, plaques Face, periorbital

Often immunocompromised

Subcutaneous palisades

Similar to Early rheumatoid GA-like, with nodule, sometimes prominent with neutrophils/ neutrophils/ leukocytoclasis leukocytoclasis

Central cholesterol clefts Foreign-body and Touton-type giant cells

Central necrosis with numerous neutrophils

Histopathologic Features Palisades Palisades Round/oval Discrete/focal Central mucin No plasma cells

“Incomplete” form Macrophages splayed between collagen fibers Central mucin

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Synonyms: Pseudorheumatoid nodule, nodular granuloma annulare. GA may involve the subcutis, most often in children. Although first thought to represent a type of cutaneous involvement in rheumatoid arthritis, patients

generally do not have symptoms or signs of rheumatoid arthritis. The pathogenesis is not fully understood, but local trauma may play a significant role.29 Cellmediated immunologic and vasculitic processes also have been implicated.

Horizontally oriented Diffuse/fullthickness No central Central eosinophilic mucin fibrinoid necrosis Plasma cells Vasculitis, No central mucin sometimes Vasculitis, sometimes Lipidized macrophages

Extremities

NECROBIOTIC XANTHOGRANULOMA

Lymphocytes/plasma cells Lymphoid follicles, sometimes Late Extravascular foci of degenerated stroma, mucin may be present

INFECTION

macrophages between individual collagen bundles (similar to the incomplete pattern of GA) (Fig. 6-9) or a prominent palisaded granulomatous dermatitis arranged around elastotic material in the superficial dermis. The giant cells contain blue-gray elastotic material, and asteroid bodies may be seen. Neither prominent mucin nor degenerated collagen typically is present. The central portion of the plaque demonstrates loss of both elastotic fibers and normal elastic fibers.

suggests deep GA. Rheumatoid nodule and rheumatic fever nodule are also subcutaneous but lack mucin and instead feature central fibrinoid necrosis, sometimes with features of a late-stage leukocytoclastic vasculitis.30 Some malignancies also may mimic deep GA. Epithelioid sarcoma is a malignant soft tissue neoplasm that most frequently affects children or young adults and occurs on the distal extremities.31 Histology reveals spindled and epithelioid cells surrounding central areas of necrosis in a palisaded array. Lymphocytes and plasma cells may be seen. In contrast to tissue macrophages, the tumor cells of epithelioid sarcoma are cytologically atypical, with vesicular nuclei and prominent nucleoli, and are immunoreactive with antibodies to cytokeratin, epithelial membrane antigen, or CD34.31

and plaques, usually on the face but also at other sun-exposed areas such as the chest, arms, and neck. Individual lesions tend to resolve spontaneously over time. HISTOPATHOLOGIC FEATURES The peripheral, “active,” part of the lesion demonstrates either an interstitial collection of

Necrobiosis Lipoidica Synonym: Necrobiosis lipoidica diabeticorum. Approximately two-thirds of patients with necrobiosis lipoidica have diabetes mellitus. On the other hand, in patients with diabetes mellitus, necrobiosis lipoidica occurs in less than 1%. The etiology and

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

 FIGURE 6-8 Subcutaneous/deep granuloma annulare. Palisaded granulomas are present in the subcutaneous tissue.

DIFFERENTIAL DIAGNOSIS The facial location and the presence of palisaded granulomas and phagocytized elastotic material (elastophagocytosis) are distinctive features. One must be cautious, however, not to overinterpret the mere presence of elastophagocytosis, for it is a nonspecific mesenchymal reaction pattern in both sun-damaged and non-sun-damaged skin.33,34 Necrobiotic xanthogranuloma also occurs on the face, but cholesterol clefts and foamy macrophages are characteristic.

Actinic Granuloma Synonyms: Annular elastolytic granuloma, Miescher granuloma, atypical necrobiosis lipoidica, granulomatosis disciformis of the face. Actinic granuloma is a controversial entity. Some consider it a distinct condition.32 Others believe that it is simply GA at sun-damaged sites. Like GA, its pathogenesis and inciting events are not understood. A cell-mediated immunologic reaction to altered elastotic fibers has been proposed.32 CLINICAL FEATURES Adult patients present with expanding arciform papules

 FIGURE 6-9 Actinic granuloma. This pattern is a granuloma annulare–type reaction on severely sundamaged skin. There is extensive phagocytosis of elastic fibers (elastophagocytosis).

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pathogenesis are not fully understood, but microangiopathic changes, immune complex–mediated vasculitis, and a thrombotic tendency have been implicated.35,36

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

CLINICAL FEATURES Females are affected more often than males (3:1). Adults present with waxy, indurated, yellow-brown patches or plaques with a surrounding erythematous, raised, and expanding margin. Lesions characteristically are found on the anterior shins but also may be seen on forearms, hands, and trunk.35 HISTOPATHOLOGIC FEATURES Biopsies of the erythematous margin show palisaded and granulomatous dermatitis, often involving full-thickness dermis and extending into subcutaneous fat (Fig. 6-10). In contrast to the circular palisades seen in GA, the palisades in necrobiosis lipoidica assume a horizontal

and parallel arrangement with respect to the overlying epidermis. The central portion of the palisade shows marked collagen degeneration without connective tissue mucin. The dermis to the periphery of the palisaded area is usually fibrotic (in contrast to a more normal dermis seen in GA), sometimes with lipid deposition.37 In many instances, the interface between the dermis and subcutis is well demarcated, linear, and parallel to the skin surface. There is an accompanying superficial and deep perivascular inflammatory cell infiltrate usually demonstrating plasma cells. Vasculitis may be seen.35 In some cases vessels at the junction of the dermis and subcutaneous fat show leukocytoclastic vasculitis in acute lesions and granulomatous vasculitis in chronic lesions. Involvement of the panniculus takes the form of a predominantly septal panniculitis. The atrophic centers of plaques demonstrate fibrosis.35-37

Rheumatoid Nodule Rheumatoid nodules are seen in approximately 20% of adults with rheumatoid arthritis. Nodules with similar histology may be seen in visceral sites, including lung, heart, and gastrointestinal tract. The pathogenesis is most likely an immune complex–mediated vasculitis, which results in ischemic damage to subcutaneous tissues and a palisaded granulomatous inflammatory reaction.36,38 CLINICAL FEATURES Rheumatoid nodules present in adults as subcutaneous nodules situated over joints, classically the elbows. Other common sites include the knuckles, Achilles tendon, and weightbearing parts of the foot. Perforating variants are also known.

A

B

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DIFFERENTIAL DIAGNOSIS Horizontally oriented arrays of palisading granulomatous dermatitis with marked collagen degeneration, diffuse as opposed to focal dermal involvement, a lack of connective tissue mucin, and the presence of plasma cells are features that distinguish necrobiosis lipoidica from GA and rheumatoid nodule. In addition, necrobiosis lipoidica usually involves the dermis and possibly the subcutis, whereas the converse is true of rheumatoid nodule37 (see Table 6-6).

 FIGURE 6-10 Necrobiosis lipoidica. ( A ) The palisaded granulomatous infiltrate alternates with degenerated collagen in a somewhat laminated array and extends in a confluent fashion from the upper reticular dermis to the subcutaneous fat. (B) Numerous plasma cells are present around the deeper vessels.

HISTOPATHOLOGIC FEATURES Within subcutaneous tissue and lower dermis there is palisaded granulomatous dermatitis surrounding a large area of homogeneous, eosinophilic fibrinoid necrosis (Fig. 6-11). The central area lacks pools of connective tissue mucin as a rule,30,39 but vasculitic changes with intact and degenerated neutrophils are usually apparent.38

DIFFERENTIAL DIAGNOSIS The predominantly subcutaneous location and central fibrinoid necrosis (without pools of connective tissue mucin) are distinctive features of rheumatoid nodules.30 In general, the histology of rheumatic fever nodule and rheumatoid nodule is identical, but patients with rheumatic fever nodule have a prior or concurrent history of rheumatic fever. The entity known as “rheumatoid papules” is currently considered as a part of the spectrum of palisaded neutrophilic and granulomatous dermatitis. The latter clinically presents as papules or plaques, rather than nodules. In subcutaneous granuloma annulare, the general architecture of the subcutaneous fat is

HISTOPATHOLOGIC FEATURES Necrobiotic xanthogranuloma demonstrates broad zones of collagen degeneration and cholesterol clefts surrounded by foamy macrophages with foreign-body and Touton-type multinucleated giant cells (Fig. 6-12). Numerous lymphocytes and plasma cells (sometimes with lymphoid follicle formation) are conspicuous. These changes extend throughout the dermis, sometimes into the subcutaneous fat.37,42

Palisaded Neutrophilic and Granulomatous Dermatitis preserved, and there are often scattered interstitial histiocytes39 (see Table 6-6). Epithelioid sarcoma is a malignant soft tissue tumor that frequently demonstrates a palisaded pattern within the subcutaneous tissue. Its constituent cells may resemble macrophages, but they exhibit cytologic atypia and are positive with antibodies to cytokeratin, epithelial membrane antigen, or CD34.31

Rheumatic Fever Nodule Rheumatic fever nodules are seen in patients with acute rheumatic fever and, early on, were studied more thoroughly than rheumatoid nodules.38 The advent of effective antistreptococcal therapy resulted in a decrease in the disease, so few lesions are currently biopsied.40 However, rheumatic heart disease is a major problem in developing countries, and recent reports have documented a rising increase of rheumatic fever in the United States and Europe.41 Similar nodules are found in the heart and are known as Aschoff nodules. Like rheumatoid nodules, the pathogenesis is most likely an immune complex–mediated vasculitis with subsequent ischemic damage followed by a palisaded granulomatous repair reaction. CLINICAL FEATURES Rheumatic fever nodules typically develop in children with a history of acute rheumatic fever.38 Sites of predilection include the

Necrobiotic xanthogranuloma occurs in association with IgG paraproteinemia (usually kappa subtype) in approximately 80% of cases. Other laboratory findings include hypocomplementemia, cryoglobulinemia, anemia, and leukopenia. Bone marrow examination may reveal plasmacytosis, and rare cases can be seen in association with multiple myeloma or B-cell lymphoma.42

Synonyms: Churg-Strauss granuloma, cutaneous extravascular necrotizing granuloma, rheumatoid papules, superficial ulcerating rheumatoid necrobiosis, interstitial granulomatous dermatitis with arthritis. In 1983, Finan and Winkelmann reported a granulomatous condition seen in the setting of systemic disease, which they termed Churg-Strauss granuloma or cutaneous extravascular necrotizing granuloma.44 Recently, two reports have further delineated the clinicopathologic features.45,46 An umbrella term, palisaded neutrophilic and granulomatous dermatitis, has been suggested to encompass the conditions cited (see “Synonyms” above) because all share GA-like or necrobiosis lipoidica-like histology and most likely represent an inflammatory reaction to a primary vasculopathy/vasculitis.45 Skin lesions in Wegener granulomatosis may demonstrate identical granulomatous inflammation, and in fact, many noninfectious palisaded granulomas (from Aschoff nodules to some cases of granuloma annulare) probably reflect a similar pathogenesis.47 Juxtaarticular nodes of syphilis also may fall under this rubric.

CLINICAL FEATURES Indurated papules, nodules, or plaques (sometimes with ulceration/atrophy) most commonly occur periobitally but can involve the trunk and extremities. Systemic manifestations can include hepatosplenomegaly, arthritis/arthralgias, or neuropathy.

CLINICAL FEATURES The associated systemic diseases include systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, Wegener granulomatosis (and other ANCA-positive vasculitides), inflammatory bowel disease, hepatitis, lymphoproliferative disease,

bony prominences (humeral condyles, olecranon processes, knuckles) and occiput. Individual nodules resolve spontaneously. HISTOPATHOLOGIC FEATURES In early lesions, neutrophils may be admixed with histiocytes and lymphocytes. Otherwise, the histology is identical to rheumatoid nodule, although individual lesions may be smaller36,38 (see “Rheumatoid Nodule” above). DIFFERENTIAL DIAGNOSIS See “Rheumatoid Nodule” above.

Necrobiotic Xanthogranuloma

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

 FIGURE 6-11 Rheumatoid nodule. Palisaded granulomatous inflammation surrounds degenerated collagen and fibrinoid material, with neutrophils and neutrophilic nuclear debris.

DIFFERENTIAL DIAGNOSIS Innumerable foam cells and cholesterol clefts distinguish necrobiotic xanthogranuloma.37 Similar changes may be seen focally in plane xanthoma, suggesting a pathogenetic relationship between the two43 (see Table 6-6). While plasma cells are seen in both necrobiotic xanthogranuloma and necrobiosis lipoidica, necrobiosis lipoidica does not involve the face and lacks numerous foam cells and cholesterol clefts.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

B

 FIGURE 6-12 Necrobiotic xanthogranuloma. ( A ) Palisaded granulomatous inflammation surrounds large areas of necrobiosis. (B) Note cholesterol clefts and foamy macrophages.

myelodysplastic syndromes, cancer, thyroid disease, diabetes mellitus, drug reactions, and infections (including bacterial endocarditis, Epstein-Barr virus, HIV, Mycoplasma pneumoniae, parvovirus, hepatitis C, and Borrelia burgdorferi). Patients present with skin-colored to erythematous papules with overlying crust, ulceration, or umbilication. The papules are found predominantly on extremities and trunk and often are distributed symmetrically.44-47 Other clinical presentations include plaques and sometimes linear papules, cords, and bands.

either GA or necrobiosis lipoidica. Except for its dermal location, palisaded neutrophilic and granulomatous dermatitis is virtually identical to rheumatoid or rheumatic fever nodules. All three conditions most likely represent a similar reaction to a primary immune complex– mediated vasculitis, which results in a fully developed GA-like repair response (also see “Granuloma Annulare” above). Emphasis should be given to the fact that patients with lesions that are histologically identical to the palisaded neutrophilic and granulomatous dermatitis may only have

skin disease, more typical of GA.48 It is incumbent on the physician to establish an associated systemic disease before more aggressive therapy is warranted because patients with disease limited to the skin disease often respond to topical steroid therapy alone49 (see Table 6-6).

Infectious Palisaded Granulomatous Dermatitis A palisaded granulomatous reaction pattern also occurs in response to infections caused by typical and atypical

HISTOPATHOLOGIC FEATURES The histology is variable and reflects the variable stages of repair to a primary vasculitis. Early lesions demonstrate collagen degeneration, pandermal infiltrates of neutrophils, nuclear debris, and focal leukocytoclastic vasculitis. The dermal vessels have characteristic broad collars of fibrin surrounded by basophilic debris.45 Fully developed lesions resemble GA and demonstrate palisaded and granulomatous dermatitis surrounding zones of fibrin deposition and necrosis, collagen degeneration, neutrophils, and nuclear dust (Fig. 6-13). The central area contains connective tissue mucin. Late-stage lesions resemble necrobiosis lipoidica and demonstrate palisaded granulomas surrounding deeply eosinophilic fibrin with scattered neutrophils.43-45

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DIFFERENTIAL DIAGNOSIS Depending on stage of disease, the lesions of palisaded neutrophilic and granulomatous dermatitis may resemble GA or necrobiosis lipoidica. At all stages, though, more neutrophils/ leukocytoclasis are seen as compared with

 FIGURE 6-13 Palisaded neutrophilic and granulomatous dermatitis. A nodular granulomatous infiltrate is present around areas of degenerated collagen containing basophilic material and scattered neutrophils.

mycobacteria, phaeohyphomycosis, syphilis, sporotrichosis, cryptococcosis, coccidioidomycosis, cat scratch disease, lymphogranuloma venereum, and schistosomiasis.50,51 Infection-related palisaded granulomatous dermatitis is rare and in some series represented only 4.3% of all cases of palisading granuloma and less than 0.44% of all granulomas.51 CLINICAL FEATURES The clinical features are mostly those of the specific infection.

DIFFERENTIAL DIAGNOSIS Neutrophils and/or neutrophilic debris in association with palisades of granulomas can be seen in rheumatoid nodule, rheumatic fever nodule, palisaded neutrophilic and granulomatous dermatitis, and infection. In infectious processes, neutrophils are more numerous, and there is central caseation necrosis.

SUPPURATIVE GRANULOMATOUS INFILTRATES Aggregations of neutrophils commonly accompany granulomatous infiltrates. When infectious agents are found in this setting, it is often in the area of suppuration that the organisms are demonstrated. Table 6-7 lists infectious diseases whose histologic pattern is typically but not exclusively suppurative and granulomatous.

Blastomycosis-Like Pyoderma Synonyms: Superficial granulomatous pyoderma, atypical plaquelike folliculitis in HIV, vegetative pyoderma gangrenosum. Blastomycosis-like pyoderma represents an exaggerated inflammatory reaction to bacterial infection (particularly Staphylococcus aureus but also Pseudomonas aeruginosa and beta-hemolytic Streptococcus), usually seen in the setting of immunosuppression and/or lymphoproliferative disorders.52,53 The condition is responsive to antibiotics, and in nearly all cases, pathogenic bacteria may be cultured, even

CLINICAL FEATURES Patients with lymphoproliferative disorders or drug, or HIV-induced immunosuppression present with isolated or disseminated, wellmarginated, verrucous plaques with multiple pustules. Plaques are distributed on head and neck, extremities, or intertriginous areas. The clinical differential diagnosis includes blastomycosis or other deep fungal infections, halogenodermas, pyoderma gangrenosum, and tuberculosis verrucosa cutis. HISTOPATHOLOGIC FEATURES There is a diffuse mixed cellular infiltrate present in the superficial reticular dermis. Typically, a central nidus of numerous neutrophils with fewer numbers of eosinophils is surrounded by macrophages with multinucleated giant cells and a more peripheral rim of lymphocytes and plasma cells.53 Pseudocarcinomatous hyperplasia is common. In some cases, the inflammation is folliculocentric and/or folliculodestructive. Vasculitis is not seen. DIFFERENTIAL DIAGNOSIS In contrast to the pandermal inflammation seen in pyoderma gangrenosum, blastomycosislike pyoderma features mostly superficial infiltrates. The histology may be virtually identical to halogenodermas, but normal serum halogen levels exclude this possibility (Table 6-8).

Halogenodermas Synonyms: Bromoderma, iododerma, fluoroderma. Halogenodermas are a group of dermatoses owing to chronic ingestion or application of iodine, bromide, or fluoride. The source of bromides and iodides often is expectorants and sedatives.55 CLINICAL FEATURES The large vegetative nodules or plaques of halogenodermas often are studded with pustules and clinically resemble deep fungal infections or blastomycosis-like pyoderma. HISTOPATHOLOGIC FEATURES The most striking and constant feature is pseudocarcinomatous hyperplasia containing intraepidermal microabscesses composed of neutrophils and fewer eosinophils (Fig. 6-14). In some cases there are dermal abscesses composed of numerous neutrophils with fewer macrophages and multinucleated giants cells.55

DIFFERENTIAL DIAGNOSIS Special stains for microorganisms are required to rule out infectious causes of suppurative granulomatous inflammation, especially deep fungal infections. The histologic appearances may resemble blastomycosislike pyoderma, and clinical history and/ or serum halogen levels are necessary to distinguish the two (Table 6-9).

Follicular Occlusion Triad Synonyms: Hidradenitis suppurativa, acne conglobata, dissecting cellulitis. Follicular occlusion triad is an umbrella term given to the three clinical conditions listed under “Synonyms” whose pathogenesis is related to a disorder of follicles resulting in subsequent occlusion, inflammation, and destruction. All three conditions may coexist in the same patient.56 CLINICAL FEATURES Dissecting cellulitis presents on the scalp as a boggy indurated plaque that may be associated with alopecia. Hidradenitis suppurativa typically presents in the axillae, groin, or perineum (areas rich in apocrine glands) as erythematous, tender, deep-seated nodules, sometimes with sinus tract formation. Acne conglobata presents on the chest, back, buttocks, or proximal extremities as erythematous, tender nodules or cysts, sometimes with sinus tract formation. HISTOPATHOLOGIC FEATURES All three conditions demonstrate a common pathology and pathogenesis, as described by Brunsting in 1952.56 The features include perifollicular dermal abscesses composed of a mixed inflammatory cell infiltrate with a predominance of neutrophils, macrophages with multinucleated giant cells, and fewer lymphocytes, plasma cells, and sometimes eosinophils (Fig. 6-15). The inflammation usually results in destruction of the follicle and sometimes the formation of epitheliallined sinus tracts. Later stages of the disease demonstrate more lymphocytes, plasma cells, and fibrosis.

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

HISTOPATHOLOGIC FEATURES In the evaluation of palisaded and granulomatous dermatitis, central necrosis (not mucin or fibrin deposition) with numerous neutrophils should suggest an infectious etiology. A palisaded granulomatous reaction pattern in immunocompromised patients should prompt a search for infection. Morphologic demonstration and/or microbiologic culture of the infectious agent are diagnostic (see Table 6-6).

though they may not be demonstrable in tissue sections. A similar exuberant inflammatory response to staphylococcal folliculitis is seen in the setting of HIV disease.54

DIFFERENTIAL DIAGNOSIS The histology of all three clinical variants is virtually identical, but the clinical locale allows distinction among the three. The multiplicity of lesions distinguishes follicular occlusion triad from ruptured hair follicles and follicular cysts.

Ruptured Follicles and Follicular Cysts and Sinuses The most common cause of a suppurative granulomatous infiltrate is a ruptured

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Table 6-7 Infectious Causes Of Suppurative Granulomatous Infiltrates

Atypical mycobacteria

Blastomycosis

TISSUE MORPHOLOGY

HISTOPATHOLOGIC FEATURES

M. marinum M. kansasii M. fortuitum M. chelonei M. avium-intracellulare M. ulcerans (Buruli ulcer) Blastomyces dermatitidis

Larger than M. tuberculosis

Variable inflammatory infiltrates

8-15 μm yeasts, broad-based budding; no hyphae Brown, 6-12 μm clustered yeastlike (copper pennies; medlar bodies); no hyphae Brown, septate hyphae and yeasts

Pseudocarcinomatous hyperplasia

Sporotrichosis

Fonsecaea pedrosi Phialophora sp. Cladosporium sp. Exophiala jeanselmei Wangiella dermatitidis Sporothrix schenckii

Paracoccidioidomycosis

Paracoccidioides brasiliensis

Coccidioidomycosis

Coccidioides immitis

Eumycetoma

Allescheria boydii Madurella sp.

Nocardiosis

N. asteroides N. brasiliensis

Actinomycosis

Actinomyces israelii

Botryomycosis Tularemia

S. aureus P. aeruginosa Francisella tularensis

Rhinosporidiosis

Rhinosporidium seeberi

Cat-scratch disease

Bartonella henselae

Lymphogranuloma venereum

Chlamydia trachomatis

Alternariosis

A. alternata A. dianthicola

Scrofuloderma

M. tuberculosis and atypical mycobacteria M. tuberculosis

Chromomycosis

Phaeohyphomycosis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

ORGANISM

Miliary tuberculosis

follicle or follicular cyst. Disruption of these structures releases hair and/or other cornified cells into the adjacent dermis, resulting in a foreign-body inflammatory response admixed with neutrophils.

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CLINICAL FEATURES Ruptured follicles or follicular cysts present as solitary

4-8 μm yeasts, some cigar-shaped; rare hyphae 10-60 μm yeasts; multiple budding no hyphae Large 20-80 μm sporangia containing 5-10 μm endospores; no hyphae Septate hyphae; Granules (gram-negative, GMS-pos) Thin, filamentous, gram-positive bacteria; granules (gram-positive, Ziehl-Neelsen-positive) Thin, filamentous gram-positive bacteria; granules (gram-positive, Ziehl-Neelsen-negative) Granules composed of numerous bacteria (gram-positive) Gram-negative coccobacillus Large (100-400 μm) sporangia containing 7 μm endospores; no hyphae Warthin-Starry-positive rods

l-4 μm Giemsa- or direct immunofluorescencepositive coccoid bodies Brown, broad (5-7 μm thick) septate hyphae; 3-10 μm brown spores Ziehl-Neelsen-positive AFB Ziehl-Neelsen-positive AFB

erythematous, tender nodules. Alternatively, ruptured follicles may be the etiology underlying recent changes in melanocytic nevi, especially hair-bearing congenital nevi. Pilonidal sinus most commonly presents in the sacrococcygeal area of hirsute males, although other sites, including the scalp and the

Pseudocarcinomatous hyperplasia

May form a cystic cavity Asteroid bodies suggestive, but nonspecific Budding yeasts resemble “pilot’s or mariner’s wheel” Sporangia large and easily seen in H&E Filaments in granules are thick hyphae, not thin as in Nocardia and Actinomyces Filaments in granules are thin and partially acid-fast Filaments in granules are same size as Nocardia, but are not acid-fast No filaments Immunomicroscopy required to visualize organism Sporangia easily seen in H&E

Central PMNs surrounded by macrophages (stellate abscess) Intracellular

Similar to phaeohyphomycosis

Caseation Caseation may be absent in very small lesions

finger webs of barbers’ hands, have been reported.57 HISTOPATHOLOGIC FEATURES There is a follicular-based, dense, nodular, mixed inflammatory cell infiltrate with a predominance of neutrophils, macrophages, and multinucleated giant cells. Keratin

Table 6-8 Blastomycosis-Like Pyoderma

debris and/or hair is seen lying free within the infiltrate or within the cytoplasm of multinucleated giant cells. In some cases, the infiltrate may extend deep and affect the panniculus preferentially, giving rise to a lobular panniculitis. The latter is the rule in pilonidal sinus, where hair shafts usually can be identified in the granulomatous inflammation.

DIFFUSE HISTIOCYTIC INFILTRATES The term histiocyte is admittedly controversial. Wood and Haber proposed that the term histiocyte “refers to all types of bone marrow–derived macrophages and immune-related dendritic cells. Similarly, the term histiocytosis refers to any proliferative disorder exhibiting the differentiation of these cells.”58 A similar definition is used to define the entities discussed, but in general, when the involvement remains as discrete cutaneous papules or nodules (single or multiple), the suffix -oma is attached (ie, histiocytoma, xanthoma). It is when lesions tend to coalesce, to progress relentlessly, and/or to involve extracutaneous sites that the suffix -osis is applied (ie, histiocytosis, reticulohistiocytosis). As always,

Table 6-9 Halogenodermas

Clinical Features Ingestion/application of bromide, iodide, fluoride Increased serum halogen levels Verrucous plaques with surface pustules Histopathologic Features Pseudocarcinomatous hyperplasia Intraepidermal microabscesses Dermal neutrophils and multinucleated giant cells Differential Diagnosis Mycobacterial and fungal infections Blastomycosis-like pyoderma Follicular occlusion triad Ruptured follicles, follicular cysts, and sinuses

there are exceptions, and some entities demonstrate overlapping clinical pictures. Table 6-10 lists infectious diseases whose histologic pattern is typically, but not exclusively, a diffuse histiocytic infiltrate. Whipple disease rarely can affect the skin and result in a diffuse histiocytic panniculitis. Whipple disease features periodic acid-Schiff (PAS)-positive bacteria (Tropheryma whipelii) within the cytoplasms of macrophages.59

Xanthomas Xanthoma (unmodified) is the generic term applied to a group of infiltrates of foamy macrophages (histiocytes). Those associated with hyperlipidemias have characteristic sites of predilection. These xanthomas include eruptive xanthoma, tuberous xanthoma, tendinous xanthoma, and xanthelasma (Table 6-11). The characteristic cell is the foam cell—a macrophage whose cytoplasm is stuffed with lipid and appears foamy in H&Estained sections. Aggregations of foam cells are the common denominator of other lesions called xanthomas-plane, verruciform, papular, plexiform—but that have distinctive clinical and/or pathologic features. Xanthoma disseminatum is more closely related to xanthogranuloma. These latter five entities are discussed separately.

 FIGURE 6-14 Halogenoderma. Suppurative granulomatous inflammation is accompanied by pseudocarcinomatous hyperplasia. Focal abscesses are seen in the epidermis.

CLINICAL FEATURES Sites of predilection for the usual xanthoma types associated with hyperlipidemia are provided in Table 6-11. With the exception of the eruptive type, the histologic appearance for all types is virtually identical. The

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Clinical Features Immunosuppressed patients Lymphoproliferative diseases Verrucous plaques with surface pustules Head, neck, extremities, intertriginous sites Normal serum halogen levels Histopathologic Features Superficial infiltrates Central neutrophils/eosinophils surrounded by multinucleated giant cells and lymphocytes Pseudocarcinomatous hyperplasia No vasculitis Differential Diagnosis Infection Halogenodermas Follicular occlusion triad Ruptured follicles, follicular cysts, and sinuses

DIFFERENTIAL DIAGNOSIS Special stains for microorganisms to rule out infection are required if keratin debris is not visualized. Similar histopathology can be seen in the follicular occlusion triad, but that condition exhibits multiple lesions. Other foreign materials besides hair and keratin can elicit suppurative and granulomatous inflammation, but they are easily recognizable on H&E-stained sections or with polarization microscopy.

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them from the non-Langerhans cell histiocytoses (see Table 6-11). Eruptive xanthoma is an exception in that it exhibits an accompanying infiltrate of lymphocytes and neutrophils.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Diffuse Normolipemic Plane Xanthoma Synonym: Generalized plane xanthoma. Diffuse normolipemic plane xanthoma is commonly associated with multiple myeloma. Other less common associations are erythroderma, cryoglobulinemia, myelogenous leukemia, lymphomas (including mycosis fungoides), and rarely, hyperlipoproteinemia types IIA, III, and IV. Some patients have no demonstrable associated disease.43

 FIGURE 6-15 Hidradenitis suppurativa. Mixed neutrophilic and granulomatous inflammation surrounds an inflamed hair follicle, with an infundibular abscess.

clinical locale is most helpful in distinguishing these (see Table 6-11). HISTOPATHOLOGIC FEATURES Tuberous xanthoma, tendinous xanthoma, and xanthelasma demonstrate virtually identical histology. There is an infiltrate almost exclusively of foam cells disposed between individual collagen bundles, in small clusters, or in large nodular aggregates (Fig. 6-16). Lymphocytes, neutrophils, and eosinophils are completely absent or present only in small numbers. Eruptive xanthomas are often smaller and more inflammatory clinically. They demonstrate greater numbers

of lymphocytes, neutrophils, and macrophages and fewer characteristic foam cells. One hallmark of eruptive xanthoma is the presence of both intracellular and extracellular lipid, producing a pattern similar to GA 60 (Fig. 6-17). This palisaded granulomatous appearance is exaggerated in those eruptive xanthomas which also contain deposits of urate-like crystals.61 DIFFERENTIAL DIAGNOSIS The almost exclusive infiltrate of foamy histiocytes with relatively few lymphocytes, neutrophils, and eosinophils is characteristic of xanthomas and serves to differentiate

CLINICAL FEATURES Well-demarcated yellow-orange plaques are distributed periorbitally and on the trunk and extremities typically in patients without elevated serum lipids. HISTOPATHOLOGIC FEATURES In addition to a perivascular lymphocytic infiltrate, there are clusters or sheets of foamy macrophages extending throughout the papillary and reticular dermis. Toutontype giant cells are variably present. DIFFERENTIAL DIAGNOSIS The presence of a perivascular lymphocytic infiltrate separates diffuse normolipemic plane xanthoma from other xanthomas. Some cases may demonstrate focal collagen degeneration and cholesterol clefts, suggesting a histologic (and with the dysproteinemia, a clinical) overlap with necrobiotic xanthogranuloma.43 Eruptive xanthomas also feature perivascular lymphocytes, but unlike diffuse normolipemic plane xanthoma, neutrophils usually accompany the lymphocytic infiltrate.

Table 6-10 Infectious Causes of Diffuse Histiocytic Infiltrates

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ORGANISM

TISSUE MORPHOLOGY

Lepromatous leprosy

M leprae

Fite-positive AFB

Histoid leprosy and atypical mycobacteria in HIV Histoplasmosis

M leprae and atypical mycobacteria H capsulatum

Leishmaniasis

L tropica L mexicana L brasiliensis L donovani

Fite-positive AFB, Ziehl-Neelsen-positive AFB 2-4 μm intracellular yeasts with clear halo; no hyphae 2-4 μm round-oval protozoa with nucleus and kinetoplast (Giemsa-positive)

HISTOPATHOLOGICAL FEATURES Foamy lepra cells; grenz zone; globi Spindle cell pseudotumor confused with neoplasm Organisms within macrophages

Organisms within macrophages; nucleus and kinetoplast stain red with Giemsa

Verruciform Xanthoma Verruciform xanthoma is a solitary lesion encountered in the oral mucosa and rarely at extraoral sites. Similar histologic changes are encountered in a wide variety of conditions, including pemphigus vulgaris, lichen planus, epidermolysis bullosa, discoid lupus erythematosus, epidermal nevi, and inflammatory linear verrucous epidermal nevus (ILVEN).62 The etiology is unknown, but there is no association with diabetes or hyperlipidemia. The theorized pathogenesis involves degeneration of keratinocytes followed by a macrophage inflammatory response.

Table 6-11 Xanthomas TUBEROUS

Clinical Features Hypercholesterolemia (IIa) Dyslipoproteinemia (III)

XANTHELASMA

ERUPTIVE

Hypercholesterolemia (IIa) Extensor tendons of hands, feet Achilles tendon

Hypercholesterolemia (IIa) Dyslipoproteinemia (III)

Lipoprotein lipase deficiency (I) Dyslipoproteinemia (III)

Idiopathic Eyelids

Hypertriglyceridemia (IV/V) Diabetes mellitus Buttocks and other sites

Same as tuberous

Same as tuberous

Fewer foam cells More Lymphocytes, Neutrophils, Eosinophils Intracellular and extracellular lipid

CLINICAL FEATURES Oral lesions may occur at any site, but the gingiva and hard palate are affected preferentially. They are described as soft, red, white, or yellow papules with a roughened surface. Cutaneous lesions have been described on the penis, the vulva, scrotum, groin, anus, and nostril.

HISTOPATHOLOGIC FEATURES There is verrucous epithelial hyperplasia with tiers of parakeratosis and associated neutrophils in some cases (Fig. 6-18). Within an expanded submucosa (or papillary dermis), there are collections of foam cells (lipid-rich macrophages) partially enclosed by hyperplastic rete pegs.62

DIFFERENTIAL DIAGNOSIS Collections of foam cells immediately below a verrucous mucosa are characteristic of verruciform xanthoma. Mucosal or epidermal hyperplasia is not seen in the other xanthoma types.

Papular Xanthoma Papular xanthoma is a non-Langerhans cell histiocytosis that primarily affects infants and children. The etiology is unknown. Patients have normal serum lipid parameters. CLINICAL FEATURES Patients present usually in the first year of life with numerous yellow papules or nodules in a generalized distribution. The mucous membranes are involved occasionally. Viscera are spared, and there is no association with diabetes insipidus.63

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Hypertriglyceridemia (IV) Elbows Knees Histopathologic Features Foam cells arranged interstitially between collagen bundles, as small clusters, or in large nodular aggregates Few to no Lymphocytes, Neutrophils, Eosinophils

TENDINOUS

HISTOPATHOLOGIC FEATURES Individual lesions are composed almost entirely of lipidized, foamy histiocytes in a diffuse or nodular pattern. Foamy Touton-type giant cells are also seen, but unlike xanthogranuloma (and benign cephalic histiocytosis, generalized eruptive histiocytosis, xanthoma disseminatum), papular xanthoma lacks an accompanying inflammatory cell infiltrate of lymphocytes, plasma cells, or eosinophils. The histiocytes are S-100negative and CD1a-negative.63  FIGURE 6-16 Xanthomas. Foamy macrophages form nests and cords that are separated by coarse collagen bundles.

DIFFERENTIAL DIAGNOSIS Diffuse or nodular collections of S-100-negative and CD1a-negative foamy histiocytes and

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

HISTOPATHOLOGIC FEATURES There are nodular collections of foamy macrophages within the dermis that merge gradually with spindle-shaped cells arranged in large sweeping fascicles. Variable features include foci of cholesterol clefts surrounded by dense collagen, nodules of spindle cells in a storiform arrangement, and a lymphocyteplasma cell infiltrate.

 FIGURE 6-17 Eruptive xanthoma. Collections of foamy histiocytes within the upper dermis are accompanied by a few neutrophils.

Touton-type giant cells and a conspicuous lack of lymphocytes, plasma cells, and eosinophils are suggestive of papular xanthoma. The generalized distribution and normal serum lipid parameters separate papular xanthoma from other xanthomas. In Langerhans cell histiocytosis, the histiocytes are S-100-positive and CD1a-positive and are not lipidized. Xanthoma disseminatum and benign cephalic histiocytosis also affect infants and children but feature more lymphocytes, plasma cells, or eosinophils.

A

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DIFFERENTIAL DIAGNOSIS The cells of plexiform xanthoma are CD68 (KP1)positive, muscle actin (HHF35)-negative, and S-100-negative. This entity may represent a lipidized benign cutaneous histiocytoma.65 The plexiform architecture and presence of foam cells are distinctive. Unlike plexiform fibrohistiocytic tumor (an intermediate-grade soft tissue neoplasm of childhood), osteoclast-like giant cells are not seen in plexiform xanthoma. Atypical fibroxanthoma is a cutaneous neoplasm that occurs most commonly on the heads of elderly patients. Pleomorphic spindled and epithelioid cells with bizarre multinucleate giant cells and numerous mitotic figures, usually with foci of fascicle formation, help to distinguish this neoplasm.

Plexiform Xanthoma Plexiform xanthoma is a recently described dermal tumor of middle-aged adults composed of foam cells in a plexiform arrangement. Some consider it neoplastic, whereas others consider it inflammatory.64 There may or may not be an association with hyperlipidemia (essential or secondary). CLINICAL FEATURES Reported cases have involved the chin, knee, and buttocks.

Langerhans Cell Histiocytosis Synonyms: Histiocytosis X, Letterer-Siwe disease, Hand-Schüller-Christian disease, eosinophilic granuloma. Langerhans cell histiocytosis is a proliferative disorder of Langerhans cells with both cutaneous and extracutaneous involvement. The term Langerhans cell histiocytosis is preferred to histiocytosis X because X was chosen to indicate a cell of unknown differentiation. The term

B

 FIGURE 6-18 Verruciform xanthoma. ( A ) Digitated squamous hyperplasia overlies papillae ( B ) containing foamy macrophages.

CLINICAL FEATURES Cutaneous lesions are variable and may include red-brown papules, nodules, plaques, vesicles, pustules, or ulcers. Lesions are distributed on the scalp, trunk, and intertriginous areas. Mucosal (especially gingival) involvement is characteristic. Extracutaneous involvement is frequently present in

Langerhans cell histiocytosis and separates it from congenital self-healing reticulohistiocytosis. Commonly involved organs include bone, bone marrow, liver, spleen, hypothalamus-pituitary (producing diabetes insipidus), and lung. HISTOPATHOLOGIC FEATURES H&E-stained sections reveal perivascular or lichenoid infiltrates of Langerhans cells confined to the papillary and upper reticular dermis. Cytologic features are bland and characterized by cells with abundant eosinophilic or pale cytoplasms and longitudinally grooved or reniform nuclei with small nucleoli70 (Fig. 6-19). Epidermotropism is often seen. Eosinophils are sometimes prominent. Langerhans cells are S-100-positive and CD1a-positive and contain Birbeck granules by electron microscopy.71 DIFFERENTIAL DIAGNOSIS A proliferation of Langerhans cells (cytologic features described earlier) with accompanying eosinophils and epidermotropism suggest Langerhans cell histiocytosis. Identical histology may be seen in congenital selfhealing reticulohistiocytosis, and clinical workup to exclude extracutaneous involvement is required to separate the two. It must be underscored that one cannot predict the biology of Langerhans cell disease from the histopathology, a tenet that has been well established in clinical oncology/hematology71 (Table 6-12).

Congenital Self-Healing Langerhans Histiocytosis (Reticulohistiocytosis) Synonyms: Hashimoto-Pritzker disease, pure cutaneous histiocytosis X, congenital, spontaneously regressing histiocytosis. Congenital self-healing reticulohistiocytosis is a disease of infants/neonates that represents the self-limited, benign end of the spectrum of Langerhans cell proliferative disorders. The disease is confined to the skin, and there is no (or only mild) systemic involvement. The skin lesions and histopathologic features can be virtually identical to other Langerhans cell histiocytoses; therefore, one must attempt to rule out systemic involvement through clinical evaluation of lymph nodes, liver, spleen, bone survey, complete blood count (CBC) with differential, and liver function tests.71,72 Although most cases regress spontaneously, these patients should be followed closely for the possible development of relapses or progression with skeletal involvement.71,72 For these reasons, the term congenital self-healing Langerhans histiocytosis is the most appropriate designation. CLINICAL FEATURES Neonates present with red-brown papules, nodules, or pustules in a generalized distribution. Mucous membrane involvement is more suggestive of the systemic variety of Langerhans cell histiocytosis. Multiple blue nodules resembling the “blueberry muffin baby” also may be encountered. HISTOPATHOLOGIC FEATURES The histologic features are identical to Langerhans cell histiocytosis, but some cases may have more of an admixture of foamy macrophages.73 Langerhans cells (characterized as mononuclear cells with copious pale eosinophilic cytoplasm and longitudinally grooved or reniform nuclei) occupy the papillary and upper reticular dermis and sometimes demonstrate epidermotropism. Eosinophils constitute a significant portion of the infiltrate. The cells are S-100-positive and CD1a-positive and contain Birbeck granules. Extensive areas of dermal necrosis (possibly indicative of involution) may be more common in congenital self-healing disease than in the systemic variety of Langerhans cell histiocytosis.72

 FIGURE 6-19 Langerhans cell histiocytosis. A diffuse infiltrate of mononuclear cells having abundant cytoplasm and reniform nuclei. A few multinucleate cells are also present in addition to scattered lymphocytes and numerous eosinophils.

DIFFERENTIAL DIAGNOSIS Clinical workup to rule out extracutaneous involvement is mandatory because the histopathology of the skin-limited form of the disease can be virtually identical to the systemic type (see Table 6-12).

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histiocyte refers to a family of bone marrow–derived dendritic cells with phagocytic or immune-related activities, of which Langerhans cells are a member. Others in this family include indeterminate cells, interdigitating cells, and follicular-dendritic cells. Langerhans cells are S-100-positive and CD1a-positive and contain Birbeck granules; indeterminate cells if they exist are S-100-positive and CD1a-positive but lack Birbeck granules. Proliferative disorders of interdigitating and follicular-dendritic cells rarely affect the skin.58,66 The nosology of Langerhans cell histiocytosis remains unsettled. Some reports, based on molecular DNA techniques, support a monoclonal proliferation and a neoplastic disorder.67,68 Others question this conclusion.69 The definitive answer awaits further clarification. Owing to overlapping clinical features, the classic subtypes of Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma are subsumed under the rubric of Langerhans cell histiocytosis.

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erythematous or yellow-red papules, nodules, or plaques that may be solitary or multiple.

Table 6-12 Langerhans Cell Proliferative Disorders

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LANGERHANS CELL HISTIOCYTOSIS (SYSTEMIC)

Clinical Features Cutaneous and extracutaneous disease Red-brown papules, nodules, plaques Vesicles, pustules, ulcers Scalp, trunk, intertriginous Gingiva and other mucosal sites Histopathologic Features Superficial perivascular or lichenoid infiltrates of Langerhans cells with grooved (reniform) nuclei Epidermotropism Eosinophils Langerhans cells S-100 protein, CDla (OKT6) positive EM: Birbeck granules

Indeterminate Cell Histiocytosis With the advent of immunohistochemical, electron microscopic, and molecular diagnostic techniques, new histiocytic subsets are being recognized. Histiocyte subsets include Langerhans cells, indeterminate cells, interdigitating cells, and folliculardendritic cells. Proliferating disorders of interdigitating and follicular-dendritic cells usually affect lymph nodes and only rarely the skin.58 Indeterminate cell histiocytoses are rare (approximately 10 cases reported to date) and represent proliferations of S-100-positive and CD1a-positive cells, which lack Birbeck granules.58 The lesions may regress completely or partially or (in two reported cases) involve lymph nodes and other extracutaneous sites. Since some consider indeterminate cells to represent one stage of Langerhans cell differentiation, further study of these rare cases is needed to determine if indeterminate cell histiocytosis is indeed a distinct entity. At this juncture, this seems doubtful.

CONGENITAL SELF-HEALING LANGERHANS HISTIOCYTOSIS (RETICULOHISTIOCYTOSIS) Cutaneous involvement only Cutaneous lesions similar to systemic Langerhans cell histiocytosis, but gingiva and other mucosal sites less commonly affected Identical to systemic Langerhans cell histiocytosis

genitourinary tract and nervous system affected less commonly. There are also cases of skin-limited Rosai-Dorfman disease.75 Black patients are affected more frequently than whites, and there is a slight male predominance. The disease resolves spontaneously.74 CLINICAL FEATURES In both skin-limited disease and secondary cutaneous disease, the clinical lesions are similar, with

HISTOPATHOLOGIC FEATURES There is a dense diffuse or nodular dermal infiltrate of histiocytes admixed with lymphocytes, plasma cells, and neutrophils. Eosinophils, if present at all, are seen in only small numbers. Although rare eosinophilic abscesses have been described, large numbers of eosinophils should suggest another histiocytic proliferation, especially Langerhans cell histiocytosis.75 Emperipolesis of lymphocytes, plasma cells, and neutrophils by histiocytes is characteristic (Fig. 6-20). The histiocytes have characteristic nuclei that are large, with vesicular chromatin, a delicate nuclear membrane, and prominent nucleoli. At the periphery of histiocytic nodules there are lymphoid aggregates with germinal centers and thick-walled vessels surrounded by numerous plasma cells. In the centers of histiocytic nodules, dilated lymphatics containing intraluminal histiocytes are seen.74,75 The histiocytes in RosaiDorfman disease are S-100-positive and CD1a-negative and lack Birbeck granules. In some cases, the subcutis, rather than the dermis, is affected primarily. DIFFERENTIAL DIAGNOSIS Emperipolesis of inflammatory cells seen among an

Rosai-Dorfman Disease

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Synonyms: Sinus histiocytosis with massive lymphadenopathy, cutaneous sinus histiocytosis. The cause of Rosai-Dorfman disease is unknown. Patients develop massive cervical lymphadenopathy accompanied by fever, leukocytosis, hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate.74 Extranodal involvement is fairly common, and the skin is the most frequent site (approximately 30% of cases), with the respiratory tract, eyes, soft tissues, bones, and

 FIGURE 6-20 Rosai-Dorfman disease. A mixed infiltrate of lymphocytes and plasma cells with accompanying tissue macrophages. Many of the macrophages contain phagocytized lymphocytes, producing the so-called beanbag appearance (emperipolesis).

Xanthogranuloma Synonyms: Juvenile xanthogranuloma, adult xanthogranuloma. Juvenile xanthogranuloma is a nonLangerhans cell histiocytosis seen in infants or children usually before the age of 6 months. The etiology is not known. Although juvenile xanthogranuloma usually is limited to the skin, it may affect other organ systems.79 The eye is the most frequently involved extracutaneous

site, but others include liver, spleen, lymph nodes, lungs, heart, testes, ovary, colon, kidneys, and bones. Adults sometimes are affected by identical lesions (adult xanthogranuloma).80 Deep subcutaneous or intramuscular forms also have been described.81 CLINICAL FEATURES Cutaneous lesions present as solitary or multiple yellowred papules or nodules on the face, neck, or upper trunk. Individual lesions regress spontaneously over time. HISTOPATHOLOGIC FEATURES The histologic picture largely depends on the stage of the lesion at the time of biopsy. Mature lesions demonstrate nodular, dense, sheetlike collections of histiocytes admixed with Touton-type giant cells (giant cells with a wreath of nuclei), lymphocytes, and eosinophils79-81 (Fig. 6-21). In contrast to the monotonous infiltrate of macrophages with foamy cytoplasms (foam cells) seen in xanthomas, xanthogranulomas feature histiocytes with varied morphology. In addition to foam cells (which usually constitute the majority), there are histiocytes with vacuolated cytoplasms, histiocytes with eosinophilic granular cytoplasms, and spindle-shaped histiocytes.80 Early lesions demonstrate few to no Touton-type giant cells and foam cells. Late lesions demonstrate areas of fibrosis. The histiocytes are positive for

HAM56 (CD64), KP1 (CD68), and vimentin; variably positive for factor XIIIa; and negative for S-100.79,80 Deep subcutaneous or intramuscular forms differ in only minor degree from the superficial forms. They are typically well circumscribed, contain fewer Touton-type giant cells, and contain more abundant eosinophils79-81 (Table 6-13). DIFFERENTIAL DIAGNOSIS The presence of Touton-type giant cells and an admixture of lymphocytes and eosinophils is distinctive; however, Touton-type giant cells may be absent in early lesions. Xanthogranuloma shows significant histologic overlap with xanthoma disseminatum, benign cephalic histiocytosis, and generalized eruptive histiocytoma, suggesting that all these conditions may be related pathogenetically.82 Intradermal Spitz nevi can resemble xanthogranuloma but are distinguished by their nested growth pattern and S-100 positivity.

Benign Cephalic Histiocytosis Benign cephalic histiocytosis is a nonLangerhans cell histiocytosis that affects infants and children younger than 3 years of age. The etiology is unknown, but overlapping clinical and histologic features suggest that benign cephalic histiocytosis, generalized eruptive histiocytosis, xanthoma disseminatum, and xanthogranuloma are closely related.82 CLINICAL FEATURES Infants or children younger than 3 years of age develop numerous brown-yellow papules distributed on the head, neck, and sometimes

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

infiltrate of S-100-positive histiocytes and plasma cells is characteristic of RosaiDorfman disease. Dilated lymphatic channels with intraluminal histiocytes and thick-walled vessels surrounded by plasma cells are distinctive in RosaiDorfman disease.74,75 Some forms of peripheral T-cell lymphoma, particularly subcutaneous panniculitis-like T-cell lymphomas, are associated with benign histiocytes that engulf erythrocytes and inflammatory cells (cytophagocytosis).76 Phagocytosis of red blood cells, lymphocytes, plasma cells, neutrophils, and other inflammatory cell elements may be encountered in a variety of other conditions, including infection (most often viral but also bacterial, fungal, and parasitic), multiple myeloma, hairy cell and other leukemias, Hodgkin disease, some high-grade carcinomas, reticulohistiocytoma, and a benign autosomal recessive familial condition.77,78

Table 6-13 Xanthogranuloma

 FIGURE 6-21 Xanthogranuloma. A diffuse infiltrate of macrophages, both single and multinucleate, is accompanied by a mixed inflammatory cell infiltrate of lymphocytes and scattered eosinophils. Toutontype giant cells containing a wreath of nuclei are present.

Clinical Features Infants/children, usually Adults, sometimes Solitary or multiple yellow-red papules, nodules Face, neck, upper trunk Extracutaneous involvement, sometimes Histopathologic Features Sheetlike aggregates composed of Foam cells Histiocytes with varied morphology Touton-type giant cells Lymphocytes and eosinophils Differential Diagnosis Benign cephalic histiocytosis Generalized eruptive histiocytosis Xanthoma disseminatum

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upper trunk. Mucous membranes and viscera are spared. Individual lesions resolve spontaneously over time.82 HISTOPATHOLOGIC FEATURES The histologic features of benign cephalic histiocytosis, generalized eruptive histiocytosis, xanthoma disseminatum, and xanthogranuloma are nearly identical (see “Xanthogranuloma” above). The histiocytes are S-100-negative and CD1a-negative. Electron microscopy reveals coated vesicles and comma-shaped bodies, but this finding is of no diagnostic aid because similar findings are present in xanthogranuloma, generalized eruptive histiocytosis, Langerhans cell histiocytosis, and congenital self-healing reticulohistiocytosis.82 DIFFERENTIAL DIAGNOSIS The clinical locale and young age of the patient distinguish benign cephalic histiocytosis, but the histopathology is not distinctive because generalized eruptive histiocytosis, xanthoma disseminatum, and xanthogranuloma probably are pathogenetically related conditions.

Generalized Eruptive Histiocytosis (Histiocytoma) Generalized eruptive histiocytosis is a non-Langerhans cell histiocytosis that affects adults. The etiology is unknown, but overlapping clinical and histologic features suggest that generalized eruptive histiocytosis, benign cephalic histiocytosis, xanthoma disseminatum, and xanthogranuloma are closely related.82,83

histiocytosis from benign cephalic histiocytosis, xanthoma disseminatum, and xanthogranuloma, but all these conditions probably are pathogenetically related. Recently, histiocytomas have been described with an eruptive, progressive presentation but with histopathology closest to xanthogranuloma, a fact that further supports the unifying concept.84

Xanthoma Disseminatum Synonym: Montgomery syndrome. Xanthoma disseminatum is a nonLangerhans cell histiocytosis that may affect all ages. The etiology is unknown, but overlapping clinical and histologic features suggest that xanthoma disseminatum, benign cephalic histiocytosis, generalized eruptive histiocytosis, and xanthogranuloma are closely related.82 Xanthoma disseminatum is also very closely related to Erdheim-Chester disease. There has been a recent proposal to consider Erdheim-Chester disease as a variant of xanthoma disseminatum, one in which there is bone involvement and an aggressive clinical course.85 CLINICAL FEATURES Patients of any age present with numerous red-brown or yellow papules that frequently become confluent to form large plaques. Flexural areas of the neck, axillae, antecubital

fossae, groin, and perianal region are preferentially affected. Mucous membrane involvement is fairly common, and lesions of the buccal mucosa or larynx may cause dysphagia or breathing difficulties. The conjunctiva and cornea are additional sites of potential involvement. Diabetes insipidus is seen in approximately 40% of patients. Individual lesions resolve spontaneously over time. The pathognomonic bone changes of Erdheim-Chester disease are seen in the long bones (distal femur and proximal tibia and fibula) and consist of bilateral and symmetric patchy osteosclerosis involving the metaphysis and diaphysis, with epiphyseal sparing. HISTOPATHOLOGIC FEATURES The histologic features of xanthoma disseminatum, benign cephalic histiocytosis, generalized eruptive histiocytosis, and xanthogranuloma are nearly identical (see “Xanthogranuloma” above) (Fig. 6-22). The histiocytes of xanthoma disseminatum are S-100-negative and CD1a-negative. The clinical features of xanthoma disseminatum usually are distinctive. These include the confluence of individual lesions to form plaques, the flexural distribution, the association with diabetes insipidus, and the involvement of mucous membranes and other organs (eg, eye).

CLINICAL FEATURES Adult patients present with numerous, generalized, brown to dark blue papules or nodules symmetrically distributed on the trunk and extremities. Mucous membranes are involved occasionally, but there is no visceral involvement. Individual lesions resolve spontaneously over time.83 HISTOPATHOLOGIC FEATURES The histologic features of generalized eruptive histiocytosis, benign cephalic histiocytosis, xanthoma disseminatum, and xanthogranuloma are nearly identical (see “Xanthogranuloma” above). The histiocytes are S-100-negative and CD1anegative. As a rule, in generalized eruptive histiocytosis lipid stains are negative, and giant cells are absent.83

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DIFFERENTIAL DIAGNOSIS The generalized distribution, older age of the patient, and lack of visceral involvement are helpful in distinguishing generalized eruptive

 FIGURE 6-22 Xanthoma disseminatum. Tissue macrophages (histiocytes) form a diffuse infiltrate in the upper dermis accompanied by a lymphocytic infiltrate. Many Touton-type giant cells are seen, and in other areas foamy macrophages are present. This lesion, taken from the axilla of a patient with typical xanthoma disseminatum, shows the histologic overlap with xanthogranuloma.

Multicentric Reticulohistiocytosis

CLINICAL FEATURES Yellow-brown cutaneous papules or nodules are distributed over the hands, forearms, and face. The oral mucosa may be involved rarely. HISTOPATHOLOGIC FEATURES There is an interstitial and/or nodular infiltrate of histiocytes and large multinucleated giant cells with distinctive eosinophilic finely granular (“ground-glass”) cytoplasm (Fig. 6-23). Lymphocytes are also present. The giant cells are relatively large (>50 μm) with randomly arranged nuclei.86 The cytoplasms of mono- and

DIFFERENTIAL DIAGNOSIS The eosinophilic, finely granular, ground-glass cytoplasm is distinctive. Solitary reticulohistiocytoma shows nearly identical histologic features, but the architectural pattern in solitary reticulohistiocytoma is typically nodular, dense, and sheetlike, and less often purely interstitial.86 Benign or malignant neoplasms composed of granular cells may resemble both multicentric reticulohistiocytosis and solitary reticulohistiocytoma due to their granular eosinophilic cytoplasm. Examples include benign and malignant granular cell schwannoma, congenital gingival epulis, granular cell fibrous papule, granular cell leiomyoma and leiomyosarcoma, granular cell basal cell carcinoma, granular cell angiosarcoma, granular cell dermatofibrosarcoma protuberans, and primitive polypoid granular cell tumor.88,89 Spitz nevi, which lack a junctional component (intradermal Spitz nevi, desmoplastic nevi), feature cells with abundant eosinophilic cytoplasm and large vesicular nuclei with prominent nucleoli arranged in an interstitial pattern between thickened collagen bundles. A nested arrangement of the cells offers a clue to this melanocytic nevus.

Reticulohistiocytoma Reticulohistiocytomas are solitary cutaneous nodules with similar histology to

 FIGURE 6-23 Multicentric reticulohistiocytoma. Mononuclear and multinucleated histiocytes form a diffuse infiltrate. The typical multinucleated cells contain 3 to 10 nuclei and have ground-glass-appearing cytoplasm.

that seen in multicentric reticulohistiocytosis (ie, mono- and multinucleated histiocytes with characteristic ground-glass cytoplasm).86,87 In fact, prior reports indicated that the two conditions were identical histologically. However, solitary reticulohistiocytomas are not associated with arthritis, and recent immunohistochemical investigations suggest that they may be variants of xanthogranulomas.86,87 CLINICAL FEATURES Solitary reticulohistiocytomas are yellow-brown nodules without any site predilection. An acral location should suggest multicentric reticulohistiocytosis. HISTOPATHOLOGIC FEATURES There is a dense, nodular, sheetlike infiltrate of monoand multinucleated histiocytes with eosinophilic, finely granular (groundglass) cytoplasm that is PAS-positive and diastase resistant (Fig. 6-24). Scattered lymphocytes are also present. The multinucleated giant cells are large (50-100 μm) and often contain bizarre, randomly arranged nuclei. Emperipolesis of other inflammatory cells by histiocytes has been observed in some cases. There are fewer numbers of Touton-type giant cells.87 Based on the presence of Toutontype giant cells and a minority population of vacuolated, foamy, and spindle-shaped histiocytes (ie, a heterogeneous population of histiocytes, similar to that seen in xanthogranuloma), some consider solitary reticulohistiocytoma to be a variant of xanthogranuloma.87 DIFFERENTIAL DIAGNOSIS A solitary cutaneous nodule composed of histiocytes with eosinophilic, ground-glass cytoplasm or large bizarre multinucleated giant cells with similar ground-glass cytoplasm is distinctive. A nonacral location and absence of associated arthritis are additional clinical features that allow distinction from multicentric reticulohistiocytosis. For those rare cases in which emperipolesis is identified, RosaiDorfman disease is a diagnostic consideration, but the histiocytes in that disease are S-100-positive. High-grade large cell lymphomas of B- or T-cell type may bear a superficial resemblance to the bizarre multinucleated cells of reticulohistiocytoma. In general, the neoplastic lymphocytes of large cell lymphomas have vesicular nuclei with prominent nucleoli and numerous mitotic figures and at times have associated areas of necrosis. The lymphoid cells usually are immunoreactive with B-cell (CD20) or T-cell (CD3) markers. Ki-1 (CD30)-positive anaplastic large cell lymphoma displays large

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Synonym: Lipoid dermatoarthritis. Multicentric reticulohistiocytosis defines a distinct clinical entity in which multiple cutaneous nodules are associated with a destructive polyarthritis. The arthritis most frequently involves the interphalangeal joints of the hands, but the knees, ankles, wrists, elbows, and shoulders also may be affected. Adult females are affected more often than males, and the cutaneous nodules may precede, occur with, or postdate the onset of arthritis. In some cases multicentric reticulohistiocytosis is associated with malignancies (gastrointestinal or ovarian), thyroid disorders, tuberculosis, diabetes mellitus, dermatomyositis, celiac disease, and systemic lupus erythematosus.86,87 The etiology is unknown.

multinucleated cells are PAS-positive and diastase resistant.

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B

A

 FIGURE 6-24 Reticulohistiocytoma. ( A ) A discrete infiltrate of histiocytes with glassy cytoplasm and single to multiple nuclei. (B) They are accompanied by a mixed inflammatory cell infiltrate predominantly of lymphocytes.

epithelioid lymphocytes, some multinucleated with striking nuclear atypia.90,91 The immunophenotype of large cell lymphomas contrasts with the KP1(CD68)positive histiocytes seen in reticulohistiocytoma.87

FIBROUS HISTIOCYTOMA (DERMATOFIBROMA) (See Chap. 30)

dermatofibroma. The clinical setting of innumerable generalized papules and nodules should suggest progressive nodular histiocytoma. This rare condition may be related to generalized eruptive histiocytosis/histiocytoma (see Chap. 30).83,84

histiocytes and lack of accompanying lymphocytes, plasma cells, or eosinophils are distinctive. None of the other diffuse histiocytoses has mucin as a prominent feature.

Hereditary Progressive Mucinous Histiocytosis

Multinucleate Cell Angiohistiocytoma

Progressive nodular histiocytoma is an extremely rare disorder with very few reported cases.92,93 The etiology is unknown, but it shares some clinical and histologic features with eruptive dermatofibromas (histiocytomas).

First described by Bork and Hoede in 1988, hereditary progressive mucinous histiocytosis is an extremely rare disorder with only nine affected patients reported.94,95 It is most likely autosomal dominantly inherited. Unlike other nonLangerhans cell histiocytoses, there is no spontaneous involution. Histologically, individual lesions demonstrate copious connective tissue mucin.

CLINICAL FEATURES Patients present with numerous, generalized lesions of two different morphologies: superficial yellowbrown papules and deep nodules with overlying telangiectases. These are distributed on the trunk, face, and extremities. Mucosal involvement was reported on the tongue, larynx, and conjunctiva.92,93

CLINICAL FEATURES The patients present in adolescence with numerous dark red, blue, or brown papules that increase in number over time. The lesions are distributed primarily on extremities, but the trunk, head, and face also are involved. Neither mucous membrane nor visceral involvement is seen.

HISTOPATHOLOGIC FEATURES The histology of lesions (whether superficial or deep) resembles the spectrum of histologic appearances encountered in dermatofibromas. Histology demonstrates either predominantly foamy, lipid-laden histiocytes or predominantly spindle cells in a vague storiform pattern. Like dermatofibroma, intracellular and extracellular hemosiderin may also be present.92,93

HISTOPATHOLOGIC FEATURES Histology reveals dilated vascular spaces and spindle-shaped and stellate histiocytes arranged either interstitially between collagen bundles or in vague, nodular aggregates. Preexisting collagen bundles are separated by abundant connective tissue mucin, which stains with alcian blue. Lymphocytes, plasma cells, and eosinophils are not seen.94,95

DIFFERENTIAL DIAGNOSIS The histology recapitulates the spectrum seen in solitary

DIFFERENTIAL DIAGNOSIS The presence of copious mucin surrounding aggregates of

Progressive Nodular Histiocytoma

Multinucleate cell angiohistiocytoma is a recently described condition that is thought to be inflammatory. Females are affected more often than males, and the average age in one series was 65 years.96 The etiology is unknown, but trauma has been implicated. Although lesions mimic Kaposi sarcoma clinically, HHV-8 does not appear to play a role.97 CLINICAL FEATURES The typical patient is an older female who presents with multiple unilateral or bilateral, smooth-surfaced, red-brown to violaceous papules of long duration that can mimic Kaposi sarcoma. Papules are distributed on the extremities, backs of hands, and less commonly the face. A generalized form also has been described.98 HISTOPATHOLOGIC FEATURES There are numerous dilated vessels with prominent but not atypical endothelial cells. The most characteristic feature is that of numerous multinucleated giant cells with scalloped eosinophilic cytoplasm scattered interstitially between thickened collagen bundles of the reticular dermis.96,98,99 The nuclei of the multinucleate giant cells are hyperchromatic and either clumped within the center of the cell or arranged at the periphery in a floret-type pattern. Variable findings include perivascular lymphocytes, plasma cells, and

neutrophils, overlying epidermal hyperplasia, basal cell hyperpigmentation, and compact hyperorthokeratosis.96,98 The multinucleated giant cells are S-100negative and CD1a-negative but vimentinpositive. Staining with factor XIIIa reveals numerous interstitial factor XIIIa-positive dermal dendrocytes, but the multinucleated giant cells fail to react with factor XIIIa.99

Malakoplakia Malakoplakia is encountered most commonly in the setting of immunosuppression. Although the etiology is not entirely understood, it is hypothesized that it may represent a chronic bacterial infection in which there is a defect in the ability of histiocytes to degrade ingested bacteria.100 Coliform bacteria (especially Escherichia coli) are isolated most frequently, but in skin lesions S aureus has been implicated. The urinary tract is affected most frequently, but the gastrointestinal tract, lymph nodes, genitalia, brain, bones, lungs, and adrenal glands are other potential sites of involvement. Skin lesions have been reported but are rare.100 CLINICAL FEATURES Cutaneous lesions of malakoplakia are yellow-pink indurated or polypoid nodules that may ulcerate and are distributed most commonly in the groin or perianally. HISTOPATHOLOGIC FEATURES There are dense sheetlike collections of histiocytes with either foamy, granular, or vacuolated cytoplasms.100 The most characteristic feature is Michaelis-Gutmann bodies. These are 5- to 15-μm, oval to spherical, concentrically laminated basophilic structures found both extracellularly and intracellularly within histiocytes (von Hansemann histiocytes). Michaelis-Gutmann bodies are PAS-positive and diastase-resistant and stain positively with von Kossa calcium stain and with Perls Prussian blue stain for iron. DIFFERENTIAL DIAGNOSIS MichaelisGutmann bodies are diagnostic of malakoplakia. None of the other diffuse histiocytoses discussed in this section exhibit Michaelis-Gutmann bodies.

Granulocyte-macrophage colony-stimulating factor (GMCSF) is a recombinant human hematopoietic growth factor used in the setting of bone marrow transplantation, systemic chemotherapy, and radiation therapy to amplify the numbers of circulating granulocytes and macrophages.101 CLINICAL FEATURES Fairly common side effects from GMCSF include fever, myalgias, peripheral eosinophilia, and bone pain. Less commonly, patients develop a maculopapular eruption on the trunk and extremities that begins within 3 days of initiation of therapy and resolves within 10 days after discontinuation.101-103 Some patients develop erythroderma after subcutaneous administration of GMCSF. HISTOPATHOLOGIC FEATURES There is a diffuse mixed inflammatory cell infiltrate of lymphocytes, eosinophils, and neutrophils present within the papillary and superficial reticular dermis.101,102 Clustered and enlarged macrophages, sometimes with phagocytized elastin fragments, are characteristic. Variable findings include epidermal spongiosis and interface vacuolar changes. The erythrodermic cases demonstrate a spongiotic dermatitis with lymphocytes and eosinophils but without macrophages.103 DIFFERENTIAL DIAGNOSIS Clustered and enlarged macrophages are distinctive of the maculopapular reactions secondary to GMCSF. In many respects this entity is similar to an incomplete GA-like tissue reaction with elastophagocytosis,33,34 but the clinical setting should allow distinction between this form of drug reaction and idiopathic GA and actinic granuloma.

Clofazimine-Induced Hyperpigmentation Leprosy patients and patients with Mycobacterium avium-intracellulare infection treated with clofazimine sometimes develop a peculiar hyperpigmentation at sites of cutaneous disease that begins as a pink macular discoloration and gradually darkens into brown over a 6- to 12-month period. The reaction is rarely biopsied by physicians familiar with the drug and its side effects.104 CLINICAL FEATURES As discussed in the preceding section.

HISTOPATHOLOGIC FEATURES There are large collections of dermal macrophages whose cytoplasm is foamy and contains brownish pigment granules and needleshaped crystals. The granules are PASpositive, autofluorescent, and react with lipofuscin stains. Iron and melanin stains are negative. By electron microscopy, the brown granules represent lipofuscin-like material within lysosomes and are probably a breakdown product of clofazimine.104 DIFFERENTIAL DIAGNOSIS The clinical setting, history of clofazimine administration, and reaction with lipofuscin stains are distinctive. Melanin and ironladen macrophages stain positively with Fontana-Masson and Perls Prussian blue stains, respectively, whereas clofazimine granules do not.

Monsel Solution Reaction Monsel solution (solution of ferric subsulfate) is a topical agent used for hemostasis after superficial biopsies. Monsel solution reaction is encountered usually when examining sections of excised malignant skin lesions that have been biopsied previously and treated with Monsel. At first glance, the reaction may be mistaken for malignant melanoma because of both the fine dark brownblack cytoplasmic granules and reactive atypia of macrophages.105 Similar changes may occur from iron sesquioxide, an archaic therapy for skin ulcers.106 CLINICAL FEATURES Brown pigmentation in the area of application can occur. HISTOPATHOLOGIC FEATURES Underlying an ulcer or scar of a previous procedure, there is a diffuse, sometimes nodular infiltrate of macrophages containing dark brown or black granular intracytoplasmic pigment (Fig. 6-25). The pigment is finer and less refractile than hemosiderin obtained from the breakdown of red blood cells and resembles intracytoplasmic melanin. Similar extracellular granules can be seen decorating dermal collagen bundles. The collagen bundles also may show amphophilic discoloration in sections stained with H&E. Foreign-body multinucleate giant cells are often seen. In some cases the macrophages exhibit atypia, with large, irregularly shaped hyperchromatic nuclei and prominent nucleoli. The intra- and extracellular pigment granules stain positively with special stains for iron (Perls Prussian blue stain).105,106

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

DIFFERENTIAL DIAGNOSIS The dilated vascular spaces and bizarre multinucleate giant cells are characteristic. The histologic appearances resemble dermatofibroma, fibrous papule, and the soft tissue neoplasm giant cell fibroblastoma, but the clinical context usually is distinctive.

Reaction to Granulocyte-Macrophage Colony-Stimulating Factor

123

not be present. In contrast to infectious organisms, the basophilic particles vary in size and shape, do not contain a nucleus or kinetoplast, and fail to stain with PAS, GMS, Giemsa, or Gram stains.107 DIFFERENTIAL DIAGNOSIS The variable size and shape of the intracytoplasmic particles, the presence of scar or ulcer from a previous procedure, and a history of prior biopsy are sufficient in distinguishing aluminum chloride solution reaction from infection.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Enzyme Deficiency Disorders Lysosomal storage diseases and other diseases associated with enzyme defects may demonstrate diffuse tissue macrophages in cutaneous lesions (Table 6-14).

NEUTROPHILIC INFILTRATES  FIGURE 6-25 Monsel solution reaction. Diffuse infiltrate of macrophages containing dark brown intracytoplasmic pigment. In addition, there are extracellular granules associated with collagen bundles.

Table 6-15 lists infectious diseases whose histologic pattern is typically but not exclusively diffuse neutrophilic.

Sweet Syndrome (See also Chap. 9) DIFFERENTIAL DIAGNOSIS The presence of scar or ulcer of previous procedure, intraand extracellular pigment, and foreignbody giant cells (sometimes seen) is helpful in differentiating Monsel reaction from a melanocytic proliferation. In case of doubt, special stains for iron (Perls Prussian blue stain) are very helpful.

Aluminum Chloride Solution Reaction Synonym: Aluminum tattoo. Aluminum chloride solution, like Monsel solution, is a topical agent used for hemostasis following superficial shave biopsies. The aluminum particles induce a

foreign-body macrophage response. The basophilic intracytoplasmic aluminum particles may bear a superficial resemblance to phagocytized Leishmania, Calymmatobacterium granulomatis, or Histoplasma.107 CLINICAL FEATURES No clinical features are distinctive; this is purely a histologic finding. HISTOPATHOLOGIC FEATURES Underlying an ulcer or scar of a previous procedure, there is a diffuse infiltrate of macrophages containing intracytoplasmic basophilic particles. Multinucleate giant cells may or may

Synonym: Acute febrile neutrophilic dermatosis. The etiology underlying Sweet syndrome is unknown, but it is seen in association with myelogenous leukemia (10% to 15% of cases), lymphoma, multiple myeloma, polycythemia vera, adenocarcinomas, and upper respiratory tract infections. The pathogenesis is not known. A pathogenesis involving immune complexes and hyperchemotaxis of neutrophils has been proposed.108 CLINICAL FEATURES Adult females are affected most frequently. Patients present with tender erythematous violaceous

Table 6-14 Enzyme Deficiency Disorders

124

DISORDER

HEREDITY

CLINICAL

HISTOLOGY/EM

Disseminated lipogranulomatosis (Farber disease)

Autosomal recessive; ceramidase deficiency

Dense fibrosis and interstitial foamy histiocytes; EM: curvilinear bodies; zebra bodies; banana bodies

Niemann-Pick disease

Autosomal recessive; sphingomyelinase deficiency

Mannosidosis

Mannosidase deficiency

Subcutaneous nodules over wrist/ankles Hoarseness Pulmonary failure Mental retardation Xanthomas CNS degeneration Hepatosplenomegaly Gargoyle facies Mental retardation Hyperplastic gingiva

Foamy histiocytes, with lymphocytes, multinucleate giant cells Vacuolated histiocytes in gingival biopsies

Table 6-15 Infectious Causes of Diffuse Neutrophilic Infiltrates ORGANISM

TISSUE MORPHOLOGY

HISTOLOGIC FEATURES

Warthin-Starry-positive rods

Verruga peruana (Bartonellosis)

Bartonella henselae B quintana B bacilliformis

Toxic shock syndrome

S aureus

Amoeba

Entamoeba histolytica Acanthamoeba

Purple clumps of bacteria (H&E); pyogenic granuloma-like Rocha-Lima bodies in endothelial cells; pyogenic granuloma-like Clusters of necrotic keratinocytes and neutrophils May show leukocytoclastic vasculitis

Suppurative folliculitis

S aureus

Erysipelas/cellulitis

Group A strep. S aureus H influenzae M fortuitum M chelonei Bacillus anthracis

Bacillary angiomatosis

Anthrax

nodules or plaques on the face, neck, and arms. Patients also have a flu-like illness with fever, malaise, arthralgias, and conjunctivitis. A peripheral leukocytosis usually is present. HISTOPATHOLOGIC FEATURES Fully developed lesions demonstrate a diffuse neutrophilic infiltrate with marked papillary dermal edema (Fig. 6-26A). Fewer numbers of eosinophils, macrophages, and lymphocytes are present, and lymphocytes may increase in number in later stages. As a rule, plasma cells are not seen in Sweet syndrome.109 In early-stage

A

12-20 μm round-ovoid cells sometimes with phagocytized RBCs (H&E) Gram-positive cocci in clusters Gram-positive cocci in chains or clusters; gram-negative rods Slightly larger than M tuberculosis Large gram-positive rod 6-10 μm long

lesions, leukocytoclasis may be prominent but should not be considered an indication of a primary vasculitis, for some leukocytoclasis may be encountered in any condition where neutrophils comprise a large bulk of the infiltrate. On the other hand, late-stage lesions may exhibit a secondary leukocytoclastic vasculitis; thus the finding of vasculitis does not exclude a diagnosis of Sweet syndrome.110 Papillary dermal edema may be so extensive that subepidermal vesiculation occurs. Intraepithelial spongiotic vesicles are sometimes seen. A rare histologic variant of Sweet known

Folliculocentric and folliculodestructive Dermal edema, sparse infiltrate

Neutrophilic panniculitis Numerous extravasated erythrocytes

as histiocytoid Sweet syndrome shows a prominent infiltrate of mononuclear cells with bent and reniform nuclei (Fig 6-26B).111 These histiocytoid cells actually represent immature granulocytes. Although most cases of the histiocytoid variant behave identically to conventional Sweet, some can eventuate in leukemia cutis, thus emphasizing the need for close and long-term clinical follow-up.112 DIFFERENTIAL DIAGNOSIS Marked papillary dermal edema and a diffuse neutrophilic infiltrate characterize Sweet

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Atypical mycobacteria

Warthin-Starry- or Giemsapositive rods Usually not seen

B

 FIGURE 6-26 Sweet syndrome. ( A ) A dense diffuse neutrophilic infiltrate fills the papillary dermis and extends into the reticular dermis. There is marked papillary dermal edema. ( B ) Histiocytoid Sweet syndrome. In addition to mature neutrophils, there is an infiltrate of histiocytoid mononuclear cells. The mononuclear cells have hyperchromatic nuclei with elongated, curved, bent, and reniform shapes, and actually represent immature granulocytes.

125

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

syndrome. The presence of plasma cells should suggest rheumatoid neutrophilic dermatitis.109 In patients with leukemia, lesions of Sweet must be distinguished from leukemia cutis. The infiltrating cells in leukemia cutis are atypical immature granulocytes or monocytes (not mature neutrophils) often arranged interstitially between dermal collagen bundles. Early lesions of erythema elevatum diutinum may demonstrate large numbers of neutrophils, but unlike Sweet syndrome, vasculitis is prominent, and there is often some dermal fibrosis that becomes more exaggerated in later stages.113 The differential diagnosis of neutrophil-predominant lesions occurring on the face includes granuloma faciale, fungal infections, and a variant of rosacea known as pyoderma faciale or rosacea fulminans. Granuloma faciale features a characteristic Grenz zone. Without benefit of a fungal stain, some cases of tinea faciei can greatly mimic Sweet histologically.

Rheumatoid Neutrophilic Dermatitis Rheumatoid neutrophilic dermatitis (dermatosis) is seen in the setting of severe rheumatoid arthritis. The pathogenesis is not understood, but in the few reports of this rare dermatosis, a true vasculitis has not been seen.114,115 CLINICAL FEATURES Patients have severe, long-standing rheumatoid arthritis and present with symmetric erythematous papules, plaques, and/or vesicles typically over the extensor surfaces of forearms and interphalangeal joints.114,115

complex–mediated neutrophilic vascular reactions and abnormalities in humoral and cell-mediated immunity have been suggested.108 Disease associations include ulcerative colitis, Crohn disease, paraproteinemia (most commonly IgA), seronegative arthritis, rheumatoid arthritis, myeloproliferative disorders (particularly chronic myelogenous leukemia and polycythemia vera), lymphoma, multiple myeloma, HIV infection, systemic lupus erythematosus, and chronic active hepatitis. Half of all cases, however, are unassociated with systemic disease. CLINICAL FEATURES Lesions of pyoderma gangrenosum begin as erythematous papules/nodules that expand centrifugally into large ulcers with characteristic heaped-up and undermined violaceous borders. The lower extremities are preferentially affected, but lesions may be seen at any site. In cases of pyoderma gangrenosum arising in the setting of leukemia, a bullous variant has been described (also known as atypical pyoderma gangrenosum or atypical Sweet syndrome) that has overlapping clinical and histologic features with Sweet syndrome (see Fig. 6-26B). Because of this overlap, Caughman et al.117 have suggested that neutrophilic dermatoses in the setting of myeloproliferative disorders be grouped under the term neutrophilic dermatosis of malignancy. HISTOPATHOLOGIC FEATURES In well-developed lesions there is a dense diffuse

neutrophilic infiltrate that characteristically begins as a folliculocentric and sometimes folliculodestructive process. Variable numbers of lymphocytes, macrophages, and eosinophils also are present. True vasculitis, as evidenced by intramural fibrin, intramural neutrophils, and intraluminal microthrombi, may be seen, but when present, the vasculitic changes probably are secondary to the abscess rather than initiating events. As in any dermatitis with significant numbers of neutrophils, some leukocytoclasis invariably is present. As the infiltrate expands, the central epidermis ulcerates, and the adjacent intact epidermis has an undermined appearance (Fig. 6-27). The more peripheral erythematous area displays a perivascular lymphocytic infiltrate. DIFFERENTIAL DIAGNOSIS A dense, deep, and diffuse folliculocentric neutrophilic infiltrate should suggest pyoderma gangrenosum. As already mentioned, in the setting of myeloproliferative disorders and leukemia, there is significant histologic overlap with Sweet syndrome, and a distinction between the two is not always possible. The term Neutrophilic dermatosis of malignancy has considerable utility for that clinical scenario.117 Like pyoderma gangrenosum, venomous spider bites may ulcerate clinically. Brown recluse spider bites feature prominent tissue necrosis, hemorrhage, and a mixed infiltrate with a predominance of neutrophils and fewer eosinophils. Vessels in

HISTOPATHOLOGIC FEATURES The histology is virtually identical to that seen in Sweet syndrome, with the following exceptions: Neutrophils tend to accumulate in and expand dermal papillae, causing histologic similarity to dermatitis herpetiformis, and plasma cells are present in the infiltrate. Like Sweet syndrome, subepidermal bulla formation or intraepithelial spongiotic vesicles may be seen in some cases.116 DIFFERENTIAL DIAGNOSIS The clinical setting of severe rheumatoid arthritis combined with Sweet-like histology, plasma cells, and expansion of dermal papillae with large numbers of neutrophils should suggest rheumatoid neutrophilic dermatitis. The differential diagnosis is otherwise similar to Sweet syndrome.

Pyoderma Gangrenosum (See also Chap. 9) 126

The pathogenesis of pyoderma gangrenosum is unknown, but immune

 FIGURE 6-27 Pyoderma gangrenosum. There is epidermal ulceration with a diffuse infiltrate of neutrophils. The neutrophilic infiltrate undermines the epidermis at the edge of the ulcer.

the vicinity of the inflammation often demonstrate intraluminal thrombi.

Bowel-Associated DermatosisArthritis Syndrome (See also Chap. 9)

CLINICAL FEATURES Patients with one of the previously mentioned clinical scenarios present with fever, gastrointestinal upset, and recurrent crops of pustules on purpuric bases that are distributed on the trunk and extremities. Erythema nodosum-like lesions also may be seen. Additional clinical manifestations may include a nonerosive arthritis or flulike symptoms of arthralgia, myalgias, and chills. HISTOPATHOLOGIC FEATURES Histology is identical to that seen in Sweet syndrome. However, like the situation encountered in atypical lesions of Sweet and pyoderma gangrenosum in the setting of myeloproliferative disorders, there is some histologic overlap with pyoderma gangrenosum.118,119 Thus some lesions may demonstrate neutrophilic infiltrates that are distinctly folliculocentric. DIFFERENTIAL DIAGNOSIS The clinical scenario of pustular lesions with Sweetlike histology in the setting of prior bowel surgery, inflammatory bowel disease, diverticular disease, liver disease, or cholangitis is distinctive (Table 6-16).

Behçet Disease Behçet disease is a multisystem disease of unknown etiology. Hypersensitivity reactions to a previous streptococcal infection have been proposed. The pathogenesis may involve an immune complex–mediated vascular reaction with hyperchemotaxis of neutrophils.108 CLINICAL FEATURES The classic clinical triad consists of oral aphthae, genital aphthae, and uveitis. Behçet disease

Clinical Features Patients with either Inflammatory bowel disease Diverticular disease Jejunoileal bypass surgery Billroth II surgery Chronic autoimmune hepatitis Primary sclerosing cholangitis Fever Gastrointestinal upset Pustules on purpuric bases, or Erythema nodosum-like lesions Trunk/extremities Nonerosive arthritis Histopathologic Features Identical to Sweet syndrome Diffuse neutrophils Papillary dermal edema Leukocytoclasis, but no true vasculitis Differential Diagnosis Sweet syndrome Rheumatoid neutrophilic dermatitis Pyoderma gangrenosum Behçet disease Infection

potentially can affect many organ systems, including joints (arthritis), central nervous system (meningoencephalitis), kidney, heart, lung, and reproductive system. Although aphthae may involve any portion of the gastrointestinal tract, it should be emphasized that patients with inflammatory bowel disease (ie, ulcerative colitis, Crohn disease) do not have Behçet disease. Mucocutaneous manifestations consist of oral ulcers (aphthae), genital ulcers, erythema nodosum-like lesions, pseudofolliculitis, pathergy-induced lesions, and papulopustular lesions or acneiform nodules.120 HISTOPATHOLOGIC FEATURES The histology is controversial, but both pathergyinduced and spontaneous lesions demonstrate a spectrum of histologies, probably reflective of stage of disease at the time of biopsy. The infiltrate ranges from a perivascular mixed inflammatory cell infiltrate with neutrophils, to a perivascular infiltrate of lymphocytes only, to a diffuse neutrophilic infiltrate resembling Sweet. The vascular changes range from intramural neutrophils without intramural fibrin or intraluminal microthrombi, to lymphocytic vasculitis, to true leukocytoclastic vasculitis;

Table 6-17 Behçet Disease

Clinical Features Oral ulcers (aphthae) Genital ulcers Erythema nodosum-like lesions Pseudofolliculitis Pathergy-induced lesions Papulopustular lesions Acneiform nodules Multiorgan involvement (including uveitis) is common Histopathologic Features Early Superficial and deep perivascular and interstitial with many neutrophils Neutrophils and fewer lymphocytes Leukocytoclasis, but no true vasculitis Late Superficial and deep perivascular with mostly lymphocytes Differential Diagnosis Sweet syndrome Rheumatoid neutrophilic dermatitis Pyoderma gangrenosum Bowel-associated dermatosis-arthritis syndrome Infection

however, true leukocytoclastic vasculitis is rare.121 On balance, a superficial and deep perivascular and interstitial mixed inflammatory cell infiltrate with numerous neutrophils and fewer lymphocytes probably best characterizes early lesions of Behçet. Later, a predominantly perivascular lymphocytic infiltrate is seen. Earlyinduced pathergy lesions show a dense but focal aggregation of neutrophils at the immediate injury site.122 Since this histology is rather nonspecific, a diagnosis of Behçet disease can only be made with clinicopathologic correlation (Table 6-17).

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Synonyms: Bowel bypass syndrome, pustular pyoderma gangrenosum. The bowel-associated dermatosis-arthritis syndrome is seen among patients with inflammatory bowel disease or diverticular disease and those who have undergone either jejunoileal bypass surgery for morbid obesity or Billroth II surgery resulting in a blind loop of bowel.118,119 A similar eruption can be seen among patients with liver disease such as chronic hepatitis (especially autoimmune hepatitis) and/or cholangitis (especially primary sclerosing cholangitis). Circulating immune complexes and hyperchemotaxis of neutrophils induced by enteropathic bacteria appear to be responsible for the clinical features.119

Table 6-16 Bowel-Associated Dermatosis-arthritis Syndrome

Granuloma Faciale (See Chap. 9) Erythema Elevatum Diutinum (See Chap. 9) REACTIONS TO GRANULOCYTE COLONYSTIMULATING FACTOR Patients receiving granulocyte colony-stimulating factor (GCSF) may develop a neutrophilic dermatosis that clinically and histologically resembles Sweet syndrome with fever and tender erythematous plaques and nodules.123 This neutrophilic dermatosis is a direct effect of GCSF, which increases absolute neutrophil counts after myelosuppressive therapy and, unlike GMCSF, specifically targets the neutrophil cell line.

127

CLINICAL FEATURES See the preceding section.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

HISTOPATHOLOGIC FEATURES Histology reveals dense dermal infiltrates of neutrophils with abundant nuclear dust and, in some cases, true leukocytoclastic vasculitis. Some cases histologically resemble bullous pyoderma gangrenosum (also known as atypical Sweet syndrome or atypical pyoderma gangrenosum).123 The clinical scenario and history of GCSF therapy are distinctive. DIFFERENTIAL DIAGNOSIS A photodistributed and photoexacerbated neutrophilic dermatosis clinically resembling Sweet syndrome has been described in some HIV-infected patients. This neutrophilic dermatosis in HIV infection may be idiopathic or related to photosensitizing medications or GCSF therapy. Like reactions to GCSF, the histology resembles bullous pyoderma gangrenosum (also known as atypical Sweet syndrome).124 Neutrophils feature prominently in other forms of drug reaction, in particular neutrophilic eccrine hidradenitis, which is a side effect of chemotherapeutic agents (especially cytarabine). It presents as tender erythematous papules and plaques with no particular distribution.125 The neutrophilic infiltrate of neutrophilic eccrine hidradenitis

is centered around the eccrine coils of the lower reticular dermis. Variable findings include vacuolar interface changes and dermal necrosis. Similar reactions may be seen with acetaminophen.125 A condition not associated with chemotherapy or other drugs has been described as palmoplantar neutrophilic eccrine hidradenitis.126,127 It is seen in otherwise healthy individuals, often children. It differs from the chemotherapy-related disease by the lack of both necrosis of the eccrine coil and syringosquamous metaplasia.126,127 Actinomycin D–induced folliculitis also features numerous neutrophils. The folliculitis affects the face, trunk, and buttocks; typically occurs 1 week after induction chemotherapy with actinomycin D; and resolves spontaneously.125

LYMPHOCYTIC-PLASMA CELLULAR INFILTRATES Table 6-18 lists infectious diseases whose histologic pattern is typically but not exclusively diffuse lymphocyticplasma cellular.

Plasmacytosis Mucosae Synonyms: Zoon balanitis, plasma cell vulvitis, plasmacytosis circumorificialis, orificial plasmacytosis, balanitis plasmacellularis, benign plasma cell erythroplasia,

balanoposthitis chronica circumscripta plasmocellularis, plasma cell gingivitis. Plasmacytosis mucosae is an encompassing term for an inflammatory accumulation of plasma cells at mucosal sites. The term Zoon balanitis is given to involvement of the prepuce or glans penis; plasma cell vulvitis, to involvement of the vulva; and plasmacytosis circumorificialis, to involvement of the oral mucosa, lips, gums, or tongue in both sexes.128 Most cases are idiopathic, but in oral mucosal lesions, immediate hypersensitivity reactions (often to chewing gum ingredients) have been implicated. CLINICAL FEATURES The clinical presentation is similar at all three sites, consisting of well-marginated erythematous patches. HISTOPATHOLOGIC FEATURES There is a dense, bandlike, mixed mononuclear inflammatory cell infiltrate with a predominance of plasma cells.128 Dilated blood vessels, sometimes with red blood cell extravasation, also are seen. The epidermis may exhibit spongiosis with exocytosis of inflammatory cells. The heterogeneous nature of the inflammatory cell infiltrate with a predominance of plasma cells in a typical locale should suggest plasmacytosis mucosae. Immunohistochemical study for

Table 6-18 Infectious Causes of Diffuse Lymphocytic–Plasma Cellular Infiltrates ORGANISM

128

TISSUE MORPHOLOGY

Syphilis

Treponema pallidum

Spirochete (Warthin-Starry-positive)

Yaws Pinta Chancroid

T. pertenue T. carateum Haemophilus ducreyi

Granuloma inguinale

Calymmatobacterium granulomatosis

Lymphogranuloma venereum

Chlamydia trachomatis

Rhinoscleroma

Klebsiella rhinoscleromatis

Lyme disease

Borrelia burgdorferi

Necrotizing fasciitis

Group A Strep, S aureus

Spirochete (Warthin-Starry-positive) Spirochete (Warthin-Starry-positive) Gram-negative bacillus (school of fish) (Warthin-Starry- or Giemsa-positive) Intracellular gram-negative bacillus (Donovan bodies) (Giemsa- or WarthinStarry-pos) l-4 μm Giemsa- or direct immunofluorescence-positive coccoid bodies Intracellular gram-negative rods (Frisch bacilli) (Warthin-Starryor PAS-positive) Spirochete (larger than T pallidum) Gram-positive cocci in chains or clusters

HISTOPATHOLOGIC FEATURES Psoriasiform hyperplasia; lichenoid and granulomatous Spirochetes in epidermis Spirochetes in epidermis Three-zone inflammation: PMNs and necrosis; granulation tissue; plasma cells Organisms within macrophages

Intracellular

Organisms within macrophages (Mikulicz cells); Russell bodies Superficial and deep perivascular or pseudolymphoma Blood vessel thrombosis

light-chain restriction may be necessary to definitively rule out plasmacytoma.

A

Multicentric Castleman Disease (Systemic and Cutaneous Plasmacytosis) Synonyms: Plasma cell type of giant lymph node hyperplasia, Castleman disease, plasma cell type of angiofollicular hyperplasia. Systemic and cutaneous plasmacytosis is a clinical variant of multicentric Castleman disease typified by a polyclonal proliferation of plasma cells that lack atypia arising in the absence of other chronic inflammatory or connective tissue diseases.133-135 By definition, the systemic variety affects more than two organ systems and typically produces lymphadenopathy, polyclonal hyperimmunoglobulinemia, and an elevated erythrocyte sedimentation rate. Commonly affected organs include lymph nodes, lungs, and skin. A skinlimited form also exists (cutaneous plasmacytosis). Both the systemic and skin-limited forms are associated with polyclonal hypergammaglobulinemia. The etiology is unknown, but patients with both systemic and skin-limited forms have increased serum levels of interleukin 6 (IL-6) that may drive the plasma cell proliferation. Serum levels of IL-6 have proved useful in moni-

toring response to therapy.133 Patients with multicentric Castleman disease have an increased risk of developing malignant lymphoproliferative disorders, including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome and nonHodgkin lymphomas; therefore, long-term clinical follow-up is necessary. CLINICAL FEATURES Cutaneous lesions consist of multiple erythematous or redbrown nodules or plaques on the trunk and extremities. HISTOPATHOLOGIC FEATURES There is a dense perivascular and periadnexal infiltrate of many plasma cells with fewer lymphocytes (Fig. 6-28). The plasma cells lack atypia and are polyclonal, as evidenced by a lack of kappa or lambda light-chain restriction using immunoperoxidase techniques.133 Nodular lesions may exhibit findings identical to those seen in affected lymph nodes, in which scattered lymphoid follicles with atrophic germinal centers are surrounded by an onion-skin or layered arrangement of small lymphocytes.136 DIFFERENTIAL DIAGNOSIS Dense perivascular and periadnexal infiltrates of benign plasma cells in the clinical setting of polyclonal hypergammaglobulinemia should suggest systemic or cutaneous plasmacytosis. Similar periadnexal infiltrates of plasma cells are seen in one form of lowgrade cutaneous B-cell lymphoma known as marginal zone lymphoma (MALToma). This form of low-grade B-cell lymphoma demonstrates either light-chain restriction by immunohistochemistry or evidence of B-cell clonality by molecular methods.

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

DIFFERENTIAL DIAGNOSIS Cutaneous plasmacytomas are monoclonal neoplastic proliferations of plasma cells. Cutaneous plasmacytomas may be primary (unassociated with multiple myeloma or extramedullary plasmacytoma) or secondary (arising in the setting of established multiple myeloma, extramedullary plasmacytoma, or plasma cell leukemia).129 Cytologic features of plasmacytoma vary from mostly mature plasma cells, to mostly immature pleomorphic forms, to mixtures of the two. In cases consisting of mostly well-differentiated plasma cells, clues to the neoplastic nature of the infiltrate include binucleated forms, many mitotic figures, and many Dutcher bodies (intranuclear PAS-positive inclusions). In poorly differentiated neoplasms, clues to the plasma cell nature of the infiltrate include eccentrically placed nuclei and peripherally placed dense chromatin (“clock face” chromatin). Unlike the polyclonal infiltrates in plasmacytosis mucosae, immunohistochemical stains reveal light-chain restriction in all cases of cutaneous plasmacytoma.129 In HIV-infected individuals, plasma cells may form a significant proportion of the inflammatory cell infiltrate in lesions of psoriasis, seborrheic dermatitis, and Kaposi sarcoma.130 Plasma cells are prominent in some cases of nodular amyloidosis, but nodular eosinophilic deposits of amyloid are distinctive. When the panniculus is exclusively affected by a prominent plasma cell infiltrate, the differential diagnosis includes dermatomyositis, fasciitis with eosinophilia, morphea

profunda, polymyositis, Sjögren syndrome, and scleroderma.131 Cutaneous inflammatory pseudotumor (plasma cell granuloma) presents as a solitary skin tumor. Histologically, it is a sharply circumscribed dermal or subcutaneous nodule that exhibits varying degrees of central sclerosis accompanied by a mixed inflammatory cell infiltrate with prominent plasma cells and lymphoid follicles.132

B

 FIGURE 6-28 Cutaneous plasmacytosis. (A) There is a superficial and deep perivascular and periadnexal infiltrate, (B ) composed almost entirely of mature plasma cells.

129

MAST CELL INFILTRATES

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Cutaneous Mastocytosis Synonyms: Solitary mastocytoma, maculopapular cutaneous mastocytosis/urticaria pigmentosa, telangiectasia macularis eruptiva perstans (TMEP). Cutaneous mastocytosis (CM) is defined by the triad of (1) typical clinical skin lesions such as maculopapular cutaneous mastocytosis/urticaria pigmentosa, diffuse cutaneous mastocytosis, mastocytoma, and TMEP, (2) the histologic demonstration of typical focal mast cell (MC) infiltrates in the dermis, and (3) the absence of criteria for systemic mastocytosis.137 Criteria for systemic mastocytosis include 1. Major: Multifocal dense infiltrates of MCs (> 15 MCs aggregating) detected in the bone marrow and/or in other extracutaneous organ(s) by tryptaseimmunohistochemistry or other stains. 2. Minor: a. In MC infiltrates detected in sections of bone marrow or extracutaneous organs, more than 25% of MCs are spindle-shaped, or in bone marrow smears, atypical MCs comprise more than 25% of all MCs. b. Detection of a c-kit mutation at codon 816 in bone marrow or blood or other extracutaneous organ(s). c. Kit MCs in bone marrow or blood or other extracutaneous organ(s) coexpress CD2 and/or CD25. d. The serum total tryptase concentration is persistently greater than 20 ng/mL (in case of an associated clonal hematologic non-MC cell

A

130

lineage disease [AHNMD]), this last item is not valid). If one major and one minor or three minor criteria are fulfilled, then the diagnosis is systemic mastocytosis. Maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP) is the most frequent form of CM and is more common in childhood. The release of vasoactive mediators (especially histamine) leads to the clinical manifestations of urticaria, wheal, and flare with pruritus (Darier sign) observed in MPCM/UP.137 In addition to classic UP, a number of rare variants of MPCM/UP have been proposed and include plaque, nodular, and telangiectatic (TMEP) subvariants. Solitary or small numbers of nodular lesions constitute mastocytomas. The prognosis of MPCM/UP is excellent because almost all cases begin in early childhood and regress at the end of puberty or in early adolescence. The serum tryptase level is a well-established marker of MC disease burden. In patients with CM (by definition having no systemic disease), the serum tryptase levels are within normal limits or only slightly elevated. Other laboratory studies are also unremarkable, and c-kit mutations are not detected in the majority of pediatric patients. Systemic mastocytosis (SM) occurs most often in adults in whom excessive numbers of MCs may occur not only in the skin but also in the bone marrow and in the viscera, such as the gastrointestinal tract (leading to diarrhea), liver, spleen, and lymph nodes. Patients with SM often have bone marrow involvement and elevated serum tryptase levels and may develop an associated clonal

hematologic non-MC lineage disease, an aggressive form of SM, and even rarely MC leukemia. TMEP occurs in adults and is rarely associated with systemic mastocytosis. CLINICAL FEATURES The cutaneous lesions of SM and MPCM/UP are reddish brown macules, papules, or nodules that may be clinically confused with melanocytic lesions (Fig. 6-29A). Stroking of the lesion causes MC degranulation with the development of an urticarial wheal and flare (Darier sign). TMEP presents as pruritic lightly pigmented macules with surface telangiectases distributed on the trunk and proximal extremities.137 HISTOPATHOLOGIC FEATURES In SM, MPCM/UP, or diffuse CM, biopsy reveals either a perivascular or diffuse infiltrate of MCs within the upper dermis (Fig. 6-29). MCs in CM exhibit a mature morphology; usually they are round to oval cells with amphophilic-basophilic cytoplasm, centrally placed nuclei, and inconspicuous nucleoli (so-called fried-egg appearance). MCs stain with toluidine blue, chloracetate esterase (neutrophils are also stained), and Giemsa stains and the specific tryptase immunostain. Especially in childhood, excessive dermal edema may cause subepidermal bulla formation.137 Eosinophils are often present as well. Rarely, dermal fibroplasia may be observed in lesions of CM. In TMEP, slightly increased numbers of MCs are distributed perivascularly around dilated superficial dermal vessels (similar to the distribution in normal skin) and are elongate to spindleshaped138,139 (Table 6-19).

B

 FIGURE 6-29 Cutaneous mastocytosis. ( A ) Reddish brown macules and papules that may be clinically confused with melanocytic lesions. ( B ) There are sheets of uniform mononucleate cells with abundant amphophilic cytoplasms and round to oval nuclei typical of mast cells.

Table 6-19 Cutaneous Mastocytosis SOLITARY MASTOCYTOMA

URTICARIA PIGMENTOSA

SYSTEMIC MASTOCYTOSIS

TMEP

Clinical Features Infants, neonates Single red-brown macule, papule, nodule Vesicle, bulla, sometimes

Infants, neonates Multiple red-brown macules, papules, nodules Vesicles, bullae, often

Adults, usually Multiple red-brown macules, papules, nodules

Adults, usually Lightly pigmented macules with telangiectases “No extracutaneous involvement usually”

No extracutaneous involvement

Extracutaneous involvement, as a rule

No extracutaneous involvement

Rare progression to systemic mastocytosis Same as solitary mastocytoma

Same as solitary mastocytoma

Subepidermal bulla formation, sometimes

DIFFERENTIAL DIAGNOSIS The cells in papules and nodules are very uniform and on scanning magnification can resemble nevus cells, histiocytes or Langerhans cells, and leukemic infiltrates. The amphophilic cytoplasm and lack of nesting help to distinguish MC disease from melanocytic nevi. Histiocytic infiltrates may be characterized by cells with a monomorphous appearance; however, in contrast to MCs, histiocytes usually have somewhat angulated or reniform nuclei. Special stains and immunohistochemistry may be needed to distinguish the latter conditions from MC disease. In TMEP, the low-power appearance resembles normal skin. Since the histology of TMEP may be subtle, Giemsa, toluidine blue, and tryptase stains are helpful in highlighting the increased numbers of perivascular MCs.138,139 Normal skin may have up to 10 MCs per 40× field.139 Dermatopathologists always should keep this diagnosis in mind when dealing with “normal skin” biopsies or patients with unexplained pruritus.

EOSINOPHILIC INFILTRATES Table 6-20 lists parasitic diseases that produce large numbers of tissue eosinophils.

Wells Syndrome Synonym: Eosinophilic cellulitis. Wells syndrome (eosinophilic cellulitis) is an uncommon condition that is thought to be a hypersensitivity reaction.

Most cases are completely idiopathic; others are associated with arthropod assaults, drug allergy, parasitic infestation, an atopic diathesis, internal malignancy, or dermatophyte infection.140 Histology reveals eosinophilic infiltrates with flame figures and later granulomas (see the following). It should be emphasized that flame figures are not pathognomonic of Wells syndrome but constitute a dermal reaction pattern that may be seen in any given lesion with numerous eosinophils, including allergic contact dermatitis, arthropod assault,

Telangiectatic vessels with increased perivascular mast cells (>10 mast cells per 40 × field)

bullous pemphigoid, and pemphigoid gestationis.141 CLINICAL FEATURES Wells syndrome presents as arcuate, erythematous, indurated plaques typically on the upper back, extremities, or buttocks. As the lesions evolve, they may become indurated, and complete resolution usually occurs within months.140 HISTOPATHOLOGIC FEATURES Histology reveals a diffuse and, early on, massive infiltrate of eosinophils with few lymphocytes

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Histopathologic Features Perivascular or diffuse mast cells within upper dermis

Rare progression to systemic mastocytosis

Table 6-20 Parasitic Causes of Diffuse Eosinophilic Infiltrates DISEASE

ORGANISM

Schistosomiasis

Schistosoma haematobium S japonicum S mansoni Taenia solium Spirometra sp. Onchocerca volvulus Dirofilaria immitis Ancylostoma braziliense Strongyloides stercoralis Gnathostoma spinigerum Trichinella spiralis Paragonimus skrjabini P westermani T canis T cati Dracunculus medinensis

Cysticercosis Sparganosis Onchocerciasis Dirofilariasis Larva migrans Strongyloidiasis Gnathostomiasis Trichinosis Paragonimiasis Toxocariasis Dracunculosis

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A

B

 FIGURE 6-30 Wells syndrome. ( A ). A superficial and deep perivascular mixed inflammatory cell infiltrate containing numerous eosinophils and flame figures. ( B ) Flame figures are formed by degranulation of eosinophils upon collagen bundles.

(Fig. 6-30A). In areas where eosinophils have degranulated, so-called flame figures are created (see Fig. 6-30B). These represent dermal collagen fibers that become coated with bright red eosinophilic granules containing major basic protein surrounded by macrophages, sometimes with giant cells. Early lesions may result in subepidermal or intraepidermal vesicle/bulla formation. In later stages, macrophages with giant cells may predominate.140,141 The panniculus occasionally may be involved, one cause of eosinophilic panniculitis.59 In the proper clinical setting, flame figures are very suggestive of Wells syndrome, but isolated lesions of common dermatoses with numerous eosinophils may exhibit flame figures.141 A search to rule out associated conditions (especially internal malignancy, parasite infestation, and drug hypersensitivity) is warranted in patients with Wells syndrome (Table 6-21). DIFFERENTIAL DIAGNOSIS Cutaneous arthropod assaults owing to insects (tungiasis, myiasis, pediculosis), scabies, ticks, and spiders demonstrate dense superficial and deep perivascular and interstitial mixed-cell infiltrates with numerous eosinophils and are the most common demonstrable cause of clinical papular urticaria. Fortuitous sections may demonstrate embedded mouth or body parts, eggs, or excreta. Lesions of chronic urticaria or of physical urticaria demonstrate a perivascular lymphocytic infiltrate with scattered interstitial mixed-cell infiltrates composed of lymphocytes, neutrophils, and eosinophils. Papular dermatitis (subacute prurigo) features a relatively sparse superficial and deep perivas-

cular lymphocytic infiltrate with scattered interstitial eosinophils and, at times, overlying epidermal spongiosis.142 Virtually identical appearances are seen in papular dermatitis of HIV.130 Changes to the side of eosinophilic folliculitis may resemble Wells syndrome. Eosinophilic folliculitis may occur as an idiopathic condition in otherwise healthy individuals (Ofuji disease) or in the setting of HIV infection. Often cutting deeper into the tissue blocks of tangential samples

Table 6-21 Wells Syndrome

Clinical Features Most cases idiopathic, but Associations with: Drug hypersensitivity Parasites Internal malignancy Dermatophytes Arcuate, erythematous, indurated plaques Upper back, extremities, buttocks Histopathologic Features Diffuse eosinophils Flame figures Eosinophilic panniculitis, sometimes Granulomas, especially in late lesions Differential Diagnosis Hypereosinophilic syndrome Arthropod assault Allergic contact dermatitis Bullous pemphigoid Herpes gestationis Pruritic urticarial papules and plaques of pregnancy (PUPPP) Urticaria

reveals a folliculocentric infiltrate of eosinophils and lymphocytes that both surround and infiltrate the follicular epithelium, sometimes producing eosinophilic pustules.143 Urticarial lesions of bullous pemphigoid may feature slight psoriasiform hyperplasia, variable spongiosis with eosinophils in the epidermis (so-called eosinophilic spongiosis), and eosinophils in number in a slightly edematous papillary dermis. Both pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy (PUPPP) (or the polymorphous eruption of pregnancy) are pregnancy-associated dermatoses that feature superficial perivascular lymphocytic infiltrates with interstitial eosinophils. Spongiosis with eosinophils is common in pemphigoid gestationis but absent in PUPPP.144 Additionally, the density of eosinophils is much greater in pemphigoid gestationis and bullous pemphigoid, and in PUPPP they tend to involve the reticular dermis more than the papillary dermis.144 Angiolymphoid hyperplasia with eosinophilia (aka epithelioid hemangioma) is a vascular lesion that occurs most commonly on the head and neck. As its name implies, histology features a vascular proliferation with prominent endothelial cells, numerous eosinophils, and lymphoid aggregates, sometimes with germinal center formation. It is unclear as to whether this represents a reactive or neoplastic condition. The differential diagnosis of panniculitis with eosinophils includes erythema nodosum, vasculitis, Wells syndrome, drug reaction, atopic dermatitis, contact dermatitis, streptococcal infection, parasitic infection

(Gnathostoma or Toxocara canis), atheromatous emboli, foreign-body, malignancy, or lupus erythematosus panniculitis.145

Hypereosinophilic Syndrome

CLINICAL FEATURES The cutaneous lesions are pruritic, erythematous papules, plaques, or nodules and/or lesions of urticaria, angioedema, or dermatographism. They are distributed on trunk, extremities, or face.146 HISTOPATHOLOGIC FEATURES Histology demonstrates a superficial and deep perivascular mixed inflammatory cell infiltrate of eosinophils and lymphocytes. In some cases neutrophils and plasma cells may be present. Flame figures typically are not seen, but cutaneous microthrombi may be present.148 Cutaneous microthrombi most likely result from the large amounts of plateletactivating factor released by eosinophils. Similar microthrombi are seen in other involved organs, and their presence portends a bad prognosis.148 DIFFERENTIAL DIAGNOSIS Histologic diagnosis of this rare disorder requires clinicopathologic correlation because similar histologic appearances may be seen in many of the entities discussed in the differential diagnosis of Wells syndrome. Evidence of systemic involve-

20.

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CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

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clonal hypergammaglobulinaemia: significant serum interleukin-6 levels. Br J Dermatol. 1992;127:49. Carey WP, Rico MJ, Nierodzik M, Sidhu G. Systemic plasmacytosis with cutaneous manifestations in a white man: successful therapy with cyclophosphamide/prednisone. J Am Acad Dermatol. 1998;38:629. Watanabe T, Tada Y, Nakamura K, et al. Failure to detect human herpesvirus type 8-DNA sequences in systemic plasmacytosis from HIV-uninfected Japanese patients. Br J Dermatol. 1999; 141:350. Kubota Y, Noto S, Takakuwa T. Skin involvement in giant lymph node hyperplasia (Castleman’s disease). J Am Acad Dermatol. 1993;29:778. Valent P, Horny H-P, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leukemia Res. 2001;25:603. Kasper CS, Freeman RG, Tharp MD. Diagnosis of mastocytosis subsets using a morphometric point counting technique. Arch Dermatol. 1987;123:1017. Sweet WL, Smoller BR. Perivascular mast cells in urticaria pigmentosa. J Cutan Pathol. 1996;23:247. Aberer W, Konrad K, Wolff K. Wells’ syndrome is a distinctive disease entity and not a histologic diagnosis. J Am Acad Dermatol. 1988;18:105. Wood C, Miller AC, Jacobs A, et al. Eosinophilic infiltration with flame figures: a distinctive tissue reaction seen in Well’s syndrome and other diseases. Am J Dermatopathol. 1986;8:186. Sherertz EF, Jorizzo JL, White WL, et al. Papular dermatitis in adults: subacute prurigo, American style? J Am Acad Dermatol. 1991;24:697. McCalmont TH, Altemus D, Maurer T, Berger TG. Eosinophilic folliculitis: the histologic spectrum. Am J Dermatopathol. 1995;17:439. Pruritic urticarial papules and plaques of pregnancy vs. herpes gestationis, urticarial stage. In: Ackerman AB, White W, Guo Y, Umbert I (eds.) Differential Diagnosis in Dermatopathology IV. Philadelphia, PA: Lea & Febiger; 1994:26. Adame J, Cohen PR. Eosinophilic panniculitis: diagnostic considerations and evaluation. J Am Acad Dermatol. 1996; 34:229. Kazmierowski JA, Chusid MJ, Parrillo JE, et al. Dermatologic manifestations of the hypereosinophilic syndrome. Arch Dermatol. 1978;114:531. Bain B, Pierre R, Imbert M, et al. Chronic eosinophilic leukemia and the hypereosinophilic syndrome. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds.) Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001:29. Fitzpatrick JE, Johnson C, Simon P, Owenby J. Cutaneous microthrombi: a histologic clue to the diagnosis of hypereosinophilic syndrome. Am J Dermatopathol. 1987;9:419.

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

102.

by clinical and histologic features. J Am Acad Dermatol. 1994;30:417. Sass U, Noel JC, Andre J. Multinucleate cell angiohistiocytoma: report of two cases with no evidence of human herpesvirus-8 infection. J Cutan Pathol. 2000;27:258. Chang SN, Kim HS, Kim S-C, Yang WI. Generalized multinucleate cell angiohistiocytoma. J Am Acad Dermatol. 1996;35:320. Annessi G, Girolomoni G, Giannetti A. Multinucleate cell angiohistiocytoma. Am J Dermatopathol. 1992;14:340. Palazzo JP, Ellison DJ, Garcia IE, et al. Cutaneous malakoplakia simulating malignant lymphoma. J Cutan Pathol. 1990;17:171. Horn TD, Burke PJ, Karp JE, Hood AF. Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol. 1991;127:49. Mehregan DR, Fransway AF, Edmonson JH, Leiferman KM. Cutaneous reaction to granulocyte-monocyte colony-stimulating factor. Arch Dermatol. 1992;128:1055. Scott GA. Report of three cases of cutaneous reactions to granulocytemacrophage colony-stimulating factor and a review of the literature. Am J Dermatopathol. 1995;17:107. Fitzpatrick JE. New histopathologic findings in drug eruptions. Dermatol Clin. 1992;10:19. Wood C, Severin GL. Unusual histiocytic reaction to Monsel’s solution. Am J Dermatopathol. 1980;2:261. Hanau D, Grosshans E. Monsel’s solution and histological lesions. Am J Dermatopathol. 1981;3:418. Elston DM, Bergfeld WF, McMahon JT. Aluminum tattoo: a phenomenon that can resemble parasitized histiocytes. J Cutan Pathol. 1993;20:326. Jorizzo JL, Solomon AR, Zanolli MD, Leshin B. Neutrophilic vascular reactions. J Am Acad Dermatol. 1988;19:983. Jordaan HF. Acute febrile neutrophilic dermatosis: a histopathological study of 37 patients and a review of the literature. Am J Dermatopathol. 1989;11:99. Malone JC, Slone SP, Wills-Frank LA, et al. Vascular inflammation (vasculitis) in Sweet syndrome. Arch Dermatol. 2002;138:345. Requena L, Kutzner H, Palmedo G, et al. Histiocytoid Sweet syndrome: a dermal infiltration of immature neutrophilic granulocytes. Arch Dermatol. 2005;141:834. Chow S, Pasternak S, Green P, et al. Histiocytoid neutrophilic dermatoses and panniculitides: variations on a theme. Am J Dermatopathol. 2007;29:334. Carlson JA, LeBoit PE. Localized chronic fibrosing vasculitis of the skin: an inflammatory reaction that occurs in settings other than erythema elevatum diutinum and granuloma faciale. Am J Surg Pathol. 1997;21:698. Delaporte E, Graveau DJ, Piette FA, Bergoënd HA. Acute febrile neutrophilic dermatosis (Sweet’s syndrome): associa-

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CHAPTER 7

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Intraepidermal Vesiculopustular Diseases Terence J. Harrist Brian Schapiro Lisa Lerner Cynthia M. Magro James Ramirez Jenny Cotton

Distinct diseases may have similar or even identical pathologic features. In addition, the histopathologic findings in each disease evolve over time. Thus the algorithmic approach to diagnosis in this group is, of necessity, complex but facilitates the diagnosis in this complex group of disorders (Figs 7-1 through 7-3, Table 7-1). Correlation of the clinical findings and historical data with the microscopic findings is often essential to derive a definitive diagnosis. The algorithm narrows the differential diagnosis to a few entities or a specific diagnosis through evaluation of the blister-cleft separation plane, the principal pathologic process, and if present, the inflammatory cell complement.

DEFINITIONS A wide variety of disorders may produce intraepidermal vesicles and pustules.

A blister is a fluid-filled cavity within or beneath the epidermis containing tissue

Level of vesicle/pustule

Subcorneal/intragranular layer of epidermis

Spongiosis Miliaria crystallina

Spinous layer Fig. 7-3

Pustule Fig. 7-2

Acantholysis

Focal transient acantholytic dermatosis (pemphigus foliaceus type)

Few acantholytic granular layer keratinocytes

+ DIF Pemphigus foliaceus

136

fluid, plasma, and a variable complement of inflammatory cells. Vesicles are blisters less than 0.5 cm in diameter, and bullae are blisters greater than 0.5 cm in diameter. A vesicopustule is a vesicle in which there is a prominent component of neutrophils. Some diseases produce microscopic slit-like spaces within the epidermis that are known as clefts. Clefts characteristically occur in the group of diseases that have focal acantholytic dyskeratosis as their histologic reaction pattern and do not, as a rule, have clinically apparent blisters. A pustule is a dense aggregate of neutrophils or eosinophils, viable or degenerated, with a small component of tissue fluid. A pustule is yellow-white clinically and resides intracorneally, within the stratum spinosum or at the dermalepidermal junction. A microabscess is a small aggregate of neutrophils or eosinophils

Diffuse

Dyskeratosis pemphigus foliaceus

– DIF SSSS

 FIGURE 7-1 Intraepidermal blistering and pustular diseases.

Suprabasal layer

Cytolysis Friction blister Epidermolytic hyperkeratosis Irritant contact dermatitis (rare)

Focal acantholytic dyskeratosis

Few rete Transient acantholytic dermatosis (Darier type)

Acantholysis

Pure acantholysis

Interface dermatitis Apoptosis Paraneoplastic pemphigus

Several rete Darier disease

Spinous layer Hailey-Hailey disease

Suprabasal only P vulgaris

Subcorneal/intragranular pustule

Neutrophils predominate

Vesiculopustule

Pustule

Infective organisms Impetigo Dermatophyte Candidiasis

Sterile

Epidermis Eosinophilic pustulosis (folliculitis)

Hair follicle Erythema toxicum neonatorum Eosinophilic folliculitis

Sterile

+ DIF

+ IgA IgA pemphigus

+ IgG Pemphigus foliaceus

– DIF Subcorneal pustular dermatosis Acropustulosis Transient neonatal pustular melanosis

Dermal plasma cells Secondary syphilis

Dermal eosinophils Drug eruption Scabies

Dermal neutrophils IgA pemphigus

 FIGURE 7-2 Intraepidermal blistering and pustular diseases.

observed histologically. At times a microabscess may be predominated by mononuclear cells usually Langerhans cells and/or lymphocytes. The separation plane is relatively constant in each vesiculobullous disease. Each process tends to reliably produce blisters in either the subcorneal/granular, spinous, or suprabasal zones in the epidermis. Occasionally, blisters may extend from one plane to another. Pustules tend to form in the subcorneal or intracorneal zone but are not limited to those locations. Spongiosis is the accumulation of extracellular fluid within the epidermis causing separation between adjacent keratinocytes. The keratinocytes often appear stellate with clear spaces separating them from their neighbors, producing a “spongy” appearance. As the degree of spongiosis increases, microscopic vesicles develop and may progress to macroscopic vesicles or bullae. In cases of

severe spongiosis, ballooning degeneration (intracellular edema) with subsequent rupture of the cell membranes (a form of cytolysis) may lead to a lacelike appearance (reticular degeneration). Spongiosis develops primarily due to transudation of serum from damaged or inflamed vessels within the superficial plexus. Ballooning degeneration occurs when the keratinocytes lose osmotic control. Acantholysis is the result of loss of appropriate keratinocyte-keratinocyte adherence. This adherence is mediated by tight junctions, adherens junctions, gap junctions, and desmosomes. The role of desmosomes in keratinocytic adhesion is paramount, and they are the last structures to split when acantholysis occurs. Acantholytic disorders that have been well characterized develop as sequelae of desmosomal dysfunction or disruption of the desmosomal connections with the intracellular keratin struc-

tural matrix. Keratinocyte-keratinocyte adhesion is a dynamic process because the relationship of one keratinocyte to another must change during epidermal maturation. Thus acantholysis may be viewed as a loss of equilibrium between the formation and dissolution of junctions. This dysequilibrium may occur primarily when the adhesion junctions are impaired directly or secondarily when keratinocytic viability is affected. Acantholytic keratinocytes are rounded with condensed eosinophilic cytoplasm, large nuclei, peripherally marginated chromatin, and prominent nucleoli. Cytolysis of keratinocytes, as well as apoptosis, may lead to blister formation. Cytolysis may occur in the normal epidermis when the structural matrix of the keratinocytes is overwhelmed by high levels of deleterious physical agents such as mechanical forces or heat. Mechanical energy applied parallel to the epidermis (friction) may lead to shearing between

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

Infective organisms Bullous impetigo (S aureus) Bullous dermatophyte Candida

Eosinophils predominate

137

Spinous layer blister/pustule

Cytolysis Herpes virus Friction blister

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Spongiosis

Lymphocytes predominate

Eosinophils predominate

Neutrophils predominate

Miliaria rubra Spongiotic/eczematous dermatitis Transient acantholytic dermatitis (spongiotic foci) Pemphigus (very early) Miliaria rubra Pityriasis rosea Eczematous drug eruption

Incontinentia pigmenti Pemphigus (eosinophilic spongiosis; early lesions) Allergic contact dermatitis Spongiotic drug eruption

Spongiotic dermatitis irritant type impetiginized Seborrheic dermatitis Dermatophytosis Pustular drug eruption Pemphigus vulgaris (rare) Kawasaki disease Perifolliculitis, epidermal changes

Variable inflammation Hailey-Hailey disease Pemphigus foliaceus P vulgaris

Little inflammation

Focal Transient acantholytic dermatosis (Hailey-Hailey type)

Diffuse Hailey-Hailey disease

 FIGURE 7-3 Pemphigus vulgaris.Relatively discreet flaccid blisters, erosions and vegetating crusted lesions are present on nonerythematous skin of the upper and mid back.

keratinocytes and within keratinocytes themselves, that is, cytolysis. Minimal friction may lead to cytolysis when keratinocytes do not have a normal structural matrix, as in epidermolysis bullosa simplex. Immune-mediated cell necrosis in the context of antibody-dependent cellmediated immunity or a delayed-type hypersensitivity reaction may lead to blister formation, which most typically is subepidermal in nature. The morphologic hallmark of this pattern of necrosis is karyolysis producing colloid bodies. This is not to be confused with apoptosis, which is a unique form of cell death whereby individual, scattered single cells die without release of cellular contents. Such a pattern of programmed cell death usually does not lead to epidermal disruption.

SPONGIOTIC DERMATITIS 138

Acantholysis

The spongiotic disorders are covered in detail in Chapter 2.

ACANTHOLYTIC DERMATITIS (See Figs 7-1 through 7-3, Tables 7-1 and 7-2)

Pemphigus Vulgaris and Variants CLINICAL FEATURES Large and flaccid bullae develop on the oral mucosa, face, scalp, central chest, and intertriginous zones in older individuals (Table 7-3). Oral lesions are the first manifestation in 10% to 15% of patients and almost invariably develop during the course of the disease.1 Since the blisters are fragile, they collapse rather quickly giving place to erosions with the most common lesions in pemphigus. Vegetative lesions with prominent crusting and granulation tissue are also characteristic of pemphigus. The surrounding skin is typically nonerythematous. The ability to extend blisters by external pressure has been referred to as Nikolsky sign.

In 1% to 2% of cases of pemphigus vulgaris, vegetative plaques containing pustules may develop principally in the intertriginous areas.2 Referred to as pemphigus vegetans, it is thought by many to be a “reactive state” in pemphigus.2,3 Polyclonal IgG develops against the pemphigus vulgaris antigen, desmoglein 3, a desmosomal cadherin that mediates cell binding.4,5 Desmoglein 3 appears to be in greater concentration in the lower epidermis, the location of the suprabasal acantholytic blister of pemphigus vulgaris. The antigen-antibody union results in desmosomal dysfunction and potentiates dyshesion by causing production of a cytoplasmic proteinase, plasminogen activator, that is released into the squamous intercellular substance. Complement fixation may potentiate the acantholysis. In pemphigus vulgaris with cutaneous involvement there are antibodies to both desmoglein 3 and desmoglein 1.6 About 80% to 90% of patients have circulating

Table 7-1 Intraepidermal Blistering And Pustular Diseases PATHOLOGIC PROCESS

INFLAMMATORY CELLS

DISEASE

Subcorneal/ intragranular

Spongiosis Acantholysis

Lymphocytes —

Pustules

Neutrophils

Miliaria crystallina Staphylococcal scalded skin syndrome Pemphigus foliaceus Transient acantholytic dermatosis (Pemphigus foliaceus–like foci) Impetigo Bullous impetigo Subcorneal pustular dermatosis IgA pemphigus Dermatophytosis Candidiasis Pustular secondary lues Pustular drug eruption Acropustulosis of infancy Transient neonatal pustular melanosis Pustular Id reaction Pemphigus vulgaris (rare) Pustular psoriasis Scabies Erythema toxicum neonatorum Miliaria rubra Spongiotic/eczematous dermatitis Transient acantholytic dermatitis (spongiotic foci) Pemphigus (very early) Miliaria rubra Pityriasis rosea Eczematous drug eruption Incontinentia pigmenti Pemphigus (eosinophilic spongiosis; early lesions) Allergic contact dermatitis Spongiotic drug eruption Spongiotic dermatitis irritant type impetiginized Seborrheic dermatitis Dermatophytosis Pustular drug eruption Pemphigus vulgaris (rare) Kawasaki disease Perifolliculitis, epidermal changes Hailey-Hailey disease Transient acantholytic dermatosis (Hailey-Hailey-like foci) Hailey-Hailey disease Pemphigus foliaceus and variants (extension from subcorneal plane) Pemphigus vulgaris and variants (extension from suprabasal plane) Irritant contact dermatitis (rare) Herpes virus infection Friction blister Friction blister Epidermolytic hyperkeratosis Irritant contact dermatitis (rare) Pemphigus vulgaris and variants Darier disease Transient acantholytic disease (Pemphigus vulgaris–like foci) .

Eosinophils Spinous

Spongiosis

Lymphocytes

Eosinophils

Neutrophils

Acantholysis

Little inflammation

Variable inflammation

Cytolysis Suprabasal

Cytolysis

Acantholysis

Marked inflammation Little inflammation

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

SEPARATION PLANE

SOURCE: Data from Elder D, Elenitsas R, Jaworsky C, Johnson B. Lever’s Histopathology of the Skin: Algorithmic Classification of Skin Diseases for Differential Diagnosis. 8th ed. Philadelphia: Lippincott-Raven; 1997:61-116.

139

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 7-2 Important Differential Diagnostic Features of Acantholytic Dermatoses

Subcorneal cleavage Intraspinous cleavage Suprabasal cleavage Cleft Blister Dyskeratosis Villi Tombstone basal keratinocyte Follicular involvement Epidermal hyperplasia Spongiotic early change Eosinophilic spongiosis

PEMPHIGUS FOLIACEUS

SSSS

+++

+++

−

−

−

−

−

0/+

−

+++

0/+

−

−

−

−

−

0/+

+++

+++

+++

+ (small)

− + + (some) − −

− + − − −

− + − + −

− + − +/+++ +++

− + − +++ +

++ − ++ +/+++ −

++ − + (some lesions) + −

+

−

−

++

+

+

−

−

−

+/++

0/+

+++

+

−

+

−

−

+

+

−

+

0/+

−

−

0/+ (some)

+++ (abscesses)

−

−

PEMPHIGUS VULGARIS

PEMPHIGUS VEGETANS

DARIER DISEASE

GROVER DISEASE

Legend: 0 = none; + = present; ++ = moderate change; +++ = marked change.

Table 7-3 Pemphigus Vulgaris and Variants

Clinical Features Flaccid bullae on skin; face, scalp, chest, and intertriginous areas (especially pemphigus vegetans) Oral mucosa involved in 100% cases Older individuals Histopathologic Features Suprabasal acantholysis with blister formation Involvement of hair follicles by acantholysis Spongiosis early Superficial perivascular mononuclear cell infiltrate Direct immunofluorescence: squamous epithelial intercellular deposition of lgG and possibly C3 Differential Diagnosis Other forms of pemphigus Benign familial pemphigus (Hailey-Hailey disease) Transient acantholytic dermatosis (Grover disease) Focal acantholytic dyskeratosis Acantholytic variants of actinic keratosis Herpesvirus infection

140

HAILEY-HAILEY DISEASE

IgG antibodies detectable by indirect immunfluorescence that show a general (but imperfect) correlation with disease activity. The IgG consists predominantly of the IgG4 subclass.7 HISTOPATHOLOGIC FEATURES The earliest stage is most often a paucicellular spongiotic dermatitis with edema most prominent in the lower epidermis. Less commonly the early phase is eosinophilic spongiosis. Later, acantholysis supervenes, leading first to the formation of clefts and then to clinically apparent blisters that arise in suprabasal location (Fig. 7-4). They frequently extend into follicular external root sheaths. The basal keratinocytes separate from one another but remain attached to the basal lumina, reminiscent of a “row of tombstones.”8 The acantholytic blister may be limited to the suprabasal plane or may extend higher within the epidermis. The acantholysis extends into appendages (Fig. 7-4E). The acantholytic keratinocytes are of relatively large size with prominent eosinophilic glassy cytoplasm, prominent nuclei with large nucleoli, and perinuclear clearing. There is a superficial perivascular lymphohistiocytic infiltrate with dermal

edema. As the lesions erode and ulcerate, a mixed infiltrate composed principally of neutrophils may develop. Older blisters may exhibit necrosis of the blister roof, with several keratinocytic layers lining the blister cavity on its lowermost aspect, due to keratinocyte migration and proliferation. As well, epidermal reti may elongate, giving rise to the so-called villi. A neutrophilic spongiotic dermatitis may be present in some cases of pemphigus vulgaris. In these, spongiosis is a much more prominent feature than acantholysis. There is a variant designated as pemphigus herpetiformis owing to the fact that the clinical lesions are small vesicles and resemble dermatitis herpetiformis. The histopathology resembles pemphigus vulgaris; however the segment of acantholysis is a fairly confined narrow zone corresponding to a clinical vesicle (Fig 7-4C,D). All patients with active pemphigus have IgG autoantibodies against the cell surface of keratinocytes detectable by direct and often indirect immunofluorescence (see also Appendix: Laboratory Methods). The pattern of intercellular space deposition of IgG may be identical in pemphigus vulgaris, pemphigus foliaceus (and their closely related variants

B

C

D

E

F

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

A

 FIGURE 7-4 Pemphigus vulgaris (A ) Relatively discreet flaccid blisters, erosions and vegetating crusted lesions are present on non-erythematous skin of the upper and mid back. (B ) Blister in suprabasilar location. In this well-developed lesion there is a suprabasalar cleft with acantholytic cells present in the blister cavity. (C ) Also seen are elongated epidermal rete below a single row of basal keratinocytes. (D,E ) In this case of pemphigus herpetiformis the lesions clinically are in the context of small vesicles which is captured histomorphologically. Note the small zone of suprabasilar acantholysis with intraepidermal tissue eosinophilia. (F,G ) In this biopsy of pemphigus there is prominent acantholysis which is most conpicuous in the lower third of the epidermis. There is prominent involvement of the follicle. Using an immunohistochemical methodology, intercellular deposits of C3d can be observed within the epidermis, hence corroborative of the diagnosis of pemphigus. (H,I,J ) There are cases whereby a mixed pemhigus pemphigoid pattern is seen despite no underlying malignancy (ie, mimicking paraneoplastic pemphigus). This particular patient was 17 years old, otherwise healthy, in whom a pemphigus-like eruption developed clinically. Histologically, a combined pemhigoid and pemphigus pattern was seen. While the direct immunofluroescent studies showed only linear deposits of IgG along the dermal epidermal junction without any supervening intercellular pattern, the C3d assay showed intercellular deposits while the C4d demonstrated a sharp linear staining pattern. ELISA studies conducted on the patient’s peripheral blood confirmed the diagnosis of a hybrid circulating antibody profile with specificity to both pemphigus and pemphigoid antigens.

141

H

I

J

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

G

 FIGURE 7-4 (Continued )

142

pemphigus vegetans and erythematosus, respectively), and the majority of patients with drug-induced pemphigus. The immunohistochemical demonstation of C3d on formalin-fixed paraffin-embedded tissue is a new technique that can be applied to highlight this pattern of diagnostic intercellular staining (Figure 7-4F).9 However, the site of predominant immunoreactivity may correspond to the location of intra-epidermal cleavage, that is, the suprabasal epidermis in pemphigus vulgaris and the superficial spinous layer in pemphigus foliaceus. The latter patterns of immunofluorescence provide evidence of pemphigus vulgaris versus pemphigus foliaceus, but final diagnosis should be based on the level of cleavage observed by light microscopy and the clinical context. In addition to IgG, C3 and other complement components are often (up to 50% of cases) found on direct immunofluorescence and exhibit a similar intercellular pattern of immunore-

activity as with IgG. Pemphigus should not be diagnosed if only C3 is present. About 30% of patients exhibit deposition of IgM and IgA. In pemphigus vegetans, the initial lesions are identical to those of pemphigus vulgaris. As the lesions age, verrucous epidermal hyperplasia develops (Fig 7-5) with prominent eosinophilic spongiosis and eosinophilic pustules. Neutrophilrich intraepidermal pustules may be present as well. Acantholysis is often focal and may be difficult to identify. DIFFERENTIAL DIAGNOSIS Although the clinical and histopathologic features of pemphigus vulgaris are often distinctive, other acantholytic disorders such as pemphigus foliaceus and variants, druginduced pemphigus, IgA pemphigus, paraneoplastic pemphigus, familial benign pemphigus, transient acantholytic dermatosis, herpesvirus infection, and acantholytic variants of actinic keratosis

may enter into the differential diagnosis. Pemphigus vulgaris is distinguished from pemphigus foliaceus and variants only by the suprabasal location of cleavage in pemphigus vulgaris versus the superficial cleavage in pemphigus foliaceus, that is, a subcorneal/granular blister with or without dyskeratosis. Pemphigus erythematosus in addition may show basal layer vacuolopathy of the epidermis and a supervening positive lupus band test, the latter being defined by a granular deposits of immunoglobulin and complement along the dermal epidermal junction. A clear association with a drug may be necessary to separate drug-induced pemphigus from pemphigus vulgaris; however, some cases with drug-induced pemphigus do not have detectable antibodies by immunofluorescence. IgA pemphigus differs from pemphigus vulgaris by demonstrating subcorneal or intraepidermal neutrophilic pustules with mininimal or no acantholysis and

crowding and atypia of the basilar keratinocytes, and the clinical presentation as a solitary lesion. The presentation of pemphigus as eosinophilic spongiosis without vesicles raises a rather extensive differential diagnosis, the principal entities of which are mentioned in Fig. 7-6 (also see Chap. 2). Clinical information and immunofluorescence studies are needed for definitive diagnosis in most instances.

Pemphigus Foliaceus and Variants

B  FIGURE 7-5 (A) Pemphigus vegetans. In this early lesion there is irregular epidermal hyperplasia with hyperkeratosis and hypergranulosis. In the suprabasal zone and lower stratum spinosum, there is acantholysis and accumulation of eosinophils, which may progress to eosinophilic pustules. (B ) In this particular case of herpes while there are features reminiscent of pemphigus, there are striking cytopathic changes that one associates with herpetic cytopathic effect, including an effaced heterochromatin, beading of the nuclear membrane, and multinucleation.

positive immunoreactivity for IgA in an intercellular pattern in the epidermis in the absence of concomitant IgG or with lesser degrees of IgG. Paraneoplastic pemphigus is distinctive because of a close relationship with cancer, the usual widespread nature of the eruption and striking mucocutaneous involvement, histologically the presence of interface alterations and dyskeratosis resembling erythema multiforme, and both intercellular and BMZ patterns of immunofluorescence in addition to acantholysis. Familial benign pemphigus (HaileyHailey disease) is discriminated from pemphigus by the usual presence of acanthosis, acantholysis involving at least half of the epidermis in a diffuse pattern, possibly some dyskeratosis, the lack of appendageal involvement, and finally, negative immunofluorescence results. Pemphigus differs from transient acantholytic dermatosis (ie, Darier and Grover diseases) by exhibiting greater

breadth of involvement of the epidermis and involvement of appendages by the acantholysis versus only focal epidermal involvement in focal acantholytic dyskeratosis and the usual absence of dykeratosis. On occasion, pemphigus may mimic herpesvirus infection by showing, in addition to acantholysis, alterations suggesting viral cytopathic changes of herpes, that is, the “ground glass” nuclear changes, rounded appearing hypereosinophilic cytoplasms, and multinucleation. Paraneoplastic pemphigus affecting the oral mucosa may be difficult to distinguish from oral herpes, both occurring in the immunosuppressed individuals. Regenerative epithelial changes encountered in paraneoplastic pemphigus can be associated with multinucleation although the characteristic nuclear changes of herpes are not seen. Acantholytic variants of actinic keratosis are usually distinguished from pemphigus by the presence of parakeratosis,

FOGO SELVAGEM Fogo selvagem is similar clinically but develops in people who live adjacent to rivers and streams in Brazil.10,11 An arthropod (Simulium sp.) vector may mediate this disorder. It has been hypothesized that a component of the saliva within the arthropod vector triggers antibody development to desmoglein 1. In both pemphigus foliaceus and fogo selvagem, polyclonal IgG in the serum is directed against desmoglein 1, a desmosomal cadherin.4,12 Desmoglein 1 may be of a greater concentration in the upper epidermis. This distribution likely explains the subcorneal-granular layer cleavage plane of the blisters and lack of intraoral lesions. As with pemphigus vulgaris the IgG is of the IgG4 subclass.6

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

CLINICAL FEATURES Flaccid, fragile bullae rupture to leave shallow crusted erosions and crusted patches and plaques on the trunk, intertriginous areas, proximal extremities, and head and neck of middle-aged and older individuals (Table 7-4). Most patients experience a chronic generalized course, although some patients present with an exfoliative dermatitis. The mucous membranes are almost never involved.

A

PEMPHIGUS ERYTHEMATOSUS This is a variant of pemphigus foliaceus that has features of both pemphigus and lupus erythematosus. It usually presents with erythematous plaques of the nose and malar areas. HISTOPATHOLOGIC FEATURES Three characteristic histopathologic patterns occur: eosinophilic spongiosis and abscesses,13,14 subcorneal/granular blisters with few acantholytic keratinocytes, and subcorneal/ granular blisters with dyskeratotic granular cells (see Table 7-4). The latter pattern is diagnostic of this disorder (Fig. 7-6). As in pemphigus vulgaris, the cleavage plane is not exact and may extend to the suprabasal zone, on occasion rendering histologic distinction of the two principal pemphigus variants difficult.15 There is an associated superficial perivascular dermatitis with

143

and cultures and negative immunofluorescence findings. Pemphigus foliaceus is separated from the other disorders by IgG or lack of any positivity on immunofluorescence studies. Both pemphigus erythematosus and paraneoplastic pemphigus usually demonstrate deposition of immunoreactants, that is, IgG in intercellular and BMZ patterns, and must be discriminated by other findings (clinical, histopathologic, and laboratory).

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

144

Drug-Induced Pemphigus

B  FIGURE 7-6 (A,B) Pemphigus foliaceus. There is acantholysis of the granular layer with loss of the stratum corneum. Accumulation of neutrophils in the acantholytic blister may lead to confusion with bullous impetigo. The acantholytic granular cells are seen in Fig. 7-3B.

Table 7-4 Pemphigus Foliaceus and Variants

Clinical Features Crusted erosions and patches Very fragile flaccid bullae Middle-aged and elderly Trunk, head and neck, intertriginous areas, and proximal extremities “Butterfly rash” mimicking lupus erythematosus seen in pemphigus erythematosus Histopathologic Features Subcorneal/granular blister with acantholytic keratinocytes or dyskeratotic granular cells Variable eosinophilic spongiosis Direct immunofluorescence: squamous epithelial intercellular deposition of IgG and possibly C3 Possible accentuation in superficial epidermis Pemphigus erythematosus usually shows linear or granular IgG and possibly C3 at the epidermal basement membrane zone Differential Diagnosis Other forms of pemphigus Impetigo Staphylococcal scalded skin syndrome Subcorneal pustular dermatosis

edema. As the lesions erode and age, a mixed infiltrate may appear. Bacterial suprainfection may lead to a picture identical to that of impetigo. The histologic features of pemphigus erythematosus are identical to those of pemphigus foliaceus; however, in rare cases, an interface dermatitis similar to that of lupus erythematosus has been present. As discussed above for pemphigus vulgaris, all patients with active pemphigus foliaceus have positive direct immunofluorescence for IgG and to a lesser degree C3 in a typical intercellular pattern that is indistinguishable from other forms of pemphigus or concentrated in the superficial epidermis. In the vast majority of cases, indirect immunofluorescence is also positive. Pemphigus erythematosus, as already mentioned, usually exhibits BMZ deposition of immunoglobulin and occasionally C3 in addition to the intercellular immunoreactivity. The most common immunoreactant is one of IgM. DIFFERENTIAL DIAGNOSIS See “Differential Diagnosis” above for pemphigus vulgaris. Other considerations not already mentioned include bacterial and fungal infections, especially impetigo and bullous impetigo; pustular drug eruption; IgA pemphigus; and subcorneal pustular dermatosis. Impetigo is distinguished from pemphigus foliaceus by a positive Gram stain (not present in bullous impetigo)

CLINICAL FINDINGS Drug-induced pemphigus usually begins as a nonspecific eruption of morbilliform, annular, or urticarial plaques without blisters (Table 7-5). Patients with penicillamine-induced pemphigus have a characteristic generalized toxic erythema that has been labeled “a toxic pre-pemphigus rash.”15,16 After a variable period of time, blisters develop on scaly crusted patches, similar to those of pemphigus foliaceus in most cases. The most common causative drugs include penicillamine and captopril.17 Drug-induced pemphigus can be separated into two subsets. In the first group, representing 10% of cases, pemphigus antibodies are produced and cause

Table 7-5 Drug-Induced Pemphigus

Clinical Features Morbilliform, annular, or urticarial plaques progress to blisters Scaly crusted plaques Penicillamine and captopril are common causative agents Histopathologic Features Plane of blister separation may occur in either subcorneal or suprabasal plane Subacute eczematous dermatitis seen in early lesions Direct immunofluorescence study: intercellular deposition of IgG and possibly C3 in epidermis in almost all active cases Differential Diagnosis Other forms of pemphigus Benign familial pemphigus (Hailey-Hailey disease) Transient acantholytic dermatosis (Grover disease) Focal acantholytic dyskeratosis Acantholytic variants of actinic keratosis Herpesvirus infection Impetigo Staphylococcal scalded skin syndrome Subcorneal pustular dermatosis

acantholysis identical to that of idiopathic pemphigus.8 Direct binding of the drugs to the pemphigus antigens may render the antigens immunogenic in such cases. In the second group, the drugs or metabolites, rich in sulfhydryl groups, accumulate within the epidermis. They may cleave the disulfide bonds of keratin and incorporate into the keratin molecule itself because of their similarity to cystine, leading to dyshesion which is nonimmunologically mediated. Another possible mechanism is the direct binding of the drugs to the pemphigus vulgaris and foliaceus antigens, disrupting their interchain disulfide bonds.

DIFFERENTIAL DIAGNOSIS See the discussions under “Pemphigus Vulgaris and Variants” and “Pemphigus Foliaceus and Variants” above.

Clinical Features Flaccid vesicles, pustules, and bullae arise on an erythematous base Middle-aged to elderly patients Histopathologic Features Subcorneal or intraepidermal pustules Direct immunofluorescence: intercellular IgA in epidermis Differential Diagnosis Other forms of pemphigus Impetigo Staphylococcal scalded skin syndrome Subcorneal pustular dermatosis

Circulating IgA is directed against adhesion molecules within the epidermis. The antigens against which the antibodies are directed are neither the pemphigus foliaceus nor vulgaris antigen but rather desmocollins and/or desmogleins.18,19 The differing clinical presentation likely relates to the fact that the antibodies are directed against desmocollins in particular Dsc1 (subcorneal pustular type) and desmogleins (intraepidermal pustular type) that have differing distributions within the epidermis.20 HISTOPATHOLOGIC FEATURES Two histologic patterns, a subcorneal pustular pattern and an intraepidermal pustular pattern, are observed18,21,22 (see Table 7-6). In the former there are subcorneal vesi-

copustules with minimal acantholysis. In the latter there are intraepidermal pustules containing small to moderate numbers of neutrophils throughout the breadth of the epidermis (Fig. 7-7). Suprabasal separation is not apparent. Minimal acantholysis is apparent such that the histologic reaction pattern is best considered an intraepidermal pustular dermatosis. In one case no neutrophil infiltration was present.23 IgA pemphigus is defined by the presence of IgA intercellular deposition on immunofluorescence. DIFFERENTIAL DIAGNOSIS The major entities to be considered include pemphigus foliaceus, subcorneal pustular dermatosis, bacterial and fungal infection (particularly impetigo), pustular psoriasis, pustular drug eruption, and nutritional deficiency such as migratory necrolytic erythema and, on occasion, Hailey-Hailey disease. Systematic evaluation with clinical history for evidence of psoriasis, drug ingestion, and so on; special stains and cultures for infective organisms; and immunofluorescence studies should facilitate making a specific diagnosis.

Paraneoplastic Pemphigus CLINICAL FEATURES Paraneoplastic pemphigus was first recognized by Anhalt et al.20,24 It is characterized by a generalized polymorphous eruption of blisters and lichenoid papules23,25 (Table 7-7). Painful oral ulcerations are a prominent

IgA Pemphigus Synonyms: IgA pemphigus foliaceus, IgA herpetiform pemphigus, intercellular IgA vesiculopustulardermatosis, intercellular IgA dermatosis, intraepidermal IgA pustulosis. CLINICAL FEATURES IgA pemphigus is a pruritic vesiculopustular eruption that develops in middle-aged to older individuals, often involving the axilla, trunk, and extremities (see Table 7-6). Many cases of subcorneal pustular dermatosis, in which immunologic investigation was not undertaken, may represent IgA pemphigus. Flaccid vesicles, pustules, or bullae arise on erythematous bases similar to the lesions of pemphigus foliaceus. The pustules tend to coalesce and form an annular pattern. Mucous membrane involvement is very rare. Patients have been segregated into two groups, one with a subcorneal pustular dermatosis and one with an intraepidermal pustular eruption.

 FIGURE 7-7 IgA pemphigus, subcorneal pustular variant. There is a large subcorneal pustule with spongiform pustulation. This picture is similar to Sneddon-Wilkinson disease, pustular psoriasis, and a pustular drug eruption.

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

HISTOPATHOLOGIC FEATURES In the early eruption there is an acute to subacute eczematous dermatitis (see Table 7-2). Eosinophils may be present, on occasion giving rise to eosinophilic spongiosis. The blister separation plane may either be in the subcorneal or suprabasal zones such that in well-developed lesions the histologic features are identical to pemphigus foliaceus or vulgaris. The immunofluorescence findings also may be indistinguishable from other forms of pemphigus; however in those cases of drug-induced pemphigus where the acantholysis is not immunologically triggered the direct immunofluorescence is characteristically negative.

Table 7-6 IgA Pemphigus

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Table 7-7 Paraneoplastic Pemphigus

146

Clinical Features Polymorphous eruption of blisters and lichenoid papules Painful oral ulcerations Remission may be seen following successful treatment of underlying malignancy Histopathologic Features Suprabasal acantholysis Interface dermatitis; either vacuolar or lichenoid type Direct immunofluorescence: squamous epithelial intercellular deposition of IgG, or IgM, and possibly C3 usually shows linear or granular IgG, or IgM, and possibly C3 in epidermal basement membrane zone Differential Diagnosis Other forms of pemphigus Benign familial pemphigus (Hailey-Hailey disease) Transient acantholytic dermatosis (Grover disease) Focal acantholytic dyskeratosis Acantholytic variants of actinic keratosis Lichen planus Erythema multiforme

feature and have been present in all cases. The ulcerations are often extensive over the lower lips, mimicking those of Stevens-Johnson syndrome. Any mucosal surface may be involved and pseudomembraneous conjunctivitis is a common occurence. Cutaneous involvement is characterized by lichenoid papules often involving the palms and the soles (which helps differentiate the disorder from pemphigus vulgaris). With one possible exception, all patients have had known or occult malignancies,26 including Hodgkin disease, thymoma, chronic lymphocytic leukemia, and other hematopoietic malignancies, as well as bronchogenic carcinoma and retroperitoneal sarcoma.27 The disorder is aggressive and generally refractory to treatment. Successful treatment of the underlying malignancy may induce a remission of the pemphigus. A panoply of autoantibodies is directed against a number of epidermal antigens and bind to simple, columnar, and transitional epithelia in addition to epidermis. Initial studies identified four proteins with molecular weights 250, 230, 210, and 190 kd. Since this discovery the antigens have been further characterized and new antigens have been described.20 A 170-kd antigen is present in nealy all PNP sera

and represents a novel transmembrane glycoprotein.20 The 210-kd protein is a doublet consisting of envoplakin and periplakin. The 250-kd protein is desmoplakin 1 and the 230-kd protein is bullous pemphigoid antigen 1; desmoplakin is structurally homologous to the bullous pemphigoid antigen and hence the antibodies to the bullous pemphigoid antigen 1 may really reflect molecular mimickry rather than being indicative of a true overlap with bullous pemphigoid. Perhaps corroborative of this theory is the fact that patients with paraneoplastic pemphigus do not demonstrate antibodies to bullous pemphigoid antigen II. In addition, antibodies to desmoglein 1 and 3 have been reported.20. HISTOPATHOLOGIC FEATURES The hallmarks include suprabasal acantholysis with principally basal layer keratinocyte apoptosis and an interface dermatitis that resembles erythema multiforme or lichen planus28

(Fig. 7-8; see also Table 7-7). Some cases may appear identical to pemphigus vulgaris without interface dermatitis and apoptosis. It is important to note that acantholysis may be focal or not present at all in a single lesion. Thus the lesions may appear as either a purely erythema multiforme-like interface dermatitis or a cell-rich lichenoid interface dermatitis.29 Thus biopsies of more than one lesion or level sections of a biopsy specimen may be necessary to make the diagnosis. One of the authors has encountered a patient assumed to have severe refractory graftversus-host disease based on the extent of interface change with epithelial destruction. The patient was subsequently established to have the classic serologic profile that one associates with paraneoplastic pemphigus. The light microscopic findings in this particular case are illustrated (Figure 7-8A,B). Direct immunofluorescence studies usually reveal (1) intercellular IgG and

A

B  FIGURE 7-8 (A ) Paraneoplastic pemphigus. There is an interface dermatitis with necrotic keratinocytes (left) in association with a suprabasalar acantholytic blister (right). (B ) In this case of paraneoplastic pemphigus, the dominant reaction pattern is a destructive interface dermatitis resembling accelerated chronic lichenoid graft-versus-host disease. From a clinical perspective, the patient had a severe erythematous scaly rash reminiscent of severe graft-versus-host disease.

atosis and only a few acantholytic keratinocytes. Few inflammatory cells are present initially, but later, neutrophilic infiltration may be striking, producing a histopathologic picture identical to that of impetigo.

DIFFERENTIAL DIAGNOSIS See the discussion for differential diagnosis under “Pemphigus Vulgaris and Variants”. One recent study revealed intercellular staining of the rat bladder incubating serum with fluoresceinated IgG. These contained circulating aAbs to a 190-kDa protein corresponding to periplakin, suggesting a role of these antibodies in the pathogenesis of TEN. There are indeed cases of paraneoplastic pemphigus which clinically and even histologicaly resemble toxic epidermal necrolysis.30 Antidesmoplakin antibodies have been identified in rare cases of pemphigus foliaceus and pemphigus vulgaris. Another study identified intercellular staining within rat bladder epithelium in 21% of sera from patients with classic pemphigus vulgaris; the majority of these patients had antibodies to both DP I (250 kDa) and DP II (210 kDa).31

Synonym: Keratosis follularis.

Generalized Staphylococcal Scalded Skin Syndrome (Ritter Disease) CLINICAL FEATURES Affected infants develop painful, tender, orange-tinged erythematous rash associated with a purulent conjunctivitis, otitis media, occult nasopharyngeal infection, or umbilical stump infection.32 The disease begins with fever and malaise followed by an erythematous rash. Within 2 days, large, flaccid bullae develop in the axillae and groin and around body orifices and become generalized. The mucous membranes are not involved. Healing usually is complete within 5 to 7 days. The associated infection is usually caused by staphylococci of group II phage type 71. They produce two epidermolysins (Exfoliative Toxins A and B) that enter the circulation and deposit in the skin, producing a subcorneal-granular layer separation plane.33 Exfoliative toxin A exerts specific protease activity on desmoglein 1.6 In adults, these epidermolysins usually are cleared rapidly due to the presence of neutralizing antibodies. Neonates do not have these neutralizing antibodies and have a decreased renal clearance of the epidermolysin. HISTOPATHOLOGIC FEATURES There is a subcorneal separation without dysker-

Darier Disease CLINICAL FEATURES Darier disease is an autosomal dominant genodermatosis presenting in the first two decades of life (Table 7-8).34 Reddish-brown papules covered by a tenacious scale coalesce into large plaques that involve the chest, back, head, and groin (Fig. 7-9A). Cobblestone papules are present on the oral mucosa. Warty papules are present acrally. Several variants have been described, including a hyperkeratotic form involving the intertriginous zones, a vesiculobullous form in which true clinical blisters may develop, and a linear pattern that likely represents an epidermal nevus with the histopathologic features of focal acantholytic dyskeratosis. The Darier disease gene has been localized to chromosome 12q23-q24.1. Mutations in the ATP2A2 gene that encodes the sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 are found in patient’s with the disease.35 This is one of the proteins that catalyses the transport of calcium from the cytosol into the lumen of the endoplasmic reticulum,36 and is a critical determinant in resulting in enhanced apoptosis. Not surprisingly therefore Bcl-2 expression is diminished in the lesional epidermis of patients

Table 7-8 Darier Disease

Clinical Features Scaly papules and plaques of the head, back, chest, and groin Autosomal dominant Histopathologic Features Acantholytic dyskeratosis with suprabasal split Corps ronds and corps grains Acanthosis and parakeratosis Direct immunofluorescence: nonspecific pattern of granular C3 at the epidermal basement membrane zone Differential Diagnosis Hailey-Hailey disease Transient acantholytic dermatosis (Grover disease) Pemphigus vulgaris

with Darier disease.37 Similar genetic defects have been discovered in patients with Hailey-Hailey disease, a point which will be alluded to presently. HISTOPATHOLOGIC FEATURES Darier disease is the prototype of focal acantholytic dyskeratosis38 (Fig. 7-9; see also Table 7-8). Over a broad zone within the epidermis there is an acantholytic suprabasal cleft, beneath which the basal cell layer is intact. The rete may be elongated, giving rise to so-called villi. Within the cleft (lacuna) are occasional acantholytic keratinocytes. Above the acantholytic cleft, the compact, enlarged keratinocytes of the stratum granulosum are surmounted by parakeratotic keratinocytes within the hyperkeratotic stratum corneum. Dyskeratosis may be apparent in the acantholytic cells or above or lateral to the acantholytic cleft. Large keratinocytes contain clumped keratohyalin granules in an eosinophilic cytoplasm and have large nuclei with perinuclear chromatin clumping and halos about prominent nucleoli. At the other end of the spectrum are small, seed-shaped cells with pyknotic, elongated nuclei and dense, eosinophilic, often elongated cytoplasm. The dyskeratotic acantholytic granular cells are referred to as corp ronds, and the dyskeratotic parakeratotic cells are referred to as corp grains. Intermediate forms may be observed. The focal acantholytic dyskeratosis occurs in the background of a papillary epidermal hyperplasia, with the dells between the papillae formed by keratotic debris. In other zones of papillary epidermal hyperplasia there may be small foci of ill-defined focal acantholytic dyskeratosis. Immunofluorescence studies do not detect any immunoreactants in Darier disease. Expectedly C3d and C4d studies conducted on paraffinembedded tissue are negative.9 DIFFERENTIAL DIAGNOSIS The principal conditions to be considered include transient acantholytic dermatosis (TAD; Grover disease), Hailey-Hailey disease, and on occasion, other acantholytic processes such as herpesvirus infection and pemphigus. TAD may be indistinguishable from Darier disease but usually shows additional histologic patterns resembling pemphigus, Hailey-Hailey disease, and spongiotic dermatitis (see below). Hailey-Hailey disease differs from Darier disease by demonstrating more diffuse or full-thickness acantholysis and less dyskeratosis. There is dyskeratosis, however it is very distinctive. Many of the cells

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

possibly C3 and (2) BMZ IgG, C3, and occasionally IgM (in both granular and linear patterns). Indirect immunofluorescence demonstrates intercellular IgG in all cases studied. When using rat bladder as substrate, the demonstration of an intercellular staining pattern is held to be diagnostic.

147

B

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

C  FIGURE 7-9 Darier disease. (A ) Brown papules with adherent scale show coalescence into a plaque involving the midline of the chest and upper abdomen. (B ) There is an epidermal invagination filled with ortho- and parakeratotic debris. A suprabasalar lacuna with dyskeratotic acantholytic cells is present. (C) At higher power, the typical large keratinocytes with perinuclear halos and clumped keratohyalin granules in eosinophilic cytoplasm (corps ronds) and the small seed-shaped cells with pyknotic nuclei and dense eosinophilic cytoplasm (corps grains) are noted.

throughout the spinous layer demonstrate perinuclear eosinophilic globules (ie, dyskeratosis), although without any alterations of the nucleus. In fact the nucleus may have a somewhat activated appearance with a finely dispersed chromatin and conspicuous nucleoli. Pemphigus shows more diffuse suprabasilar acantholysis with involvement of appendages, usually no dyskeratosis (except for pemphigus foliaceus), and positive immunofluorescence as compared with none in Darier disease. Herpesvirus is discriminated by clear-cut viral cytopathic changes, that is, multinucleate keratinocyte giant cells with molding of nuclei and “ground glass” chromatin. Perhaps one of the cardinal hallmarks that is rarely emphasized is the characteristic beading of the nuclear membrane, the sequelae of virions exiting the cells with segments of the nuclear membrane.

Hailey-Hailey Disease 148

Synonym: Familial benign pemphigus.

CLINICAL FEATURES This autosomal dominant genodermatosis presents in adolescence or adulthood with localized, recurrent vesicles arising on erythematous bases (Table 7-9). The vesicles often become eroded and develop scale crust. The plaques expand serpiginously, with healing or ensuing vegetation (Fig. 7-10A). Lesions are usually limited to the intertriginous areas, sides of the neck, and less commonly, the antecubital, perianal, and inframammary zones. Lesions may extend elsewhere and in rare cases become widespread. Maceration and fissuring may be prominent, particularly in intertriginous areas. The Hailey-Hailey disease gene has been mapped to chromosome 3q.39 Recent studies have shown mutations in the ATP2C1 gene that codes for a P-type Ca2+ transport ATPase is the cause of the disease.40 It is unclear how the gene products result in keratinocyte dyshesion but they may be involved in assembly of the desmosomes.36 Cell cultures of keratinocytes derived from patients with Hailey-Hailey disease will result in epi-

dermal monolayers associated with acantholysis. Friction or superinfection may augment the acantholysis. HISTOPATHOLOGIC FEATURES Full-thickness acantholysis of the stratum spinosum develops in a hyperplastic epidermis, resulting in an appearance resembling a “dilapidated brick wall” without a discrete suprabasal cleft (Fig. 7-10; see also Table 7-9). The acantholysis does not extend down follicles. Basal layer budding and villi are usually less prominent than those observed in Darier disease. Dyskeratosis is usually minimal. The roof of the blister consists of intact upper stratum spinosum or stratum granulosum. In the later lesions, the upper portion of the epidermis degenerates into a parakeratotic crust, above the residual acantholytic epidermis. In some cases a subacute to chronic eczematous dermatitis may be present. Immunofluorescence studies are also negative, as in Darier disease. DIFFERENTIAL DIAGNOSIS One must primarily consider pemphigus and Darier

Table 7-9 Hailey-Hailey Disease

(Fig. 7-11; Fig 7-11A see also Table 7-10): focal acantholytic dyskeratosis resembling Darier disease, full-thickness acantholysis mimicking Hailey-Hailey disease, small suprabasalar clefts as observed in pemphigus vulgaris, and a spongiotic dermatitis. Any or all of these histologic patterns may be present in an individual biopsy from an individual patient.43 The most common pattern is pemphigus

A

Table 7-10 Transient Acantholytic Dermatosis (Grover Disease) B  FIGURE 7-10 Hailey-Hailey disease. (A ) Erythematous vegetative and scaling plaque in axilla. (B ) There is extensive acantholysis of the stratum spinosum in a hyperplastic epidermis. The degree of acantholysis is much greater than that seen in Pemphigus vulgaris.

disease (see preceding discussions for the differential diagnosis for each respective condition).

Transient Acantholytic Dermatosis Synonym: Grover disease. CLINICAL FEATURES Also known as Grover disease, transient acantholytic dermatosis (TAD) is characterized by pruritic discrete papulovesicles on the chest, back, and thighs, usually in middle-

aged or elderly men (Table 7-10), often following sun exposure.41 The appellation transient is appropriate in some cases; however, in others, the process may persist for several years. The pathogenesis is unknown. Some recent work suggests an association with miliaria.42 In some studies a loss of desmosomal proteins has been reported. HISTOPATHOLOGIC FEATURES Any of four histologic patterns may be observed in small foci, often only several rete wide

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

Clinical Features Fragile flaccid blisters give rise to scale crust Intertriginous areas, neck, perianal, inframammary, and antecubital regions Autosomal dominant Histopathologic Fearures Acantholysis giving rise to dilapidated brick wall appearance in at least half of epidermis Acanthosis Often slight dyskeratosis Direct immunofluorescence: nonspecific pattern Differential Diagnosis Darier disease Transient acantholytic dermatosis (Grover disease) Pemphigus vulgaris

Clinical Features Pruritic papulovesicles on chest, back, and thighs Middle-aged or elderly men Histopathologic Features Acantholytic dyskeratosis in small foci Four histological patterns: Focal acantholytic dyskeratosis as in Darier disease Hailey-Hailey disease pattern Pemphigus vulgaris or foliaceus pattern Spongiotic dermatitis pattern Any or all four patterns may be present in a single biopsy Direct immunofluorescence: nonspecific pattern Differential Diagnosis Darier disease Hailey-Hailey disease Pemphigus vulgaris or foliaceus Spongiotic dermatitis

149

sites of the keratin 1 gene and keratin 10 gene complexes.44 It is thought that the abnormal keratins cannot form a normal cytoskeleton and result in the aggregated tonofilaments that have been observed on electron microscopic evaluation.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

B  FIGURE 7-11 (A ) Grover disease, Darier pattern.There are two well-developed foci of acantholytic dyskeratosis. In the dermis, a superficial perivascular lymphocytic infiltrate is present. Eosinophils may be seen in the infiltrate. (B ) Grover disease. The biopsy shows small foci of suprabasilar acantholytic dyskeratosis associated with an area of bandlike lymphocytic infiltration. Typically the foci of acantholysis are very small in this setting and there may be an accompanying prominent inflammatory cell infiltrate.

vulgaris-like, with Darier-like the second most common.43 DIFFERENTIAL DIAGNOSIS Because the four histologic patterns just described may occur in TAD, the differential diagnosis includes Darier disease, Hailey-Hailey disease, pemphigus, and a spongiotic dermatitis. TAD is distinguished from the latter entities based on the presence of two or more histologic patterns and their limitation to small foci, often only several rete wide. On occasion, these foci may be larger, rendering it difficult to make a specific diagnosis without clinical information.

also occur, including localized annular hyperkeratotic plaques and palmoplantar keratoderma. Recent studies have shown mutations on chromosomes 12 and 17, the respective

HISTOPATHOLOGIC FEATURES Beneath compact hyperorthokeratosis, there is striking keratinocytic cytoplasmic vacuolization extending from the granular layer to the suprabasal zone (Fig. 7-12). At the periphery of the vacuoles there is condensation of cytoplasmic elements, including markedly enlarged keratohyalin granules and dense eosinophilic granules that resemble trichohyalin. The irregularly shaped shrunken nuclei are preserved. The blisters occur in irregular fashion throughout the stratum malpighii due to coalescence of the vacuoles. The background epidermis exhibits irregular psoriasiform hyperplasia, but this feature may not be present in early lesions. It should be remembered that these exact histologic events can occur as a part of congenital ichthyosiform bullous erythroderma, as the principal histologic findings of epidermal nevi, and as incidental small foci within the epidermis, analogous to focal acantholytic dyskeratosis. DIFFERENTIAL DIAGNOSIS Although the clinical and histopathologic features are distinctive, one might consider verruca, a viral vesicle, or a spongiotic dermatitis as other diagnostic possibilities.

Friction Blisters CLINICAL FEATURES These blisters develop mainly on the soles and palms as a result of repetitive actions producing mechanical forces applied parallel to the cutaneous

CYTOLYTIC DERMATITIS

Epidermolytic Hyperkeratosis

150

CLINICAL FEATURES Epidermolytic hyperkeratosis is an autosomal dominantly inherited genodermatosis that presents at birth with widespread blistering followed by a generalized icthyosis (see Chap. 14). Other milder phenotypes

 FIGURE 7-12 Epidermolytic hyperkeratosis. Beneath diffuse hyperorthokeratosis there is vacuolization of the suprabasalar keratinocytes. The vacuolated keratinocytes have a characteristic appearance with large keratohyalin granules. Trichohyalin granules are often present as well.

Table 7-11 Friction Blister

Clinical Features Palms and soles most common sites affected History of mechanical injury at site affected Histopathologic Features Blister with intraepidermal cleavage Individual necrotic keratinocytes Hemorrhage is common Differential Diagnosis Epidermolysis bullosa simplex superficialis

HISTOPATHOLOGIC FEATURES The intraepidermal cleavage, a result of cytolysis of keratinocytes, may be present in the superficial or lower stratum spinosum46 (see Fig 7-13 and Table 7-11). There are individual necrotic keratinocytes with cytoplasmic strands of disrupted keratinocytes. Pale degenerated keratinocytes, which have been sheared, are located on the superior and inferior aspects of the blister.45-47 The blister fluid is usually clear due to transudation. When the shearing force extends into the dermis, hemorrhage into the blister cavity is common. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes epidermolysis bullosa simplex superficialis (see Chap. 14).

Thermal Burns First-degree burns are those in which the lower epidermis is intact and only the upper epidermis is necrotic. The nuclei appear pyknotic and the cytoplasm pale, giving the upper epidermis a mummified, ghostlike appearance. Extensive dermal edema leads to transudation of fluid above the intact lower superficial vessels and forming a purulent layer beneath the necrotic epidermis.48 Second- and thirddegree burns are not discussed because they do not give rise to intraepidermal blisters or pustules.

 FIGURE 7-13 Friction blister. In this biopsy from an acral site, there is intraepidermal cleavage in the stratum spinosum with a minimal inflammatory cell infiltrate.

VESICULOPUSTULAR DISEASES

Impetigo and Bullous Impetigo CLINICAL FEATURES In impetigo, red papules that transform into vesicles and pustules develop at sites where abrasions, insect bites, or excoriations disrupt the cutaneous barrier. Honey-colored crusts develop rapidly. Secondary, impetigo may develop in all varieties of eczematous dermatitis, particularly atopic eczema. Ordinary impetigo is caused by infection by group A streptococci.49 Bullous impetigo is almost entirely due to infections by S aureus, primarily phage group 2, type 71, which produces an epidermolysin identical to that implicated in staphococcal scalded skin syndrome. The exfoliatin targets desmoglein 3 resulting in a picture that closely resembles pemphigus foliaceus. In bullous impetigo, vesicles, bullae, and vesicopustules form on erythematous macules and plaques. HISTOPATHOLOGIC FEATURES In ordinary nonbullous impetigo, neutrophils migrate throughout the epidermis to form subcorneal pustules. The exocytosis of neutrophils as single cells and clusters into the hyperplastic and spongiotic epidermis resembles psoriasis. There is usually prominent edema in the upper

dermis and diapedesis of neutrophils from the superficial vessels. In contrast, bullous impetigo begins as a fluid-filled acantholytic blister in a subcorneal location. Few acantholytic keratinocytes are present, and neutrophils may be sparse. As the vesicopustule ages, it usually becomes filled with neutrophils (Figure 7-14 A,B). Otherwise, the features are similar to those of nonbullous impetigo, although the inflammatory infiltrate and reactive epidermal changes are usually less intense. Bacterial cocci, often few in number, may be noted within the stratum corneum, pustules, or vesicopustules and are best demonstrated by a tissue Gram stain (Figure 7-14 C,D). DIFFERENTIAL DIAGNOSIS The major entities to be considered include other infective processes such as dermatophytosis, Candida infection, syphilis, pemphigus foliaceus, IgA pemphigus, subcorneal pustular dermatosis, pustular psoriasis, pustular drug eruption, pustular bite reaction, pustular vasculitis, a neutrophilic dermatosis such as pyoderma gangrenosum, and a nutritional deficiency such as that due to zinc or an amino acid, resulting in an eruption such as migratory necrolytic erythema. Systematic evaluation with clinical history for evidence of

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

surface in normal individuals (Table 7-11). In the mechanobullous diseases, only minimal friction will produce blisters due to a lack of appropriate structural integrity of the epidermis and dermis. Friction blisters are caused by shearing forces within the epidermis. They tend to occur where the epidermis is thick and firmly attached to the underlying tissues.45

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A

B

C

D

 FIGURE 7-14 (A,B,C, and D). In this case of bullous impetigo there is a rather striking superficial acantholysis resulting in a picture that closely resembles pemphigus foliaceus. However a Gram stain shows numerous gram-positive cocci within the blister cavity.

psoriasis, drug ingestation, and so on; special stains and cultures for infective organisms; and immunofluorescence studies should facilitate making a specific diagnosis.

Candidiasis

152

CLINICAL FEATURES Red papules and plaques develop, most frequently in the intertriginous areas. Pustules may develop at the surface, often at the edges. Satellite pustules also may develop around the spreading plaque. Candida albicans is the most frequent infectious agent. It is a dimorphic fungus that produces both yeasts (2-5 μm) and pseudohyphae. Local disruption of the integrity of the upper epidermis, such as maceration and abrasion, facilitates infection. While other mechanisms are at play, mannin in the fungal cell walls fixes complement, which then leads to neutrophilic infiltration.

HISTOPATHOLOGIC FEATURES There is neutrophilic permeation of the parakeratotic stratum corneum.50 Beneath the stratum corneum, micropustules coalesce into larger pustules. Neutrophils, as single cells and small clusters, permeate the underlying stratum spinosum, which is spongiotic. The underlying dermis is edematous, with a perivascular and interstitial infiltrate composed principally of neutrophils. Although the yeasts and branching pseudohyphae, which are 2 to 5 μm in diameter, may be demonstrable on routine H&E stain, PAS stain is more reliable in revealing the organisms. It may be difficult to specifically identify the agent as C albicans, leading to the need for culture in selected cases. DIFFERENTIAL DIAGNOSIS See “Impetigo and Bullous Impetigo” above.

Pustular Secondary Lues CLINICAL FEATURES Approximately 3 to 6 weeks after the chancre, secondary lesions may develop. Macules and papules (mimicking pityriasis rosea) develop on the trunk, extremities, and palms and soles. Mucous patches are common. Pustules are usually a later development. Dissemination of Treponema pallidum to distant sites is the etiology. They are spiral bacteria that range from 7 to 15 μm in length and 0.25 μm in width. Intact spirochetes are demonstrated in histopathologic sections in up to 30% of secondary lesions using Warthin-Starry silver stain or Dieterle stain. HISTOPATHOLOGIC FEATURES Subcorneal pustules surmount a variably platelike acanthotic or psoriasiform epidermis. Numerous neutrophils transverse the stratum spinosum. In the dermis there is a

variable perivascular and lichenoid lymphohistiocytic infiltrate often rich in plasma cells. In fact, plasma cells are observed in up to 75% of these late-stage lesions. This is in contrast to early lesions of secondary syphilis, in which only a perivascular lymphohistiocytic infiltrate may be observed. The infiltration extends into the interstitium in some lesions with numerous macrophages. DIFFERENTIAL DIAGNOSIS See “Impetigo and Bullous Impetigo” above.

CLINICAL FEATURES Pustules and vesicopustules develop on erythematous skin (Table 7-12). The lesions may be annular or serpiginous and have a predilection for flexural surfaces as well as axillary and inguinal folds. Subcorneal pustular dermatosis may occur in association with IgA gammopathy, multiple myeloma, or other neutrophilic dermatoses. It also has been described in association with rheumatoid arthritis and inflammatory bowel disease.51-54 It is presumed that the neutrophils are responding to chemotactic factors present in the subcorneal zone, in particular tumor necrosis factor alpha, which has been identified in the blister fluid (Fig. 7-4). Those cases of subcorneal pustular dermatosis with squamous intercellular deposits of IgA are best classifed as IgA pemphigus.52

Table 7-12 Subcorneal Pustular Dermatosis (Sneddon-Wilkinson)

Clinical Features Pustules develop in erythematous skin Predilection for flexural skin, axillary and inguinal folds Histopathologic Features Subcorneal neutrophil-rich pustules Superficial and deep perivascular mononuclear cell infiltrates Direct immunofluorescence: negative Differential Diagnosis Impetigo Candida Dermatophytosis Staphylococcal scalded skin syndrome Psoriasis Keratoderma blenorrhagicum (Reiter disease) IgA pemphigus Pemphigus foliaceus Pustular drug eruption

 FIGURE 7-15 Subcorneal pustular dermatosis (Sneddon-Wilkinson disease). There is a florid subcorneal pustule containing neutrophils. This tense pustule is distinct from the flaccid pustule of bullous impetigo.

HISTOPATHOLOGIC FEATURES Subcorneal neutrophil-rich pustules and scale crust are present (Fig. 7-15 ; see also Table 7-13). The pustules tend to be tense rather than flaccid (see Fig. 7-4 ). In most cases the underlying edematous spongiotic stratum malphigii contains only few neutrophils, and eosinophils are absent or rare. Occasional acantholytic keratinocytes may be present at the lower edge of the pustule, primarily in older lesions. These changes surmount a psoriasiform epidermis with little change or, in older lesions, a psoriasiform eruption with exocytosis of lymphocytes as well. There is a superficial and deep perivascular infiltrate of lymphocytes and histiocytes that on occasion may give rise to a bandlike pattern. DIFFERENTIAL DIAGNOSIS See “IgA Pemphigus” and “Impetigo and Bullous Impetigo” above.

Table 7-13 Erythema Toxicum Neonatorum

Clinical Features Pustules and macules arise in the first few days of life Face, torso, and extremities Histopathologic Features Intraepidermal and subcorneal eosinophilic pustules in hair follicles Differential Diagnosis Scabies Incontinentia pigmenti Eosinophilic folliculitis

Pustular Drug Reaction CLINICAL FEATURES Drug-induced pustular eruptions have been reported infrequently. Drugs implicated include antibiotics (including streptomycin, cotrimoxazole, and oxytetracycline) and other drugs, including chloramphenicol, pyrimethamine, diltiazem, furosemide, and carbamazepine. Patients usually present 3 to 10 days after initiation of therapy with diffuse macular erythema and multiple non-follicular-based pustules. In addition, malaise, chills, and low-grade fever may be present. The term acute generalized exanthematous pustulosis describes a pustular drug reaction characterized by fever, leukocytoclasis, and a rapidly evolving pustular eruption on an erythematous base.55 The dermatitis rapidly resolves after withdrawal of the offending drug.

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

Subcorneal Pustular Dermatosis/ Sneddon-Wilkinson Disease

HISTOPATHOLOGIC FEATURES Foci of neutrophilic spongiosis with or without subcorneal or intraepidermal pustules are seen. The process may be based around the acrosyringium or follicle. There is underlying papillary dermal edema and a perivascular infiltrate usually containing eosinophils. DIFFERENTIAL DIAGNOSIS See “IgA Pemphigus” and “Impetigo and Bullous Impetigo” above. The differential diagnosis includes pustular psoriasis,56 Reiter disease, subcorneal pustular dermatosis, impetigo, pemphigus foliaceus, and a pustular id reaction. The presence of eosinophils excludes pustular psoriasis, Reiter disease, subcorneal pustular

153

dermatosis, and impetigo. In Reiter disease, vasculitis is usually present. In pustular psoriasis, a background of conventional psoriasis may or may not be present. Pemphigus foliaceus shows acantholysis. In difficult cases, immunofluorescence will help distinguish neutrophil-rich pemphigus foliaceus from a pustular drug reaction.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Infantile Acropustulosis CLINICAL FEATURES Recurrent crops of intensely pruritic vesicles or pustules develop most commonly in black infants at birth or during the first year of life.57,58 The lesions involve predominantly the distal extremities, particularly the palms and soles, dorsa of the hands and feet, and the sides of the fingers and toes. Individual lesions heal with hyperpigmentation, and the process resolves within 2 years in most cases. Some patients have a history of atopic dermatitis, and in several patients there has been associated scabetic infestation. The etiology is unknown. HISTOPATHOLOGIC FEATURES Early lesions reveal spongiosis and small foci of epidermal necrosis, apoptosis, and exocytosis of neutrophils and eosinophils. Later lesions reveal subcorneal and intraepidermal vesicopustules59,60 containing numerous neutrophils and admixed eosinophils (Fig. 7-16 ). A few cases have shown a predominance of eosinophils. There is minimal papillary dermal edema and a sparse mixed-cell perivascular infiltration. As in all intraepidermal pustular disorders, PAS stain and tissue Gram stain should be performed in order to exclude infection. DIFFERENTIAL DIAGNOSIS See “IgA Pemphigus” and “Impetigo and Bullous Impetigo” above.

Transient Neonatal Pustular Melanosis CLINICAL FEATURES Flaccid vesicopustules on the trunk and diaper area are present at birth.61 The vesicopustules rupture after 1 to 2 days, leaving hyperpigmented macules with collarettes of scale. The pathogenesis is unknown.

154

HISTOPATHOLOGIC FEATURES Vesicopustules in the intracorneal or subcorneal zones contain neutrophils with an admixture of eosinophils. There is slight spongiosis. The papillary dermis is edematous with an infiltrate of neutrophils and eosinophils around superficial vessels. Later lesions consist only of basal hypermelanosis.

 FIGURE 7-16 Infantile acropusulosis. There is a vesicopustule involving the follicular epithelium. The vesicle is composed of neutrophils admixed with eosinophils.

DIFFERENTIAL DIAGNOSIS See “Impetigo and Bullous Impetigo” above. Some have suggested that erythema toxicum neonatorum and neonatal pustular melanosis are related disorders.

Erythema Toxicum Neonatorum CLINICAL FEATURES Erythema toxicum neonatorum is characterized by pustules that develop on macules, papules, or wheals distributed on the face, torso, and proximal extremities (Table 7-13). The pustules arise within the first 2 days of life, being occasionally present at birth. On occasion, vesicles precede the development of the pustules. The pathogenesis is unknown. HISTOPATHOLOGIC FEATURES In macular lesions, a sparse perivascular infiltrate is associated with mild papillary dermal edema. The papules reveal numerous eosinophils and some neutrophils in the outer root sheath of hair follicles, giving rise to eosinophilic pustules overlying follicular orifice (see Table 7-13). Intraepidermal subcorneal pustules consisting predominantly of eosinophils are also present.62 DIFFERENTIAL DIAGNOSIS See “Neonatal Pustular Melanosis” above. One also might consider eosinophilic pustular folliculitis/ pustulosis in the differential diagnosis.

REFERENCES 1. Younus J, Ahmed AR. The relationship of pemphigus to neoplasia. J Am Acad Dermatol. 1990;23:498.

2. Korman N. Pemphigus. J Am Acad Dermatol. 1988;18:1219. 3. Korman NJ. Pemphigus. Dermatol Clin. 1990;8:689. 4. Stanley JR, Koulu L, Thivolet C. Pemphigus vulgaris and pemphigus foliaceus autoantibodies bind different molecules (abstract). J Invest Dermatol. 1984; 82:439. 5. Thivolet J. Pemphigus: past, present and future. Dermatology. 1994;189(suppl 2):26. 6. Devries DT, Warren SJ. Recent advances in intraepidermal blistering diseases. Adv Dermatol. 2002;18:203. 7. Sitaru C, Mihai S, Zillikens D. The relevance of the IgG subclass of autoantibodies for blister induction in autoimmune bullous skin diseases. Arch Dermatol Res. 2007 April;299(1):1-8. 8. Korman NJ, Eyre RW, Zone J, et al. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus. J Invest Dermatol. 1991;96:273. 9. Magro C, Dyrsen M. The Use of C3d and C4d as a diagnostic adjunct in the evaluation of inflammatory skin disease Journal of the American Academy of Dermatology. In press 10. Crosby DL, Diaz LA. Endemic pemphigus foliaceus. Fogo selvagem. Dermatol Clin. 1993;11:453. 11. Warren SJ, Lin MS, Giudice GJ, et al. The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research. N Engl J Med. 2000;343:23. 12. Koulu L, Kusumi A, Steinberg MS, et al. Human autoantibodies against a desmosomal core protein in pemphigus foliaceus. J Exp Med. 1984;160:1509. 13. Emerson RW, Wilson Jones E. Eosinophilic spongiosis in pemphigus. Arch Dermatol. 1968;97:252. 14. Jablonska S, Chorzelski TP, Beutner EH, et al. Herpetiform pemphigus, a variable pattern of pemphigus. Int J Dermatol. 1975;14:353.

31. 32. 33.

34. 35.

36.

37.

38. 39.

40.

41. 42.

43. 44.

contain autoantibodies to periplakin. Br J Dermatol. 2006;155:337-343. Cozzani E, Dal Bello MG, Mastrogiacomo A. Antidesmoplain antibodies in pemphigus vulgaris. Br J Dermatol. 2006;154:634-638. Resnick SD. Staphylococcal toxin-mediated syndromes in childhood. Semin Dermatol. 1992;11:11. Florman AL, Holzman RS. Nosocomial scalded skin syndrome. Ritter’s disease caused by phage group 3 Staphylococcus aureus. Am J Dis Child. 1980;134:1043. Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27:40. Sakuntabhai A, Ruiz-Perez V, Carter S, et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet. 1999;21:271,. Dhitavat J, Fairclough RJ, Hovnanian A, et al. Calcium pumps and keratinocytes: lessons from Darier’s disease and HaileyHailey disease. Br J Dermatol. 2004;150:821. Pasmatzi E, Badavanis G, Monastiri LA, Tsambaos D. Reduced expression of the antiapoptotic proteins of the BCL-2 genfamily in the lesional epidermis of patients with Darier’s disease. J Cutan Pathol. 2007;34:234-238. Pani B, Singh BB. Darier’s disease: a calcium-signaling perspective. Cell Mol Life Sci. 2008;65:205. Ikeda S, Welsh EA, Peluso AM, et al. Localization of the gene whose mutations underlie Hailey-Hailey disease to chromosome 3q. Hum Mol Genet. 1994;3:1147. Dobson-Stone C, Fairclough R, Dunne E, et al. Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene. J Invest Dermatol. 2002;118:338. Grover RW. Transient acantholytic dermatosis. Arch Dermatol. 1970;101:426. Hu CH, Michel B, Farber EM. Transient acantholytic dermatosis (Grover’s disease). A skin disorder related to heat and sweating. Arch Dermatol. 1985; 121:1439. Davis MD, Dinneen AM, Landa N, et al. Grover’s disease: clinicopathologic review of 72 cases. Mayo Clin Proc. 1999;74:229. Syder AJ, Yu QC, Paller AS, et al. Genetic mutations in the K1 and K10 genes of patients with epidermolytic hyperkeratosis. Correlation between location and disease severity. J Clin Invest. 1994;93:1533.

45. Sulzberger MB, Cortese TA, Fishman L, et al. Studies on blisters produced by friction. I. Results of linear rubbing and twisting technics. J Invest Dermatol. 1966; 47:456. 46. Naylor PF. Experimental friction blisters. Br J Dermatol. 1955;67:327. 47. Brehmer-Andersson E, Goransson K. Friction blisters as a manifestation of pathomimia. Acta Derm Venereol. 1975;55:65. 48. Sevitt S. Histological changes in burned skin. In: Sevitt S (eds.) Burns: Pathology and Therapeutic Application. London: Butterworth & Co; 1957:18. 49. Dajani AS, Ferrieri P, Wannamaker LW. Natural history of impetigo. II. Etiologic agents and bacterial interactions. J Clin Invest. 1972;51:2863. 50. Lever W, Schaumburg-Lever G. Histopathology of the Skin. 7th ed. Philadelphia, PA: Lippincott: 1990:368. 51. Burns RE, Fine G. Subcorneal pustular dermatosis. AMA Arch Derm. 1959;80:72. 52. Cheng S, Edmonds E, Ben-Gashir M, et al. Subcorneal pustular dermatosis: 50 years on. Clin Exp Dermatol. 2008;33:229. 53. Dal Tio R, Di Vito F, Salvi F. Subcorneal pustular dermatosis and IgA myeloma. Dermatologica. 1985;170:240. 54. Wilkinson DS. Subcorneal pustular dematosis. Bull Soc Fr Dermatol Syphiligr. 1962;69:674. 55. Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113. 56. Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drug exposure: is it pustular psoriasis or a pustular drug eruption? Br J Dermatol. 1994;130:514. 57. Jarratt M, Ramsdell W. Infantile acropustulosis. Arch Dermatol. 1979;115:834. 58. Newton JA, Salisbury J, Marsden A, et al. Acropustulosis of infancy. Br J Dermatol. 1986;115:735. 59. Bundino S, Zina AM, Ubertalli S. Infantile acropustulosis. Dermatologica. 1982; 165:615. 60. Palungwachira P. Infantile acropustulosis. Australas J Dermatol. 1989;30:97. 61. Ramamurthy RS, Reveri M, Esterly NB, et al. Transient neonatal pustular melanosis. J Pediatr. 1976;88:831. 62. Freeman RG, Spiller R, Knox JM. Histopathology of erythema toxicum neonatorum. Arch Dermatol. 1960;82:586.

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

15. Perry HO. Pemphigus foliaceus. Arch Dermatol. 1961;83:52. 16. Pisani M, Ruocco V. Drug-induced pemphigus. Clin Dermatol. 1986;4:118. 17. Ruocco V, Sacerdoti G. Pemphigus and bullous pemphigoid due to drugs. Int J Dermatol. 1991;30:307. 18. Ebihara T, Hashimoto T, Iwatsuki K, et al. Autoantigens for IgA anti-intercellular antibodies of intercellular IgA vesiculopustular dermatosis. J Invest Dermatol. 1991;97:742. 19. Hashimoto T, Yasumoto S, Nagata Y, et al. Clinical, histopathological and immunological distinction in two cases of IgA pemphigus. Clin Exp Dermatol. 2002;27:636. 20. Robinson ND, Hashimoto T, Amagai M, et al. The new pemphigus variants. J Am Acad Dermatol. 1999;40:649. 21. Hodak E, David M, Ingber A, et al. The clinical and histopathological spectrum of IgA-pemphigus—report of two cases. Clin Exp Dermatol. 1990;15:433. 22. Teraki Y, Amagai N, Hashimoto T, et al. Intercellular IgA dermatosis of childhood. Selective deposition of monomer IgA1 in the intercellular space of the epidermis. Arch Dermatol. 1991;127:221. 23. Neumann E, Dmochowski M, Bowszyc J, et al. The occurrence of IgA pemphigus foliaceus without neutrophilic infiltration. Clin Exp Dermatol. 1994;19:56. 24. Anhalt GJ, Kim SC, Stanley JR, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med. 1990; 323:1729. 25. Mutasim DF, Pelc NJ, Anhalt GJ. Paraneoplastic pemphigus. Dermatol Clin. 1993;11:473. 26. Ostezan LB, Fabre VC, Caughman SW, et al. Paraneoplastic pemphigus in the absence of a known neoplasm. J Am Acad Dermatol. 1995;33:312. 27. Camisa C, Helm TN, Valenzuela R, et al. Paraneoplastic pemphigus: Three new cases (abstract). J Invest Dermatol. 1992;98:590. 28. Horn TD, Anhalt GJ. Histologic features of paraneoplastic pemphigus. Arch Dermatol. 1992;128:1091. 29. Stevens SR, Griffiths CE, Anhalt GJ, et al. Paraneoplastic pemphigus presenting as a lichen planus pemphigoides-like eruption. Arch Dermatol. 1993;129:866. 30. Park GT, Quan G, Lee JB. Sera from patients with toxic epidermal necrolysis

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CHAPTER 8 Subepidermal Blistering Diseases

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Mosaad Megahed Akmal Saad Hassan

The epidermis binds to the dermis through the basement membrane (BM) zone which is a complex network of interconnecting proteins located at the dermo-epidermal junction (DEJ).1,2 Perturbing the functions of these proteins, for example due to mutation3 or circulating autoantibodies,4 leads to loss of tissue adhesion at the DEJ causing subepidermal blistering diseases. These diseases can be classified into three main groups (Fig. 8-1). These are as follows: I. Autoimmune subepidermal blistering diseases

The cutaneous BM zone is located between the epidermis and the dermis and was originally defined as a 0.5- to 1.0μm-thick, bandlike structure that is positively stained by periodic acid-Schiff (PAS).5 Subsequently, ultrastructural, biochemical, and molecular biological studies have shown that this zone is an extraordinarily complex network of interconnecting proteins that provide integrity and mechanical stability to the skin.1,2 They are also involved in signal transduction and many other important functions. Ultrastructurally the cutaneous BM zone consists of three regions6,7(Fig. 8-2). 1. Hemidesmomes into which the keratin intermediate filaments (KIF) insert 2. Lamina lucida, an electron-lucent region, which is traversed by anchoring filaments 3. Lamina densa, an electron-dense area from which anchoring fibrils extend into the papillary dermis

1. Bullous pemphigoid

Hemidesmosomes

2. Herpes gestationis

Hemidesmosomes (HDs) appear as electron-dense condensations of less than 50 nm that reside at intervals on the plasma membrane of the basal keratinocyte (Fig.8-2). They are highly complicated adhesion structures that are implicated in signal transduction, influencing cytoskeletal architecture, cell differentiation, and cell growth.8-10 Hemidesmosomal proteins known to play a role in subepidermal blistering diseases are: bullous pemphigoid antigen 1,11,4,12 plectin,13,14 bullous pemphigoid antigen 2,15,16 and α6β4 integrin.17,18

3. Lichen planus pemphigoidis 4. Cicatricial pemphigoid 5. Dermatitis herpetiformis 6. Linear IgA disease (LAD) 7. Epidermolysis bullosa acquisita (EBA) 8. Bullous systemic lupus erythematosus II. Subepidermal blistering diseases due to mutations of proteins of the BM zone 1. Junctional epidermolysis bullosa 2. Dystrophic epidermolysis bullosa 3. Kindler syndrome III. Miscellaneous subepidermal blistering diseases 1. Toxic epidermal necrolysis (TEN) 2. Porphyria cutanea tarda (PCT) 3. Pseudoporphyria 4. Coma blister 5. Bullosis diabeticorum

156

ULTRASTRUCTURE AND MOLECULAR ANATOMY OF THE CUTANEOUS BM ZONE

To be able to comprehend subepidermal blistering diseases, their histopathology, and diagnostics we need first to understand the ultrastructure and the protein constituents of the BM zone. Therefore, the latter will be discussed first in this chapter followed by the histopathology.

Bullous Pemphigoid Antigen 1 Bullous pemphigoid antigen 1 (BPAG1) is a 230-kDa glycoprotein19 that represents the major antigenic determinant of bullous pemphigoid, with greater than 90% of patients having circulating autoantibodies targeting the protein.19,20 BPAG1 represents also one of the target autoantigens of paraneoplastic pemphigus21 and cicatricial pemphigoid,22 and is reportedly the autoantigen in some cases of lichen planus pemphigoides (LPP)23 and herpes gestationis.24

Plectin Plectin is a 300-kDa protein. The plectin gene is mutated in patients suffering from

the recessive form of epidermolysis bullosa simplex associated with muscle dystrophy,14,25,26 a disease characterized by skin blistering and late-onset progressive muscle dystrophy. Circulating autoantibodies against plectin occur in patients with bullous pemphigoid27,28 and paraneoplastic pemphigus.29

Bullous Pemphigoid Antigen 2 Bullous pemphigoid antigen 2 (BPAG2, COL17A1) is a transmembrane glycoprotein of 180 kDa. BPAG2 is mutated in patients with junctional epidermolysis bullosa.30 BPAG2 also serves as autoantigen for immunobullous skin diseases, such that about 50% of bullous pemphigoid sera and most sera from patients with herpes gestationis and lichen planus pemphigoides react with it.20,31,32,33,34 BPAG2 is also one of the autoantigens of cicatricial pemphigoid.35

α6β4 Integrin α6β4 Integrin is a transmembrane hemidesmosomal protein serving as an autoantigen in ocular and oral cicatricial pemphigoid.36,37 Furthermore, it is mutated in junctional epidermolysis bullosa with pyloric atresia,38,39 a disease characterized by intra-lamina lucida skin blistering and congenital pyloric atresia.40

Lamina Lucida and Anchoring Filaments Lamina lucida (LL) is an electron-lucent zone situated between the plasma membrane of the basal keratinocyte and the lamina densa6,7 (Fig. 8-2). In the areas beneath HDs, the LL is traversed by fine threadlike structures called anchoring filaments. Anchoring filaments are composed mainly of laminin 5.41,42-45

Laminin 5 Laminin 5 consists of the chains α3,46 β3,47 and γ2,48 which assemble into a cross-like structure. Laminin 5, which serves as target autoantigen in a subset of patients with cicatricial pemphigoid26 is mutated in patients with junctional epidermolysis bullosa.3,49

Lamina Densa and Anchoring Fibrils The lamina densa (LD) is a continuous electron-dense layer that runs parallel to the plasma membrane of basal

Site of blister

Intraepidermal (Chap.7)

Minimally inflammatory

Subepidermal

Lymphocytes predominate

Epidermal necrosis

Necrotic keratinocytes

No necrotic keratinocytes

Epidermolysis bullosa acquista Epidermolysis bullosa Bullosis diabeticorum Pseudoporphyria Porphyria cutanea tarda Bullous pemphigoid (cell poor)

Toxic epidermal necrolysis Thermal injury

Lichen planus pemphigoides Fixed drug eruption Erythema multiforme

Polymorphous light eruption Lichen sclerosus et atrophicus

Neutrophils predominate

Bullous drug reaction Arthropod bite reaction Herpes gestationis Bullous pemphigoid

Epidermolysis bullosa acquisita Sweet syndrome Bullous lupus erythematosus Bullous vasculitis Cicatricial pemphigoid Linear IgA bullous dermatosis Dermatitis herpetiformis

 FIGURE 8-1 Subepidermal blistering diseases algorithm.

keratinocytes (Fig. 8-2). It consists mainly of type IV collagen.50,51 Antibodies to type IV collagen can therefore be used to define the LD. This helps to localize

the site of blister formation in subepidermal blistering diseases, providing a useful diagnostic tool for the differentiation of those diseases.

Anchoring fibrils are cross-banded fibrillar structures that are mainly composed of type VII collagen and extend from the lamina densa into the papillary dermis, where they loop back into the lamina densa or insert into anchoring plaques.52,53 Anchoring plaques are small electron-dense islands present in the papillary dermis and composed mainly of type IV collagen.

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

No epidermal necrosis

Eosinophils predominate

Type VII Collagen Type VII collagen is a 290-kDa protein of three α1(VII) chains.54 It is the autoantigen in epidermolysis bullosa acquisita,55,56 bullous systemic lupus erythematosus,57 and a subset of linear IgA bullous disease.58 Mutations in type VII collagen gene have been identified in patients with dystrophic epidermolysis bullosa.59,60 Figure 8-3 displays a simplified diagrammatic presentation of the proteins of the cutaneous BM zone.

HISTOPATHOLOGY OF SUBEPIDERMAL BLISTERING DISEASES

 FIGURE 8-2 Ultrastructure of the BMZ of the skin. AF = anchoring filaments, Afb = anchoring fibrils, C = collagen fibers, Pd = papillary dermis, HD = hemidesmosome, LL = lamina lucida, LD = lamina densa, Pm = plasma membrane of basal keratinocyte, Ap = anchoring plaque.

Autoimmune Subepidermal Blistering Diseases BULLOUS PEMPHIGOID Bullous pemphigoid (BP) is an acquired autoimmune subepidermal blistering disease characterized

157

Keratin intermediate filaments

Plectin

Pm

BPAG1

Hemidesmosome

BPAG2

Lamina lucida

α6β4 integrin

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Laminin 5

158

Laminadensa (Type IV collagen) Anchoring fibrils (Type VII collagen) Anchoring plaque (Type IV collagen)

 FIGURE 8-3 Diagrammatic presentation of the protein constituents of the BMZ of the skin. Pm = plasma membrane of the basal keratinocyte.

by in vivo deposition of IgG autoantibodies along the cutaneous basement membrane zone.61-63 BP is considered the most common autoimmune blistering disease, with a reported incidence of 10 cases per 1 million population.63 It affects mainly elderly people61-63 but can also occur in any age, including infants6 and children.64 No ethnic or gender predominance has been found.61 Patients with BP have circulating IgG autoantibodies against BPAG113,17 and BPAG2.29,65 BPAG1 is considered the major antigenic determinant of BP, such that greater than 90% of sera from BP patients immunoprecipitate it. About 50% of bullous pemphigoid sera react with BPAG2. CLINICAL FEATURES BP is clinically characterized by large serous or hemorrhagic, tense blisters that arise on normal or erythematous skin (Table 8-1) (Fig. 8-4 A).66 The sites of predilection are the inner and anterior thighs, groin, flexor surfaces of the upper extremities, and lower abdomen.61,62 Any skin region may, however, be involved. Erosions and crusts as a consequence of the blisters’ rupture are usually present,61 and the lesions characteristically heal without scar formation. In the early stage of the disease, there are urticarial papules and plaques.61,62 Occasionally, pruritus is present and may range from mild to severe.67

Table 8-1 Bullous Pemphigoid

Clinical Features Usually elderly patients Tense blisters on erythematous base Blisters remain intact Predilection for extremities Mucosal surfaces can be involved Histopathologic Features Subepidermal blister Scarce or moderate to dense infiltrate of lymphocytes, eosinophils, and/or neutrophils, or perivascular and interstitial infiltrate of lymphocytes, eosinophils, and sometimes neutrophils No necrosis of overlying epidermis Laboratory Evaluation Blister mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination Perilesional intact human skin: Linear deposits of IgG and C3 along the BM zone Perilesional salt-split skin: IgG deposits, along the epidermal, dermal, or both sides of the split IIF examination Linear deposits of IgG along the BM zone in most cases ELISA test Circulating IgG antibodies to BPAG1 and/or BPAG2

Western blot Circulating IgG antibodies to 180- and/or 230-kDa protein bands Differential Diagnosis Cell-poor bullous pemphigoid Classical epidermolysis bullosa acquisita Toxic epidermal necrolysis Junctional epidermolysis bullosa Dystrophic epidermolysis bullosa Porphyria cutanea tarda Pseudoporphyria Cell-rich bullous pemphigoid with numerous eosinophils Inflammatory epidermolysis bullosa acquisita Linear IgA disease Herpes gestationis Cicatricial pemphigoid Bullous drug eruption Cell-rich bullous pemphigoid with numerous neutrophils Inflammatory epidermolysis bullosa acquisita Linear IgA disease Dermatitis herpetiformis Bullous systemic lupus erythematosus Bullous pemphigoid, urticarial stage Urticarial stage of intraepidermal autoimmune bullous disease Urticarial stage of inflammatory EBA Linear IgA disease Herpes gestationis Drug reaction Insect bite

HISTOPATHOLOGICAL FEATURES A fully developed lesion of BP is characterized histopathologically by formation of a subepidermal blister66 (Table 8-1). The blisters are usually accompanied by moderate to dense infiltrates of lymphocytes, numerous eosinophils, and a few neutrophils (cell rich BP) (Fig. 8-4B). Occasionally, the accompanying infiltrate is very sparse (cell poor BP) (Fig. 8-5). Plasma, fibrin, and inflammatory cells, for example, lymphocytes, eosinophils, and sometimes neutrophils, are usually present within the blister. The epidermis above the blister is flattened along its base and may be necrotic. In cell-rich BP, the infiltrate is usually present at the base and at the sides of the blister (Fig. 8-4). Sometimes the infiltrate extends to the deep dermis. In some cases of cell-rich BP, neutrophils may dominate in the infiltrate and can be located along the dermoepidermal junction, which usually shows vacuolar degeneration. The neutrophils may also collect in the dermal papillae resulting in papillary neutrophilic abscesses

B

 FIGURE 8-4 Bullous pemphigoid. (A) Tense bullae are characteristically present on erythematous skin. (B) Histopathology of cell-rich bullous pemphigoid, showing a subepidermal blister containing fibrin and inflammatory cells. At the sides and base of the blister, there is a lymphocytic infiltrate with numerous eosinophils and some neutrophils.

similar to those seen in dermatitis herpetiformis. Early urticarial lesions of BP are characterized by a superficial perivascular and interstitial infiltrate of lymphocytes, numerous eosinophils, and variable

neutrophils (Fig. 8-6). Eosinophils and neutrophils may be observed in the epidermis and at the dermo-epidermal junction, which usually shows vacuolar degeneration. Eosinophilic or neutrophilic

spongiosis, or a combination of both, also may be present. On immunomapping using antibodies to type IV collagen, the blister in BP is located within the lamina lucida (Fig. 8-7). OTHER DIAGNOSTIC TESTS Direct immunofluorescence (DIF) on clinically normalappearing, perilesional skin shows, in almost all cases of BP,62 linear deposits of IgG along the BM zone (Fig. 8-8). With salt-split, clinically normal-appearing, perilesional skin, the deposits of IgG usually reside along the epidermal side of the split66,68 (Fig. 8-9). However, the IgG deposits may be also detected on the dermal side or even on the dermal and epidermal sides of the split.66,68 Indirect immunofluorescence (IIF) examination with patients’ sera applied to normal human skin as substrate demonstrates circulating IgG antibodies to proteins of the BM zone in 65% to 80% of the cases with active disease.67 By Western blot and ELISA, the antibodies recognize BPAG1 and/or BPAG2.20,31

 FIGURE 8-5 Histopathology of cell-poor bullous pemphigoid, displaying a subepidermal blister containing fibrin and inflammatory cells. In the dermis, there is a sparse lymphocytic infiltrate with few eosinophils and neutrophils.

DIFFERENTIAL DIAGNOSIS Epidermolysis bullosa acquisita may be indistinguishable from bullous pemphigoid on clinical and histologic grounds and on routine direct immunofluorescence (Table 8-1).66 In the routine laboratory setting, the differential diagnosis hinges on direct immunofluorescence studies performed on salt spit skin. IgG is deposited on the

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 FIGURE 8-6 Urticarial lesion of bullous pemphigoid showing perivascular and interstitial lymphocytic infiltrates with numerous eosinophils. Eosinophils are aligned along the basement membrane zone, accompanied by vacuolar degeneration.

floor of the blister in epidermolysis bullosa acquisita and localizes almost exclusively to the roof of the blister in bullous pemphigoid. The more specialized techniques that differentiate between the two entities, such as immunoblotting, immunoprecipitation, and immunoelectron microscopy are limited to few facilities. The histopathologic alterations and direct immunofluorescence findings in cicatricial pemphigoid are the same as those seen in bullous pemphigoid. Clinical features usually differentiate the two diseases. The usual variant of cicatricial pemphigoid affects almost exclusively the mucous membranes as opposed to

bullous pemphigoid that mainly involves the skin. Direct immunofluorescence performed on salt-split skin is of little help as cicatricial pemphigoid is a heterogeneous disease on the molecular level and the majority of antigens targeted by the autoantibody localize to the roof of the blister as in bullous pemphigoid. The histologic differential diagnosis also includes herpes gestationis. This entity is best distinguished by the clinical presentation. Direct immunofluorescence may be of some help: C3 is deposited in a linear fashion along the dermalepidermal junction in nearly 100% of

 FIGURE 8-7 Epitope mapping (using antibodies against type IV collagen) in a bullous lesion of bullous pemphigoid. The blister is located in the lamina lucida region.

cases of herpes gestationis and bullous pemphigoid. IgG, in contrast, can be seen in 60% to 80% of cases of bullous pemphigoid but only in 30% to 50% of patients with herpes gestations. On histology, the presence of necrotic basal keratinocytes may also favor a diagnosis of herpes gestationis over bullous pemphigoid. Occasional cases of dermatitis herpetiformis and linear IgA dermatosis may have increased numbers of eosinophils. Conversely, occasional cases of bullous pemphigoid may display increased numbers of neutrophils. In these situations, direct immunofluorescence is probably the easiest way to distinguish these entities. Other conditions which may give rise to a subepidermal blister with abundant eosinophils include bullous arthropod bite reaction and bullous drug eruption. Bullous arthropod bite reactions tend to have an inflammatory infiltrate which is more intense, extends deeper into the reticular dermis and subcutaneous fat, and may have eosinophils individually dispersed between collagen bundles. Bullous drug eruptions may also have a deeper infiltrate, but can be histologically indistinguishable from bullous pemphigoid. Bullous arthropod bite reactions and bullous drug eruptions will be negative, or demonstrate only nonspecific features of vascular leakage on direct immunofluorescence examination. Lesions of cell-poor bullous pemphigoid must be distinguished from each of the entities described as subepidermal blisters with minimal inflammation. These distinctions are best made on the basis of clinical and immunologic methods.

 FIGURE 8-8 DIF on perilesional clinically normal-appearing skin from a patient with bullous pemphigoid. There are linear IgG deposits along the basement membrane zone.

Cell-rich bullous pemphigoid with numerous eosinophils Inflammatory epidermolysis bullosa acquisita Linear IgA disease Cicatricial pemphigoid Bullous drug reaction Bullous arthropod bite reaction Urticarial lesion of herpes gestationis Urticarial stage of intraepidermal autoimmune bullous diseases Urticarial stage of inflammatory EBA, linear IgA disease, BP Pruritic urticarial papules and plaques of pregnancy Drug reaction Arthropod bite reaction

Herpes Gestationis (Pemphigoid Gestationis) Herpes gestationis (HG) is an acquired, autoimmune, subepidermal blistering disease that develops in association with pregnancy. It is estimated to occur in 1 of 3000 to 1 of 10000 pregnancies70 and usually begins in the second or third trimester. However, it may occur at any time during pregnancy70-74 or even in the postpartum period. In rare cases HG may develop with the trophoblastic tumours, hydratiform mole, and chorioncarcinoma. CLINICAL FEATURES HG presents as severe pruritic, erythematous, urticarial papules and plaques (Table 8-2).66,70-75 Occasionally, blisters develop and are usually arranged in a herpetiform pattern. Lesions of HG usually begin on the abdomen, with a predilection for the periumbilical region. As the disease evolves, the blisters spread peripherally and may become generalized. The lesions resolve within weeks or months and subside at the end of pregnancy; however, many patients may experience exacerbation of skin lesions immediately or shortly after delivery. Recurrence of HG may occur with resumption of menstruation, on administration of oral contraceptives, or within subsequent pregnancies. HISTOPATHOLOGICAL FEATURES The histopathology of HG is similar to that of cellrich BP66 and shows subepidermal blisters with infiltration of lymphocytes, numerous eosinophils, and a few neutrophils (Table 8-2). The blister usually contains plasma, fibrin, and inflammatory

Table 8-2 Herpes Gestationis

Clinical Features Uncommon Usually in second or third trimesters of pregnancy Recurs with subsequent pregnancies Most lesions on trunk and extremities Newborn may have blisters Mucosal lesions uncommon Histopathologic Features Subepidermal blister with sparce or moderate to dense infiltrate of lymphocytes, eosinophils, and/or neutrophils or Perivascular and interstitial infiltrate of lymphocytes, eosinophils, and sometimes neutrophils Papillary dermal edema Rare necrotic keratinocytes Laboratory Evaluation Blister mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination Perilesional intact human skin: Linear deposits of C3, IgG along the BM zone Perilesional salt-split skin: C3, IgG deposits on the epidermal sides of the split Complement fixation assay Detection of HG factor ELISA test Circulating IgG antibodies to BPAG1 or BPAG2 Western blot Circulating IgG antibodies to 180- or 230-kDa protein bands Differential Diagnosis Blistering lesion of herpes gestationis

cells (lymphocytes, eosinophils, and sometimes also neutrophils). Urticarial lesions of HG are also histopathologically similar to those of BP. On immunomapping with antibodies to type IV collagen, the blister in HG is located within the lamina lucida. OTHER DIAGNOSTIC TESTS DIF with perilesional, clinically normal-appearing skin shows deposits of C3 (in 100% of the cases) and IgG (in 27% of the cases) along the BM zone.76 Patients with HG have circulating antibodies mainly directed against BPAG2 and, in rare cases, against BPAG1.24,33,77,78 These circulating autoantibodies can be detected by IIF testing in about 21% of the patients with normal human skin as a substrate.76 The circulating IgG antibodies in HG are of IgG1 and IgG3 classes and have the ability to fix normal human complement to the BM zone of normal human skin.79,80 These circulating IgG antibodies are called HG factor and can be detected by the complement fixation assay.73,79,80 Complement fixation assay is more sensitive than conventional IIF and is performed by incubating the test serum with normal human skin, followed by normal human complement, and then a fluorescein-conjugated antibody specific for the complement.80 By complement fixation assay, circulating IgG antibodies are detected in 91% of HG patients.76 The circulating IgG antibodies in HG can also be detected by ELISA using recombinant proteins of BPAG1 and BPAG2.78,82 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis includes bullous pemphigoid, bullous arthropod bite, bullous drug eruption, and pruritic urticarial

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

 FIGURE 8-9 DIF using salt-split, perilesional, clinically normal-appearing skin from a patient with bullous pemphigoid. There are linear IgG deposits along the epidermal side of the split.

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papules and plaques of pregnancy (Table 8-2). On histologic sections, the presence of individually necrotic keratinocytes would favor herpes gestationis over bullous pemphigoid, but in most cases these two entities can most easily be distinguished by the clinical setting as well as differences in immunologic findings. Bullous arthropod bite reactions usually have a more dense infiltrate which extends deeper into the dermis. Direct immunofluorescence examinations are invariably negative for immune complexes in arthropod bite reactions and bullous drug eruptions. Subepidermal blisters are not seen in pruritic urticarial papules and plaques of pregnancy, but in some cases of pemphigoid gestationis, eosinophilic spongiosis without fully formed blisters may be present. In these cases, the histologic features of these two entities may be identical. The clinical features are most often different, and pruritic urticarial papules and plaques of pregnancy are always negative on direct immunofluorescence examination.

Lichen Planus Pemphigoides LPP is a rare, acquired, autoimmune subepidermal blistering disease characterized by the simultaneous occurrence of lichen planus lesions and blisters.83 Circulating autoantibodies in sera from patients with LPP recognize in most instances BPAG2 and in few cases a 200-kDa protein that remains uncharacterized.84-87 Epitope mapping using BPAG2 fusion proteins show that LPP sera and BP sera react with different epitopes of BPAG2.87 These results suggest that LPP is a distinct disease and not a coexistence of BP and lichen planus, as previously suggested.

Table 8-3 Lichen Planus Pemphigoides

Clinical Features Adults, rarely in children Lesions indistinguishable from lichen planus, ie, flat-topped violaceous papules with whitish scale Tense blisters on normal-appearing skin or surmounting preexistent lesions of lichen planus Histopathologic Features Subepidermal blister with sparse or moderate to dense infiltrate of lymphocytes, eosinophils, and/or neutrophils or Subepidermal as well as typical histopathological changes of lichen planus Laboratory Evaluation Blister mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination Perilesional intact human skin: Linear deposits of IgG along the BM zone Perilesional salt-split skin: IgG deposits on the epidermal side of the split ELISA test Circulating IgG antibodies to BPAG2 Western blot Circulating IgG antibodies to 180-kDa protein band Differential Diagnosis Lichenoid lesion Lichen planus Lichenoid drug eruption Bullous lesion Inflammatory epidermolysis bullosa acquisita Linear IgA disease Herpes gestationis Cicatricial pemphigoid Bullous drug eruption

CLINICAL FEATURES Clinically, there are typical lesions of lichen planus as well as tense blisters that surmount lesions of lichen planus or develop in clinically normal skin (Table 8-3).83 Extremities, trunk, and oral mucosa are the sites of predilection. The age of onset ranges between 9 and 85 years, with a mean age of 46 years. There is no race predominance.

planus lesions will display a subepidermal vesicle as well as typical histopathological changes of lichen planus, namely compact stratum corneum, acanthosis, hypergranulosis, and a bandlike infiltrate of lymphocytes. Using antibodies to type IV collagen, the blister of LPP (with or without concurrent changes of lichen planus) is located within the lamina lucida.

HISTOPATHOLOGICAL FEATURES The histopathological findings in LPP are lesion dependent.66 Blisters on clinically normal skin will display a subepidermal blister with perivascular and interstitial infiltrate of lymphocytes and eosinophils (Table 8-3). Occasionally, the accompanying infiltrate is sparse, as in cases of cell-poor BP. A blister forming on lichen

OTHER DIAGNOSTIC TESTS DIF on perilesional skin shows in all patients with LPP linear IgG deposits along the BM zone.83 On NaCl-split perilesional skin, the deposits are located on the epidermal side of the split. IIF with sera of LPP using human skin (intact or NaCl split) as a substrate shows, in about 64% of the reported cases, circulating IgG autoanti-

bodies to proteins of the BM zone.83 Via ELISA testing these autoantibodies predominantly recognize BPAG2.88 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of lichen planus pemphigoides is dependent upon the type of lesion biopsied (Table 8-3).66 A biopsy from a lichenoid lesion will be difficult to distinguish from lichen planus, and one from a blister, indistinguishable from bullous pemphigoid. Clinical history in conjunction with direct immunofluorescence studies should enable accurate distinction.

Cicatricial Pemphigoid Cicatricial pemphigoid (CP) is a rare, heterogeneous, acquired, autoimmune, subepithelial blistering disease of mucous membranes and/or the skin (Tables 8-4 and 8-5). 66,89-91 It affects mainly elderly persons and occurs in females more than in males. No ethnical or geographic predominance is evident.89,90 CLINICAL FEATURES The clinical spectrum of CP varies widely89-91 (Table 8-4). It affects squamous mucosa, especially that of the oral cavity (85%), conjunctiva (65%), nasopharynx (20%), genitalia (20%), larynx (8%), esophagus (4%), and anus (3%).89,90 The skin is reportedly involved in 25% of the cases. The primary lesion of CP is a tense blister that on rupture heals slowly and usually with scar formation. HISTOPATHOLOGICAL FEATURES In CP, three histological patterns can be defined.66 (Table 8-4). In the first pattern, there is a subepidermal blister and a lymphocytic infiltrate at its base and sides. Eosinophils and occasionally neutrophils may be present. In oral and genital lesions, plasma cells are also present. In the second pattern, there is a subepidermal blister, fibrosis, and lymphocytic infiltrates with eosinophils and sometimes also neutrophils (Fig. 8-10). In the third pattern, the changes of the epithelium are similar to that seen in lichen planus. This histological pattern is observed only in oral and genital lesions. On immunomapping using antibodies to type IV collagen, the blister in CP localizes within the lamina lucida. OTHER DIAGNOSTIC TESTS DIF examination using perilesional clinically normalappearing skin or mucosa shows, in 80% to 100% of the cases of CP, linear IgG and/or C3 deposits along the basement membrane zone.91 IIF examination with

Table 8-4 Cicatricial Pemphigoid

Table 8-5 Antigenic Targets in Cicatricial Pemphigoid The antigen (its molecular weight) 1. BPAG1 (230 kDa) 2. BPAG2 (180 kDa) 3. α3 chain of laminin 5 and laminin 6 (145 kDa) 4. β integrin subunit (205 kDa) 5. α integrin subunit (130 kDa)

 FIGURE 8-10 Cicatricial pemphigoid. The subepidermal blister is associated with fibrosis and a mixed infiltrate of lymphocytes, eosinophils, and neutrophils.

CP patients’ sera demonstrates circulating IgG antibodies to the BM zone. These antibodies are usually present in a very low titer. The sensitivity of IIF on using conventional substrates (monkey esophagus, normal human skin) is reportedly 10% to 36%.92 On using 1 M NaCl-split normal human skin, the sensitivity of IIF in CP is markedly improved.91 The deposition of IgG in CP may be limited to the epidermal or dermal side of the split92 or even to both sides. Western blot or immunoprecipitation examinations as well as ELISA-testing using recombinant fusion proteins of the BM zone identify the target autoantigen in CP (Table 8-5). DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis depends upon the degree of dermal inflammatory infiltrate. In lesions which are intensely inflammatory, the differential diagnosis would include Sweet syndrome and linear IgA bullous dermatosis, neither of which is associated with dermal scarring. Dermatitis herpetiformis could also be in the differential diagnosis, but usually has neutrophils which are more localized to dermal papillae than is seen in cicatricial

pemphigoid. Bullous lupus could appear quite similar to cicatricial pemphigoid on routine histology. The differences in direct immunofluorescence staining patterns are helpful in discriminating between these diseases. Epidermolysis bullosa acquisita would also be in the differential diagnosis and can also produce dermal scarring. Direct immunofluorescence on salt-split skin probably offers the most reliable method for distinguishing between these two entities.

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

Clinical Features Elderly patients More common in women Vesiculobullous eruption primarily involves mucous membranes Extensive scarring Skin involvement in only 25% of cases Histopathologic Features Subepidermal blister Moderate to dense infiltrate of lymphocytes, eosinophils, and/or neutrophils With or without fibrosis or Subepidermal blister Bandlike infiltrate of lymphocytes and eosinophils (occasionally also neutrophils and plasma cells) Lichen planus–like changes of the epithelium Fibrosis Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination Perilesional intact human skin: Linear deposits of IgG, C3 along the BM zone Perilesional salt-split skin: IgG deposits, along the epidermal, dermal, or both sides of the split ELISA test Circulating IgG antibodies to BPAG1 and/or BPAG2; at present ELISA test for other proteins of the BMZ is not available Western blot Circulating IgG antibodies to 180-, 230-, 145-, 205-, or 130-kDa protein bands Differential Diagnosis Bullous pemphigoid Linear IgA disease Epidermolysis bullosa acquisita Dystrophic epidermolysis bullosa Bullous drug eruption Dermatitis herpetiformis Bullous lupus erythematosus Epidermolysis bullosa acquisita Sweet syndrome

Dermatitis Herpetiformis Dermatitis herpetiformis (DH) is an acquired, pruritic, autoimmune, subepidermal blistering disease characterized by IgA deposits in the dermal papillae.93,94 It occurs in males more than in females3 and usually begins in the second to fourth decade.2 It can, however, commence at any age. DH affects mainly Caucasians and is rarely seen in blacks or Asians.3,7 CLINICAL FEATURES The condition is characterized by erythematous papules, urticarial plaques, papulovesicles, vesicles,

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and rarely bullae, either isolated or in herpetiform grouping (Table 8-6 and Fig. 8-11A). 94,95 The lesions are intensely pruritic and often heal with scarring. The lesions are symmetrically distributed and appear mainly on elbows, knees, nape, scapular region, sacral region, and buttocks. All patients with DH have glutensensitive enteropathy indistinguishable from celiac disease. However, only 10% have clinical manifestations of intestinal disease.95

164

HISTOPATHOLOGICAL FEATURES In early lesions of DH, infiltrates of lymphocytes and neutrophils are arrayed about the superficial plexus and within the edematous papillary dermis (Table 8-6). 66,97-100 The neutrophils are also present in the epidermis and at the dermoepidermal junction, which usually shows vacuolar degeneration. With evolution of the

A

Table 8-6 Dermatitis Herpetiformis

Clinical Features Intensely pruritic Usual onset in early adulthood Symmetrical vesicles on extensor surfaces of extremities Mucous membrane involvement uncommon Gluten-sensitive enteropathy associated with HLA-A1, HLA-B8, HLA-DR3 Histopathologic Features Depends on the stage of the lesions Subepidermal blister Neutrophilic microabscesses in papillary dermal tips Lymphocytic infiltrate around superficial vascular plexus Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination (using perilesional, normal-appearing skin) Granular IgA, C3 deposits in the dermal papillae or Linear IgA deposits along the basement membrane zone, as well as granular IgA deposits in the dermal papillae ELISA test Circulating IgA antibodies to tissue transglutaminase Differential Diagnosis Linear IgA bullous dermatosis Epidermolysis bullosa acquisita Bullous lupus erythematosus Cicatricial pemphigoid Bullous pemphigoid Pustular drug eruption

B  FIGURE 8-11 Dermatitis herpetiformis. (A) Grouped papules and vesicles on elbows and flanks with extensive excoriations. (B) There is a subepidermal blister, which contains neutrophils, eosinophils, and fibrin. At the sides of the blister, there are papillary neutrophilic abscesses and subepidermal clefts. The dermis contains perivascular and interstitial infiltrates of lymphocytes, neutrophils, and eosinophils.

lesions, neutrophils collect in some of the dermal papillae, and fibrin often appears at their tips. Eosinophils may also be present in the dermal infiltrate and in the papillary abscesses. With further lesional evolution, a subepidermal blister develops. The blister usually contains serum, fibrin, neutrophils, and eosinophils (Fig. 8-11B). The dermis displays perivascular and interstitial infiltrates of lymphocytes, neutrophils, and eosinophils, the latter often numerous. The infiltrate may be dense and deep. At the sides of the blister, neutrophilic

abscesses in the dermal papillae and subepidermal clefts are usually present (Fig. 8-12). On immunomapping using antibodies to type IV collagen, the blister of DH is located in the lamina lucida. OTHER DIAGNOSTIC TESTS DIF examination shows granular IgA deposits in the dermal papillae (Fig. 8-13).66,93,94 In some patients, linear IgA deposits occur concomitantly along the basement membrane zone.66,101 In DH by IIF examination, there is no evidence for circulating autoantibodies against proteins of

 FIGURE 8-12 Dermatitis herpetiformis. Neutrophilic abscesses and subepidermal clefts are present in the dermal papillae.

keratinocytes or the basement membrane zone.94 However, patients with DH have IgA antibodies to gliadin102 (a component of gluten) and endomysium103 (connective tissue surrounding smooth muscles). The anti-endomysial antibodies target tissue transglutaminase, which was recently identified as the autoantigen of celiac disease. IgA antibodies to tissue transglutaminase

(detected via ELISA) serve nowadays as the serological diagnostic marker for DH and celiac disease.104,105 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of dermatitis herpetiformis includes linear IgA bullous dermatosis, epidermolysis bullosa acquisita, bullous lupus erythematosus, cicatricial pemphigoid, pustular drug

 FIGURE 8-13 DIF using perilesional, normal-appearing skin in DH. There is granular IgA deposition in the dermal papillae.

Linear IgA Disease LAD is an acquired, autoimmune, subepithelial blistering disease of the skin and/or mucous membranes characterized by the presence of linear IgA deposits along the BM zone.106,107 LAD may affect adults,13 children,108 or even neonates.109 CLINICAL FEATURES The clinical picture of LAD is heterogenous.13,106-111 The disease may simulate clinically BP, DH, erythema multiforme, erythema annulare centrifugum, or Lyell syndrome (Table 8-7).17,18,106,107,112,113,114 However in its classical form there are annular, tense, large blisters on normal or erythematous skin.13,106-110 The individual blisters may be elliptical in shape, and the new blisters usually appear around those resolving, forming rosette or jewellike clusters. Occasionally, the blisters will lie within an erythematous area in a linear distribution (“string of pearls”). Itching is often an accompanying complaint and may be mild to severe. Urticarial patches and plaques may be present, especially in the early stage of the disease. The sites of predilection are the trunk, limbs, face, groin, and perineum. Involvement of the mucous membranes, especially that of the oral cavity and conjunctiva, is not uncommon and may be the only presenting manifestations.115,116 HISTOPATHOLOGICAL FEATURES Like the clinical picture, the histology of LAD is

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

eruptions, and occasional cases of bullous pemphigoid. Dermatitis herpetiformis is the only one of these entities in which the neutrophils tend to aggregate within papillary dermal tips. The blister spaces tend to be smaller in dermatitis herpetiformis than in the other entities. Epidermolysis bullosa acquisita is less inflammatory in many cases, and bullous pemphigoid demonstrates a predominantly eosinophilic infiltrate in most cases. Pustular drug eruptions may exhibit papillary dermal collections of neutrophils similar to dermatitis herpetiformis, but in contrast to dermatitis herpetiformis also show evidence of leukocytoclastic vasculitis with fibrinoid necrosis of vessel walls.52 The serological detection of antiendomysial antibodies should allow distinction of DH from the other entities and direct immunofluorescence staining patterns will be different for each of the disorders in this differential diagnosis and probably represent the most reliable method of distinguishing between them.

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Table 8-7 Linear IgA Bullous Dermatosis

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Clinical Features Childhood disease has onset within 5-6 years of birth Adult onset in sixth to eighth decades Often antecedent infection Annular erythematous patches with tense blisters at edges Trunk and extremities most commonly affected sites Histopathologic Features Subepidermal blister Neutrophils linearly aligned along dermal-epidermal junction Papillary dermal edema Occasional eosinophils present Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister (rarely sub-lamina densa blister) DIF examination Perilesional intact human skin: Linear deposits of IgA along the BM zone Perilesional salt-split skin: IgA deposits, along the epidermal, dermal, or both sides of the split ELISA test Circulating IgG antibodies to BPAG1 and/or BPAG2 Western blot Circulating IgA antibodies to different protein bands Differential Diagnosis Cell-rich bullous pemphigoid Inflammatory variant of epidermolysis bullosa acquisita Herpes gestationis Bullous drug eruption Cicatricial pemphigoid Dermatitis herpetiformis Bullous systemic lupus erythematosus Bullous arthropod bite reaction Sweet syndrome

heterogenous (Table 8-7). 66 Fully developed lesions show subepidermal blisters, accompanied by infiltrates of lymphocytes, eosinophils, and neutrophils (Fig. 8-14). The infiltrate is superficially situated at the sides and base of the blister. In most of the cases, neutrophils predominate over eosinophils in the infiltrate. They are usually present along the BM zone, which shows vacuolar degeneration. The neutrophils also accumulate in some of the dermal papillae as abscesses resembling those of DH. The histopathology of fully developed oral lesions of LAD is similar to that of the

 FIGURE 8-14 Histopathology of linear IgA disease, displaying a subepidermal blister and lymphocytic infiltrates of numerous neutrophils and a few eosinophils. The blister contains neutrophils, eosinophils, and fibrin.

cutaneous lesions, but in the former there are many plasma cells. The ocular lesions of LAD are not distinguishable from those of CP. Early urticarial lesions of LAD show perivascular and interstitial lymphocytic infiltrates of neutrophils and eosinophils. Eosinophilic or neutrophilic spongiosis, or a combination of both, may also be present. The site of the blister formation in LAD patients is within the lamina lucida. However, in LAD

patients with circulating autoantibodies to type VII collagen, the blister is located beneath the lamina densa. OTHER DIAGNOSTIC TESTS DIF examination of perilesional skin or mucosa displays linear IgA deposits along the BM zone (Fig. 8-15). IIF examination with patients’ sera demonstrates circulating IgA antibodies to proteins of the BM zone. The sensitivity of IIF is 62% with normal

 FIGURE 8-15 DIF using perilesional, normal-appearing skin from a patient with linear IgA disease. IgA is deposited in a linear fashion along the basement membrane zone.

human intact skin as substrate and 73% with NaCl-split normal human skin.117 With NaCl-split skin, the antibodies bind to the epidermal side of the split in most cases.117 In a few cases they bind to the dermal side,118 or both, of the split.117 Western blot or immunoprecipitation examinations, as well as ELISA-testing using recombinant fusion proteins of the BM zone, may define the target autoantigen in LAD (Table 8-8).

Table 8-8 Autoantigens of Linear IgA Disease ANTIGEN

MOLECULAR WEIGHT

1. BPAG1 2. BPAG2 3. LAD1 (LABD 97) (cleaved ectodomin of BPAG2) 4. Ladinin 5. LAD225 (still not characterized) 6. LAD285 (still not characterized) 7. Type VII collagen

230 kDa 180 kDa 120/97 kDa

95 kDa 255 kDa 285 kDa 290 kDa

Epidermolysis Bullosa Acquisita Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal autoimmune blistering disease of the skin and/or mucous membranes which is characterized by the presence of IgG deposits along the BM zone and circulating IgG autoantibodies targeting type VII collagen.55,56,66,119,120 It affects mainly adults but can also occur in children and even infants. The mean age at onset is 47 years. EBA affects all races and is reported to be slightly more common in females. CLINICAL FEATURES Clinically, EBA can be divided in three variants66: Classical variant of EBA, where there are trauma-induced blisters and erosions on the extensor surface of the limbs (Table 8-9). The blisters arise on normal-appearing skin, are tense, clear, or hemorrhagic, and heal with scarring and milia formation. The inflammatory variant of EBA, displays widespread eruptions with tense blisters spontaneously forming on erythematous or nonerythematous skin. These lesions occur on flexural and/or intertriginous areas and tend to heal with less scarring and milia formation. And mucosal EBA, where the lesions are limited to the mucous membranes of the mouth, nose, pharynx, larynx, esophagus, eye, and genitourinary tract.

Table 8-9 Epidermolysis Bullosa Acquisita

Clinical Features Usually affects middle-aged to elderly adults Blisters on noninflammatory skin Scarring and milia Predilection for trauma-prone sites Nail dystrophy may be present Histopathologic Features Subepidermal blister Sparce or moderate to dense infiltrates of lymphocytes, eosinophils, and/or neutrophils or Eosinophilic and/or neutrophilic spongiosis No keratinocyte necrosis Dermal scarring may be present Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Sub-lamina densa blister DIF examination Perilesional intact human skin: Linear deposits of IgG,C3 along the BM zone Perilesional salt-split skin: IgG deposits, along the dermal side of the split ELISA test Circulating IgG antibodies to collagen type VII Western blot Circulating IgG antibodies to a 290-kDa protein band Differential Diagnosis Classical epidermolysis bullosa acquisita Cell-poor bullous pemphigoid Bullous systemic lupus erythematosus Toxic epidermal necrolysis Junctional epidermolysis bullosa Dystrophic epidermolysis bullosa Porphyria cutanea tarda Pseudoporphyria Inflammatory epidermolysis bullosa acquisita Cell-rich bullous pemphigoid Linear IgA disease Herpes gestationis Cicatricial pemphigoid Dermatitis herpetiformis Bullous systemic lupus erythematosus Bullous drug reaction Epidermolysis bullosa acquisita (urticarial stage) Urticarial stage of intraepidermal autoimmune bullous diseases Urticarial stage of cell-rich bullous pemphigoid Linear IgA disease Herpes gestationis Drug reaction Arthropod bite reaction

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

DIFFERENTIAL DIAGNOSIS The major histologic differential diagnosis is dermatitis herpetiformis. In the classic situation, dermatitis herpetiformis has a less diffuse and more abscess-like distribution of neutrophils, confined to papillary dermal tips, whereas linear IgA dermatosis and chronic bullous disease of childhood display neutrophils in a more evenly distributed pattern along the dermalepidermal junction. However, there is great overlap in these cases, and frequently, direct immunofluorescence demonstrating a linear or granular staining pattern with IgA is the only way to distinguish these entities. Clinical parameters such as HLA-B8/DR3 haplotype and small bowel abnormalities in dermatitis herpetiformis may further aid in the differential diagnosis. Occasional arthropod bite reactions can display neutrophil-predominant infiltrates, and these cases resemble linear IgA dermatosis. The presence of a punctum, or a deep component to the inflammatory infiltrate, as well as a negative or nonspecific direct immunofluorescence study would favor a bite reaction. The neutrophilic infiltrate in Sweet syndrome is usually far more florid and diffuse than that seen in linear IgA dermatosis or chronic bullous disease of childhood. In addition, Sweet syndrome

is characterized by much more papillary dermal edema. Bullous lupus erythematosus can present with a histologic picture similar to linear IgA disease. Patients with bullous lupus erythematosus have serologic findings of systemic lupus. On direct immunofluorescence, the staining pattern of lupus is granular and bandlike and is usually observed with several immunoglobulins and not just IgA. Epidermolysis bullosa acquisita, cicatricial pemphigoid, and bullous pemphigoid may have histologic features similar to linear IgA disease but can be discerned by direct immunofluorescence. Cases with neutrophilic blisters and with linear deposition of IgA and IgG along the dermal-epidermal junction are more problematic. One approach is to classify the disease according to the stronger staining immunoglobulin, that is, as linear IgA disease if IgA is the predominant immunoglobulin or as bullous pemphigoid when IgG predominates. Some authors accept as linear IgA disease only cases with exclusive staining with IgA and classify all others as bullous pemphigoid or epidermolysis bullosa acquisita.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

HISTOPATHOLOGICAL FEATURES Histopathologically, lesions of EBA are characterized by formation of subepidermal blisters associated with no or sparse perivascular and interstitial infiltrates of lymphocytes in the upper dermis (classic variant of EBA) (Table 8-9) (Fig. 8-16).66 On occasion, a few eosinophils and/or neutrophils are present. In the inflammatory variant of EBA, the blister is associated with moderately dense lymphocytic infiltrates with eosinophils and neutrophils. Early urticarial lesions of the inflammatory variant are histopathologically not distinguishable from urticarial lesions of other autoimmune blistering diseases, showing perivascular and interstitial infiltrates of lymphocytes, neutrophils, and eosinophils. The eosinophils or the neutrophils may dominate the infiltrate and are present along the dermal-epidermal junction, which displays vacuolar degeneration. Eosinophilic and/or neutrophilic spongiosis may be present. Fibrosis, with or without milia, may occur in relapsing lesions of EBA. Mucosal EBA has findings similar to those of the inflammatory variant of EBA, although usually the infiltrate is denser and contains plasma cells. The blisters in all variants of EBA localize to the sublamina densa region. OTHER DIAGNOSTIC TESTS DIF using perilesional skin or perilesional mucosa displays in all active cases linear deposits of IgG along the BM zone. Using NaClsplit perilesional skin or mucosa, the deposits segregate to the dermal side of the split (Fig. 8-17).66 Circulating IgG antibodies to proteins of the BM zone occur by IIF testing in about 25% to 50% of the patients with normal human skin or monkey esophagus as substrate.119 The sensitivity increases markedly with NaCl-split normal skin.121 The circulating antibodies react by Western blot or

 FIGURE 8-17 DIF of salt-split, perilesional, normal-appearing skin from a patient with epidermolysis bullosa acquisita. IgG is deposited in linear array along the dermal side of the split.

immunoprecipitation assay with a 290-kDa protein band which represents type VII collagen.119 These antibodies also react positively with recombinant fusion protein of type VII collagen by ELISA.122 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis is dependent upon the histologic subtype of epidermolysis bullosa acquisita. In relatively noninflammatory lesions, the differential diagnosis includes porphyria cutanea tarda and cellpoor bullous pemphigoid. These two conditions can be distinguished from epidermolysis bullosa acquisita on the basis of immunofluorescence staining patterns (requiring salt-split skin to differentiate bullous pemphigoid and epidermolysis bullosa acquisita). Porphyria cutanea tarda can be further distinguished with urine, fecal, and blood porphyrin studies.

In more inflammatory cases of epidermolysis bullosa acquisita with abundant dermal neutrophils, bullous lupus erythematosus is the major differential diagnostic possibility. Bullous lupus erythematosus may display other histologic features of lupus, such as a superficial and deep perivascular and periappendageal lymphocytic infiltrate, but these features are often absent. In fact, the histologic features of epidermolysis acquisita and bullous lupus erythematosus may be indistinguishable. Patients with the latter disease meet the criteria of the American, Rheumatologic Association for systemic lupus erythematosus. Further, the granular nature of the immunoglobulin deposits seen in lupus erythematosus on direct immunofluorescence often differentiates this entity from the linear deposits seen in epidermolysis bullosa acquisita.

Bullous Systemic Lupus Erythematosis Bullous SLE is an acquired autoimmune disease characterized by the occurrence of vesiculobullous eruptions, often in a herpetiform arrangement, in patients diagnosed as having SLE by criteria of the American Rheumatism Association (ARA).123-125 It affects mainly adults but may also occur in children.

168

 FIGURE 8-16 A classical lesion of epidermolysis bullosa acquisita illustrates a subepidermal blister and sparse perivascular and interstitial lymphocytic infiltrates.

CLINICAL FEATURES Clinically, there are tense blisters on normal or erythematous skin (Table 8-10). The blisters are usually herpetiform, with a predilection to the trunk and flexural surfaces.123-125

Table 8-10 Bullous Systemic Lupus Erythematosus63

Oral lesions have been frequently observed, and pruritus, which may be severe, has also been reported. HISTOPATHOLOGICAL FEATURES The histopathology of bullous SLE is similar to that of dermatitis herpetiformis, with subepidermal blisters and infiltrate of lymphocytes and numerous neutrophils (Table 8-10) (Fig. 8-18). 66 In contrast to dermatitis

 FIGURE 8-18 Bullous SLE. The subepidermal blister is associated with lymphocytic infiltrates and many neutrophils. The neutrophils also distribute to the basement membrane zone and the dermal papillae.

herpetiformis, the infiltrate in bullous SLE is also present around the hair follicles. Moreover, in bullous SLE there are interstitial mucin deposits. Also in contrast to dermatitis herpetiformis, the blister in bullous SLE localizes to the sublamina densa region. OTHER DIAGNOSTIC TESTS DIF of perilesional skin of patients with bullous SLE displays linear and/or granular deposits of IgG and/or IgA, IgM, and C3 at the BM zone.124,125 With NaCl-split perilesional skin, the deposits are located on the dermal side of the split. Patients’ sera contain circulating IgG autoantibodies to the BM zone by IIF assay.125 These circulating IgG autoantibodies recognize in Western blot or by immunoprecipitation a 290-kDa protein band which represents type VII collagen.57 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of bullous lupus erythematosus includes dermatitis herpetiformis, linear IgA bullous dermatosis, Sweet syndrome, epidermolysis bullosa acquisita, and cicatricial pemphigoid. The presence of leukocytoclastic changes favors the diagnosis of lupus over the other entities listed. The most compelling diagnostic information is found on direct immunofluorescence examination, which separates out each of these entities.

SUBEPIDERMAL BLISTERING DISEASES DUE TO MUTATIONS OF PROTEINS OF THE BASEMENT MEMBRANE ZONE

Junctional Epidermolysis Bullosa Junctional epidermolysis bullosa (JEB) is a group of congenital disorders characterized by trauma-induced bullae and caused by mutations of the genes coding for BPAG2,126,127 the α3, the β3, and the χ2 polypeptide chains of laminin 5,3,128-132 and the α639 and the β438,133 integrin subunits.

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

Clinical Features Young adults, women > men, particularly African American women Widespread vesicles and bullae often on an erythematous base or plaques Trunk and flexural surfaces most commonly involved Predominately sun-exposed skin or any site Four or more ARA criteria Histopathologic Features Subepidermal blister Often numerous neutrophils in papillary dermis, often dermal papillae or in a more diffuse pattern Usually prominent papillary dermal edema Superficial and mid-dermal perivascular lymphoid infiltrates with occasional neutrophils and eosinophils Uncommonly microvascular injury, rarely leukocytoclastic vasculitis Extravasation of erythrocytes on occasion Rarely typical features of lupus erythematosus: basal layer vascuolopathy, epidermal atrophy, thickened basement membrane, thickening Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Sub-lamina densa blister DIF examination Perilesional intact human skin: Linear deposits of IgG along the BM zone Perilesional salt-split skin: IgG deposits along the dermal side of the split ELISA test Circulating IgG antibodies to collagen type VII Western blot Circulating IgG antibodies to a 290-kDa protein band Differential Diagnosis Dermatitis herpetiformis Linear IgA bullous dermatosis Epidermolysis bullosa acquisita Cicatricial pemphigoid Drug eruption Neutrophilic dermatoses such as Sweet syndrome

CLINICAL FEATURES JEB can be classified into three main subgroups distinguished by their clinical characteristics: junctional epidermolysis bullosa of the Herlitz type, junctional epidermolysis bullosa of the non-Herlitz type, and junctional epidermolysis bullosa with pyloric atresia. Tables 8-11 to 8-13 display the clinical features and molecular defects of JEB variants.66 HISTOPATHOLOGICAL FEATURES Histologically, all variants of JEB are characterized by the formation of subepidermal blisters associated with sparse infiltrates in the dermis (Fig. 8-19).66 On immunomapping using antibodies to type IV collagen, the split localizes to the lamina lucida.

169

Table 8-11 Variants of Junctional Epidermolysis Bullosa and Their Molecular Defects66

Junctional epidermolysis bullosa of Herlitz type (JEB-H)

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Junctional epidermolysis bullosa of the non-Herlitz type (JEB-nH)

Junctional epidermolysis bullosa with pyloricatresia (JEB-PA)

MOLECULAR DEFECT

MODE OF INHERITANCE

ONSET

BLISTERS

OTHER CHANGES

Mutations of the genes coding for the α3, the β3, and the χ2 polypeptide chains of laminin 5 Mutations of the genes encoding for BPAG2 or any of the three polypeptide chains of laminin 5 Mutations of the genes encoding for α6 or the β4 integrin subunits

Autosomal recessive

Birth or shortly thereafter

Generalized

Autosomal recessive

Birth, shortly thereafter or in early childhood Birth or shortly thereafter

Localized or generalized

Dystrophic nails, dysplastic teeth, growth retardation, anemia, mucous membrane lesions There may be pigmentary changes, dystrophic nails, and dysplastic teeth

OTHER DIAGNOSTIC MEASURES DIF and IF examinations are negative.66 Mutation analysis demonstrating the gene defect confirms the diagnosis. DIFFERENTIAL DIAGNOSIS The histology of JEB is not diagnostic and can be seen in such other diseases as cell-poor BP, EBA, PCT, pseudoporphyria, and dystrophic EB.66 Therefore, it should be correlated with the clinical picture, immunofluorescence findings, and immunomapping to establish the diagnosis. Table 8-12 displays the diagnostic criteria of JEB.66

Table 8-12 Diagnostic Criteria of Junctional Epidermolysis Bullosa 1. Histology: Subepidermal blister with sparse infiltrates in the dermis 2. Epitope mapping using antibodies against type IV collagen: Intra-lamina lucida split 3. Mutation analysis: • Mutations of the genes coding for the α3, β3, or χ2 polypeptide chains of laminin 5 • Mutations of the gene encoding for the α6 or the β4 integrin subunits • Mutations of the gene encoding for BPAG2

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Autosomal recessive

Dystrophic Epidermolysis Bullosa Dystrophic epidermolysis bullosa (DEB) is a group of congenital disorders caused by mutations of the gene encoding type VII collagen and is characterized by trauma-induced blisters that heal with scarring and milia.134-136 CLINICAL FEATURES DEB may be autosomal dominant or autosomal recessive. Autosomal dominant DEB comprises four subtypes: (1) epidermolysis bullosa and congenital, localized absence of the skin (Bart syndrome)137; (2) dystrophic epidermolysis bullosa—CockayneTouraine134,136,138,139; (3) albopapuloid dystrophic epidermolysis bullosa, or dystrophic epidermolysis bullosa, Pasini type134; (4) and transient bullous dermatolysis of new-born.140,141 Autosomal recessive DEB encompasses two subtypes: (1) dystrophic epidermolysis bullosa—Hallopeau-Siemens type, (2) dystrophic epidermolysis bullosa—nonHallopeau-Siemens type. Table 8-13 lists the clinical features and molecular defects of DEB variants.66 HISTOPATHOLOGICAL FINDINGS Histopathologically, all variants of DEB are characterized by the formation of a subepidermal blister with sparse lymphocytic infiltration in the upper dermis.66 In recurrent lesions, fibrosis and/or milia may be present. On immunomapping using antibodies to type IV collagen, the blister localizes to the sublamina densa region.

Generalized

Congenital esophageal, pyloric or duodenal atresia, aplasia cutis congenita, renal abnormalities

OTHER DIAGNOSTIC TESTS DIF and IF examinations are negative.66 Mutation analysis confirms the diagnosis by showing the gene defect. DIFFERENTIAL DIAGNOSIS The histology of DEB is not diagnostic and can be seen in such other diseases as cell-poor BP, EBA, PCT, pseudoporphyria, and JEB.66 It should therefore be correlated with the clinical findings, the results of IF, and immunomapping with antibodies to type IV collagen. Table 8-14 displays the diagnostic criteria of DEB.66

Kindler Syndrome Kindler syndrome is a rare autosomal recessive disorder caused by mutation of the KIND1 gene.142,143 That gene codes the kindlin1 protein, which is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix. CLINICAL FEATURES Clinically, blisters, poikiloderma-like changes, photosensitivity, and marked cutaneous atrophy may involve a large area of the skin (Table 8-15). 144,145 Often, nail dystrophy and syndactyly of fingers and toes are present. The blisters are trauma induced, heal with scarring, and occur mainly on the hands and feet. The blisters appear at birth, persist usually through infancy and childhood, and

Table 8-13 Variants of Dystrophic Epidermolysis Bullosa. Features and Molecular Defects66 MOLECULAR DEFECT

MODE OF INHERITANCE

ONSET

BLISTERS

OTHER CHANGES

1. Bart syndrome

Mutations of the gene coding for type VII collagen

Autosomal dominant

Birth

2. Dystrophic epidermolysis Cockayne-Touraine (DEB-CT) 3. Dystrophic epidermolysis bullosa, albopapulodea

Mutations of the gene coding for type VII collagen Mutations of the gene coding for type VII collagen

Autosomal dominant Autosomal dominant

Congenital absence the skin, dystrophic or absent nails Dystrophic nails

4. Transient bullous dermatolysis of newborn

Mutations of the gene coding for type VII collagen

Autosomal dominant

Birth, infancy, early childhood Blisters: birth, infancy, early childhood: adolescence Birth

Affects skin and mucous membranes Localized mainly to extremities Localized mainly to extremities

-

5. Dystrophic epidermolysis bullosa-Hallopeau-Siemens

Mutations of the gene coding for type VII collagen

Autosomal recessive

Birth or shortly thereafter

Generalized, disappear spontaneously in the first few months of life Generalized and heal with marked scarring

6. Dystrophic epidermolysis bullosa-non-HallopeauSiemens

Mutations of the gene coding for Type VII

Autosomal recessive

Birth or shortly thereafter

HISTOPATHOLOGICAL FINDINGS Examination of blistering lesions of patients with Kindler syndrome show histopathologically a subepidermal blister with fibrosis and perivascular and interstitial infiltrate in the upper and mid-dermis.66 On immunomapping using antibodies to type IV collagen, the blister of Kindler syndrome is located in the lamina lucida.

and can be seen in other diseases such as EBA, CP, JEB, and DEB. Correlations of the histopathology with the clinical picture, the results of the immunomapping, IF, and/or electron microscopy are necessary for diagnosis of Kindler syndrome.66

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

tend to decrease with age. The poikiloderma-like changes usually occur on the face and neck. Like the blisters, the photosensitivity abates with age.

Albopapuloid papules, dystrophic nails

 FIGURE 8-19 Junctional epidermolysis bullosa. The subepidermal blister is associated with sparse perivascular and interstitial infiltration by lymphocytes in the dermis.

171

findings in Kindler syndrome are characteristic and show branching and duplication of the lamina densa.66 DIFFERENTIAL DIAGNOSIS The histopathology of Kindler syndrome is not diagnostic

Generalized

Contracture, mittenlike deformities, scarring alopecia, ,dysplastic teeth, dystrophic nails, mucosal strictures ocular involvement Dysplastic teeth, dystrophic nails

OTHER DIAGNOSTIC TESTS DIF and IIF examinations are negative. Ultrastructural

Table 8-14 Diagnostic Criteria of Dystrophic Epidermolysis Bullosa Histology: Subepidermal blister with sparse infiltrates in the dermis Epitope mapping using antibodies against type IV collagen: Sublamina densa blister Mutation analysis: Mutations of the gene coding for type VII collagen

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 8-15 Kindler Syndrome

Table 8-16 Toxic Epidermal Necrolysis

Clinical Features Rare autosomal recessive Blisters present at birth Poikiloderma-like changes Photosensitivity Marked cutaneous atrophy Nail dystrophy and syndactyly Histopathologic Features Subepidermal blister with basketweave stratum corneum Minimal inflammation with lymphocytes Fibrosis Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Intra-lamina lucida split DIF and IIF examinations Negative Electron microscopy Branching and duplication of the lamina densa Mutation analysis Mutation within the KIND1 gene Differential Diagnosis Junctional and dystrophic epidermolysis bullosa Epidermolysis bullosa acquisita Cicatricial pemphigoid

Clinical Features Rapid onset Fever, malaise Frequent drug history 30% mortality Histopathologic Features Subepidermal blister with basketweave stratum corneum Full-thickness epidermal necrosis Extensive basal vacuolization Minimal inflammation with lymphocytes and occasionally a few neutrophils Laboratory Evaluation Negative direct immunofluorescence Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister Differential Diagnosis Thermal injury Erythema multiforme Graft vs host disease Staphylococcal scalded skin syndrome

MISCELLANEOUS SUBEPIDERMAL BLISTERING DISEASES

Toxic Epidermal Necrolysis (Lyell Syndrome) Toxic epidermal necrolysis (TEN) is a severe life-threatening drug reaction, in which necrosis of keratinocytes is widespread, affecting large areas of the epidermis. By definition, more than 30% of the body surface is affected by separation of the epidermis from the dermis through the level of the dermal-epidermal junction, producing a scalded skin appearance.146-149 It occurs in all age groups, including children, infants, and neonates.150-154 TEN is a rare disorder, occurring at an estimated incidence of 0.4 to 1.2 cases per million population.146

172

CLINICAL FEATURES Clinically, the cutaneous and mucous membrane lesions147,150-155 are usually preceded by a prodrome that may last for 2 to 3 days and that resembles an upper respiratory tract infection (Table 8-16). The cutaneous lesions begin most often on the

face or the trunk and consist of a morbilliform exanthem, with discrete areas of macular erythema or targetoid lesions (Fig. 8-20A). The lesions coalesce rapidly and spread quickly to other areas of the body. The epidermis in the affected areas becomes necrotic and is raised by flaccid, large blisters. The necrotic epidermis may adhere over the dermis, resulting in a characteristic wrinkled appearance or sheetlike desquamation. About 97% of TEN patients have mucosal lesions.153,155 These usually occur shortly before the onset of the cutaneous lesions. StevensJohnson syndrome (SJS) is a milder form of TEN, where the epidermal necrosis involves less than 10% the body’s surface area.148,156 Patients whose disease involves 10% to 30% of their body surface area have SJS/TEN overlap. HISTOPATHOLOGICAL FINDINGS TEN is characterized histologically by formation of a subepidermal blister.66 The epidermis forming the blister roof shows full thickness necrosis and has a basket weave stratum corneum (Fig. 8-20B). In the dermis is a sparse perivascular and interstitial infiltrate of lymphocytes and occasional eosinophils neutrophils. Erythrocytes may have extravasated. Epidermal necrosis and the subepidermal blister usually affect the entire width of the biopsy. The subepidermal blisters of TEN are located in the lamina lucida region. On immunomapping using

antibodies to type IV collagen, the split localizes to the lamina lucida. OTHER DIAGNOSTIC TESTS DIF is negative. DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of toxic epidermal necrolysis includes severe thermal injury, in which full-thickness epidermal necrosis is seen. However, in the thermally damaged skin, there is an elongation of keratinocyte nuclei not seen in toxic epidermal necrolysis and the dermal homogenization characteristic of thermal injury is not present. Severe erythema multiforme also enters the histologic differential diagnosis for those who believe it to be a separate entity. There is generally slightly more of a lymphocytic infiltrate within the papillary dermis accompanied by exocytosis in erythema multiforme than is seen in toxic epidermal necrolysis. In the earliest lesions of toxic epidermal necrolysis, distinction from erythema multiforme may be impossible. Graft versus host disease, grade III also has a subepidermal blister with abundant necrotic keratinocytes, but in most cases has a more prominent inflammatory infiltrate. The presence of necrotic keratinocytes within eccrine structures is also more commonly seen in graft versus host disease than in toxic epidermal necrolysis. Another entity which enters into the clinical differential diagnosis and must be distinguished from toxic epidermal necrolysis is staphylococcal scalded skin syndrome. Clinically, toxic epidermal necrolysis and staphylococcal scalded skin syndrome may present in a very similar manner with extensive blistering and denudation. Both entities constitute potentially life-threatening diseases but require different lines of therapy. Frozen section diagnosis is therefore often required for rapid therapeutic intervention. Full-thickness epidermal necrosis is characteristic for toxic epidermal necrolysis and differentiates this disorder from staphylococcal scalded skin syndrome, which shows an intraepidermal blister with a cleavage plane in the uppermost epidermis. Also, paraneoplastic pemphigus and linear IgA disease may clinically resemble TEN.157,158 These diseases can, however, be distinguished from TEN by microscopic findings and IF.

Porphyria Cutanea Tarda The porphyrias comprise a group of disorders characterized by excessive accumulation of porphyrins or their precursors

A

B

in tissues due to inherited or acquired deficiencies in any one of the enzymes that synthesize heme (Table 8-17).159,160 There are several types of porphyrias. Porphyria cutanea tarda is the most common of them.159 It has an estimated incidence of 1:1000 to 1:30000. About 60% of the affected patients are males.159 PCT is due to reduced activity of the enzyme uroporphyrinogen decarboxylase (UROD), which catalyzes several steps in heme synthesis.161-163 CLINICAL FEATURES Clinically, blisters develop on the dorsal surfaces of the hands, in association with increased fragility of sun-exposed skin and hypertrichosis of the periorbital area (Table 8-17). There is mottled pigmentation of sunexposed areas and sometimes morphealike changes.159,160,164 The blisters are usually induced by minor trauma and heal with atrophic scars and milia. HISTOPATHOLOGICAL FINDINGS Bullous lesions of PCT are characterized histopathologically by the formation of subepidermal blisters (Table 8-17 and Figs. 8-21 and 8-22).66,165 The bullae may contain fibrin and a few inflammatory cells. The epidermis forming the blister roof is usually effaced and may be necrotic.66 In the dermis, there is actinic elastosis and a sparse superficial perivascular and interstitial infiltration by lymphocytes. The blood vessels of the superficial dermal plexus usually have thickened walls that can be best demonstrated by PAS stain. On immunomapping with antibodies to type IV collagen, the blister in PCT is located in the lamina lucida.66 OTHER DIAGNOSTIC TESTS IIF examinations in patients with PCT are negative.66,166 DIF usually reveals C3 depositis

around the upper dermal vascular plexus and/or at the DEJ.165,167 Sometimes linear deposits of IgG and/or IgA may be seen at the DEJ.

Table 8-17 Porphyria Cutanea Tarda

Clinical Features Sporadic or familial Blisters at sites of sun exposure and trauma Scarring and milia Facial hypertrichosis Hyperpigmentation Often associated with liver disease Histopathologic Features Subepidermal blister Sparse perivascular and interstitial lymphoid infiltrates Usually solar elastosis Thick-walled blood vessels Caterpillar bodies—basement membrane material (segment eosinophilic structures) Laboratory Evaluation Direct immunofluorescence Linear dermal-epidermal and perivascular C3, and sometimes IgG, IgM, IgA Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister Porphyrin laboratory tests Elevated total porphyrin levels in urine Isocoproporphyrin is demonstrable in feces Differential Diagnosis Cell-poor bullous pemphigoid Epidermolysis bullosa (hereditary and acquired) Thermal injury Toxic epidermal necrolysis Bullosis diabeticorum Pseudoporphyria Traumatic blisters

Confirmation of the diagnosis of PCT requires porphyrin laboratory tests.159,160 In PCT, total porphyrin levels in urine are elevated (10 to 100 times than normal), with a predominence of uroporphyrin and heptacarboxyporphyrin. Isocoproporphyrin is demonstrable in feces. DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis is that of the minimally inflammatory subepidermal blistering disorders and includes hereditary and acquired epidermolysis bullosa, pseudoporphyria, penicillamine dermopathy, cell-poor bullous pemphigoid, traumatic blisters, bullosis diabeticorum, and blisters overlying recent scars. The markedly thickened papillary dermal vessel walls and the prominent dermal elastosis are helpful in making a diagnosis of porphyria. Direct immunofluorescence demonstrating linear deposits of IgG and C3 around the papillary dermal vessels and less frequently along the dermal epidermal junction is also helpful in confirming the diagnosis and ruling out epidermolysis bullosa acquisita and cell-poor bullous pemphigoid. The histologic and immunologic findings in pseudoporphyria are identical to those of porphyria. The distinction between the two entities hinges on porphyrin studies, which are negative in pseudoporphyria.

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

 FIGURE 8-20 Toxic epidermal necrolysis. (A) The patient demonstrates striking facial edema and hemorragic crusting of lips. (B) The epidermis is necrotic, generating a subepidermal blister. In the dermis is a sparse lymphocytic infiltrate, with few neutrophils.

Pseudoporphyria Pseudoporphyria is a bullous disorder that is clinically and histopathologically similar to PCT, but with normal UROD activity.159,168 CLINICAL FEATURES The clinical findings in pseudoporphyria are similar to those

173

Cell-poor bullous pemphigoid Epidermolysis bullosa (hereditary and acquired) Thermal injury Toxic epidermal necrolysis Bullosis diabeticorum Traumatic blisters

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Coma Blisters Coma blisters are bullae that appear at pressure sites in patients with druginduced and non-drug-induced coma.169,170

 FIGURE 8-21 Porphyria cutanea tarda. The subepidermal blister contains fibrin and few inflammatory cells. The epidermis is effaced. In the upper dermis are found actinic elastosis and a scant infiltrate of lymphocytes.

of PCT (Table 8-18). Pseudoporphyria may occur in patients undergoing hemodialysis for chronic renal insufficiency (dialysis-induced pseudoporphyria) or in those taking drugs such as naproxen, furosemide, nalidixic acid, and tetracycline (drug-induced pseudoporphyria)159,168. Pseudoporphyria has also been attributed to PUVA therapy, excessive sun exposure, and tanning bed use (UVA-induced pseudoporphyria).168 HISTOPATHOLOGICAL FINDINGS Blisters of pseudoporphyria are histopathologically indistinguishable from those of PCT (Table 8-18). 66 Similarly, the splits in the two disorders localize to the lamina lucida on immunomapping. OTHER DIAGNOSTIC TESTS Results of IIF and DIF in pseudoporphyria are similar to those of PCT.20 Porphyrin levels in drug-induced pseudoporphyria and UVA drug-induced pseudoporphyria are normal. In dialysis-induced pseudoporphyria, serum porphyrins are increased, although UROD activity is normal.

174

DIFFERENTIAL DIAGNOSIS The histology of pseudoporphyria is not diagnostic and can be seen in such other diseases as PCT, EBA, DEB, JEB, and cell-poor BP.66 It should therefore be correlated with porphyrin assay, IF, and immunomapping. Table 8-18 shows the diagnostic criteria of pseudoporphyria.66

Table 8-18 Pseudoporphyria

Clinical Features Features often identical to porphyria cutanea tarda Chronic renal failure with hemodialysis common Secondary to particular medications: Furosemide Nalidixic acid Tetracycline Naproxen Tense bullae in sun-exposed skin Histopathologic Features Subepidermal blister In the dermis: Sparse perivascular and interstitial infiltration by lymphocytes Actinic elastosis and thick-walled blood vessels Laboratory Evaluation Blister mapping using antibodies against type IV collagen Intra-lamina lucida split Porphyrin laboratory tests Dialysis-induced pseudoporphyria: elevated serum porphyrin levels, normal UROD activity Drug-induced and UVA-induced pseudoporphyrias: normal UROD activity and serum porphyrin levels Differential Diagnosis Porphyria cutanea tarda

CLINICAL FEATURES Coma blisters are tense, usually clear, and occur at sites subjected to pressure, such as the hands, wrists, scapulae, sacrum, knees, legs, ankles, and heels (Table 8-19). 169-171 They appear on normal or erythematous skin, often in a linear distribution, and may reach substantial size. HISTOPATHOLOGICAL FEATURES Histopathologically, subepidermal blisters occur in association with necrosis of the eccrine

Table 8-19 Coma Blisters

Clinical Features Blisters at sites of pressure in comatose patients: hands, wrists, scapulae, sacrum, knees, legs, ankles, heels Often linear distribution Tense clear blisters on normal-appearing or erythematous skin Often quite large in size Histopathologic Features Subepidermal blister Necrosis of eccrine sweat glands and ducts and less commonly pilosebaceous units Sparse inflammation Laboratory Evaluation Direct immunofluorescence Negative Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister Differential Diagnosis Cell-poor bullous pemphigoid Epidermolysis bullosa (hereditary and acquired) Thermal injury Bullosis diabeticorum Pseudoporphyria Traumatic blisters

sweat glands and ducts (Table 8-19).66,171-173 Necrosis of pilosebaceous units may also be present. On immunomapping with antibodies against type IV collagen, the split localizes within the lamina lucida. OTHER DIAGNOSTIC TESTS DIF and IIF examinations in coma blisters are negative.66 DIFFERENTIAL DIAGNOSIS The histology of coma blisters is diagnostic based on the necrosis of appendageal structures and in combination with the clinical picture allows definitive diagnosis.66 Table 8-19 shows the diagnostic criteria of coma blisters.66

Cutaneous manifestations of diabetes mellitus occur in about 30% of diabetic patients.174 One of these is blister formation, known as bullosis diabeticorum or bullous diabeticorum (BD). BD usually affects patients with long-standing DM; however, it has been reported in newly diagnosed cases.175-178 CLINICAL FEATURES Clinically, clear painless blisters of several millimetres to many centimeters appear abruptly and spontaneously and are mainly located on the feet and lower legs and occasionally on the hands and forearms. They heal spontaneously in 2 to 5 weeks, without scarring, although the lesion(s) may relapse (Table 8-20). HISTOPATHOLOGICAL FEATURES BD is characterized histopathologically by formation of a subepidermal blister that may contain fibrin and a few inflammatory cells (Table 8-20). 66,177-178 The epidermis forming the blister roof is usually necrotic. In the dermis, there is sparse, superficial perivascular, and interstitial infiltration by lymphocytes. The blood vessels may have thickened walls. On immunomapping using antibodies against type IV collagen, the split is located in the lamina lucida.176,178 OTHER DIAGNOSTIC TESTS DIF and IIF examinations in BD are negative.66,176-179 Laboratory tests reveal the presence of diabetes mellitus. DIFFERENTIAL DIAGNOSIS The histology of BD is not diagnostic, and similar changes can be seen in such other diseases as PCT, EBA, DEB, JEB, and cellpoor BP.66 Interpretation requires correlation with the clinical presentation, laboratory test for diabetes mellitus, IF, and immunomapping.180

Clinical Features Patients with long-standing diabetes and other conditions Feet, lower legs, hands, forearms most affected Spontaneous healing without scarring in 2-5 weeks Painless clear blisters on normal-appearing or erythematous skin Several millimeters to several centimeters in size Histopathologic Features Subepidermal blister often with necrotic blister roof Fibrin Sparse perivascular and interstitial lymphocytic infiltrate Thickened walls of blood vessels Laboratory Evaluation Direct immunofluorescence Negative Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister Differential Diagnosis Cell-poor bullous pemphigoid Epidermolysis bullosa (hereditary and acquired) Porphyria cutanea tarda Pseudoporphyria Traumatic blisters

8.

9. 10.

11.

12.

13.

14.

15.

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Bullosis Diabeticorum

Table 8-20 Bullosis Diabeticorum

175

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London: Chapman and Hall Ltd.;1990: 263-275. McGrath JA, Gatalica B, Christiano AM, et al. Mutations in the 180-kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa. Nature Genet. 1995;11:83-86. Gatalica B, Pulkkinen L, Li K, et al. Cloning of the human type XVII collagen gene (COL17A1), and detection of novel mutations in generalized atrophic benign epidermolysis bullosa. Am J Hum Genet. 1997;60:352-365. Vidal F, Baudoin C, Miquel C, et al. Cloning of the laminin alpha-3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics. 1995;30:273-280. McGrath JA, Kivirikko S, Ciatti S, et al. A homozygous nonsense mutation in the alpha-3 chain gene of laminin 5 (LAMA3) in Herlitz junctional epidermolysis bullosa: prenatal exclusion in a fetus at risk. Genomics. 1995;29:282-284. Pulkkinen L, Christiano AM, Gerecke D, et al. A homozygous nonsense mutation in the beta-3 chain gene of laminin 5 (LAMB3) in Herlitz junctional epidermolysis bullosa. Genomics. 1994;24:357-360. Pulkkinen L, Meneguzzi G, McGrath JA, et al. Predominance of the recurrent mutation R635X in the LAMB3 gene in European patients with Herlitz junctional epidermolysis bullosa has implications for mutation detection strategy. J Invest Derm. 1997;109:232-237. Aberdam D, Galliano M-F, Vailly J, et al. Herlitz’s junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma-2 subunit of nicein/kalinin (laminin-5). Nature Genet. 1994;6:299-304. Pulkkinen L, Rouan F, BrucknerTuderman L, et al. Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. Am J Hum Genet. 1998;63:1376-1387. Haber H, Russel B. Sisters with familial benign chronic pemphigus (Gougerot, Hailey and Hailey). Br J Dermatol. 1950;62:458-460. Uitto J, Chung-Honet LC, Christiano AM. Molecular biology and pathology of type VII collagen. Exp Dermatol. 1992 Jul;1(1):2-11. Gedde-Dahl T, Jr. Epidermolysis bullosa syndromes. Curr Probl Dermatol. 1987;16: 129-145. Christiano AM, Bart BJ, Epstein EH, Jr, Uitto J. Genetic basis of Bart’s syndrome: a glycine substitution mutation in the type VII collagen gene. J Invest Derm. 1996;106:778-780. Cockayne EA. Inherited abnormalities of the skin and its appendages. London: Oxford University Press; 1933. Touraine MA. Classification des epidermolyses bulleuses. Ann Derm Syph. 1942;8:138-144. Hashimoto K, Matsumoto M, Iacobelli D. Transient bullous dermolysis of the newborn. Arch Derm. 1985;121:1429-1438. Hashimoto K, Burk JD, Bale GF, et al. Transient bullous dermolysis of the

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newborn: two additional cases. J Am Acad Derm. 1989;21:708-713. Shimizu H, Sato M, Ban M, et al. Immunohistochemical, ultrastructural, and molecular features of Kindler syndrome distinguish it from dystrophic epidermolysis bullosa. Arch Dermatol. 1997 Sep;133(9):1111-1117. Yasukawa K, Sato-Matsumura KC, McMillan J, Tsuchiya K, Shimizu H. Exclusion of COL7A1 mutation in Kindler syndrome. J Am Acad Dermatol. 2002 Mar;46(3):447-450. Kindler T. Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy. Brit J Derm. 1954;66:104-111. Al Aboud K, Al Githami A. Kindler syndrome in a Saudi kindred. Clin Exp Dermatol. 2002 Nov;27(8):673-676. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998 Oct 16;282(5388):490-493. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994 Nov 10;331(19):1272-1285. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993 Jan;129(1):92-96. Paul C, Wolkenstein P, Adle H, et al. Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol. 1996 Apr;134(4):710-714. Lyell A. Toxic epidermal necrolysis. An eruption resembling scalding of the skin. Br J Dermatol. 1956;68:361-366. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol. 1990 Dec;23(6 Pt 1):1039-1058. Ringheanu M, Laude TA. Toxic epidermal necrolysis in children—an update. Clin Pediatr (Phila). 2000 Dec;39(12):687-694. Becker DS. Toxic epidermal necrolysis. Lancet. 1998 May 9;351(9113):1417-1420. Avakian R, Flowers FP, Araujo OE, Ramos-Caro FA. Toxic epidermal necrolysis: a review. J Am Acad Dermatol. 1991 Jul;25(1 Pt 1):69-79. Revuz JE, Roujeau JC. Advances in toxic epidermal necrolysis. Semin Cutan Med Surg. 1996 Dec;15(4):258-266. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol. 1997 Nov; 24(11): 726-729. Lyon CC, Carmichael AJ. Toxic epidermal necrolysis and paraneoplastic pemphigus. Lancet. 1998 Jul 11;352(9122):149. Hughes AP, Callen JP. Drug-induced linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. Dermatology. 2001;202(2):138-139. Fritsch C, Lang K, von Schmiedeberg S, et al. Porphyria cutanea tarda. Skin Pharmacol Appl Skin Physiol. 1998 NovDec;11(6):321-335. Goerz G, Fritsch C, Bolsen K. Porphyrien aus dermatologischer Sicht. In: Macher E, Kolde G, Brocker EB, eds. Jahrbuch der Dermatologie. Stoffwechsel und Haul. Zülpich: Biermann Veriag; 1996: 75-99.

161. Kushner JP, Barbuto AJ, Lee GR. An inherited enzymatic defect in porphyria cutanea tarda: decreased uroporphyrinogen decarboxylase activity. J Clin Invest. 1976;58:1089-1097. 162. Elder GH, Lee GB, Tovey JA. Decreased activity of hepatic uroporphyrinogen decarboxylase in sporadic porphyria cutanea tarda. New Eng J Med. 1978;299: 274-278. 163. Felsher BF, Carpio NM, Engleking DW, Nunn AT. Decreased hepatic uroporphyrinogen decarboxylase activity in porphyria cutanea tarda. New Eng. J. Med. 1982;306:766-769. 164. Grossman ME, Bickers DR, PohFitzpatrick MB, Delco VA, Harber LC. Porphyria cutanea tarda: clinical features and laboratory findings in 40 patients. Am J Med. 1979;67: 277-286. 165. Dabski C, Beutner EH. Studies of laminin and type IV collagen in blisters of porphyria cutanea tarda and druginduced pseudoporphyria. J Am Acad Dermatol. 1991 Jul;25(1 Pt 1):28-32. 166. Bickers DR. Photosensitization by porphyrins. In: Goldsmith LA, ed. Biochemistry and Physiology of the Skin. New York: Oxford University Press; 1983:755-762. 167. Maynard B, Peters MS. Histologic and immunofluorescence study of cutaneous porphyrias. J Cutan Pathol. 1992 Feb;19(1):40-47. 168. Green JJ, Manders SM. Pseudoporphyria. J Am Acad Dermatol. 2001 Jan;44(1):100-108. 169. Mehregan DR, Daoud M, Rogers RS, III. Coma blisters in a patient with diabetic ketoacidosis. J Am Acad Dermatol. 1992 Aug;27(2 Pt 1):269-270. 170. Wenzel FG, Horn TD. Nonneoplastic disorders of the eccrine glands. J Am Acad Dermatol. 1998 Jan;38(1):1-17. 171. Dunn C, Held JL, Spitz J, Silvers DN, Grossman ME, Kohn SR. Coma blisters: report and review. Cutis. 1990 Jun; 45(6):423-426. 172. Ackerman AB. Histologic diagnosis of inflammatory skin diseases. Philadelphia, PA: Lea & Febiger; 1978. 173. Sanchez Yus E, Requena L, Simon P. Histopathology of cutaneous changes in drug-induced coma. Am J Dermatopathol. 1993 Jun;15(3):208-216. 174. Perez MI, Kohn SR. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol. 1994 Apr;30(4):519-531. 175. Kramer DW. Early or warning signs of impending gangrene in diabetes. Med J Rec. 1930;132: 338-342. 176. Basarab T, Munn SE, McGrath J, Russell Jones R. Bullosis diabeticorum. A case report and literature review. Clin Exp Dermatol. 1995 May;20(3):218-220. 177. Derighetti M, Hohl D, Krayenbuhl BH, Panizzon RG. Bullosis diabeticorum in a newly discovered type 2 diabetes mellitus. Dermatology. 2000;200(4):366-367. 178. Toonstra J. Bullosis diabeticorum. Report of a case with a review of the literature. J Am Acad Dermatol. 1985 Nov;13(5 Pt 1): 799-805. 179. Oursler JR, Goldblum OM. Blistering eruption in a diabetic. Bullosis diabeticorum. Arch Dermatol. 1991 Feb;127(2):247, 250. 180. Megahed M. Krankheiten mit subepidermaler Blasenbildung. In: Kerl H, Garber S, Wolf H. Histopathologie der Haut. New York: Springer Verlag, Heidelberg: 2003.

CHAPTER 9 Vasculitis and Related Disorders Sarah K. Barksdale Raymond L. Barnhill

CLINICAL AND HISTOLOGIC DEFINITIONS The clinical manifestations of vascular damage include edema, livedo reticularis, and various manifestations of subcutaneous hemorrhage or purpura. Hemorrhagic lesions less than 3 mm in diameter are called petechiae. If they are larger, they are called ecchymoses. Raised or palpable purpura generally indicate the presence of an inflammatory cell infiltrate. If vascular damage is severe, vascular occlusion may lead to ischemic injury resulting in necrosis, gangrene, and/or ulceration. Vascular injury can occur in forms limited to the skin. However, in many instances vascular injury occurs in the context of a systemic disease. Vascular damage may be the principal event of a disease process, such as in polyarteritis nodosa (PAN); a significant component of a complex disease, as in connective tissue disease; or simply a secondary effect to a localized injury, such as an arthropod bite or traumatic ulcer. Histologically, vascular injury may occur with or without inflammation. The composition and cellularity of the associated inflammatory cell infiltrate, as well as the extent of vascular damage, may also vary (Table 9-1). Vasculitis is defined as an inflammatory process resulting in clear-cut vascular damage. Histologic recognition of vasculitis relies on the recognition of two components: an inflammatory cell infiltrate and evidence of vascular injury (see Table 9-1; Fig. 9-1). If vasculitis is defined as an inflammatory process, the absence of inflammation, even if vascular damage is present, precludes the diagnosis. The composition and cellularity of the

Primary Vascular Injury Vasculitis Inflammatory cell infiltrate Clear-cut vascular damage (eg, fibrinoid necrosis of vessel wall) Inflammatory vascular reaction Inflammatory cell infiltrate Limited vascular damage (insufficient for vasculitis) Vasculopathy Lack of inflammation Vascular damage of any degree Secondary Vascular Injury May present as vasculitis, inflammatory vascular reaction, or vasculopathy Secondary to another insult such as external trauma, ulceration Variable vascular alterations with sparing of some vessels Peripheral perivascular fibrinoid deposition

inflammatory infiltrate of a vasculitis may correlate with the chronology of the process, but not always. Early on, neutrophils and/or eosinophils may predominate. In the late healing stage, the inflammatory cell infiltration may be minimal with an excess of lymphocytes and macrophages. The histologic criteria for recognizing microvascular injury are somewhat arbitrary, and the minimal criteria for vasculitis remain controversial. Various histologic

Table 9-2 Histological Manifestations of Vascular Damage Necrosis of vessel wall with deposition of fibrinoid materiala Leukocytoclasis Extravasation of erythrocytes Endothelial cell swelling Luminal thrombosis Edema a

Generally required for a diagnosis of vasculitis.

features are considered to be indicative of vascular injury (Table 9-2). Certain changes, including edema, extravasation of erythrocytes, infiltration of vessel walls by inflammatory cells, leukocytoclasis, and thrombosis, may occur without actual damage to the structural integrity of the vessel. Vessels become leaky for physiologic reasons, leading to edema or even extravasation of erythrocytes and leukocytes. Leukocytoclasis may result from the breakdown of a perivascular neutrophilic infiltrate during the resolution of an inflammatory process unrelated to vasculitis. Similarly, fibrin thrombi may be present in essentially uninjured vessels in the setting of a hypercoagulable state. Unequivocal injury to the vascular wall is manifested by deposition of fibrinoid material and/or necrosis. In other words, a diagnosis of vasculitis is established histologically if vascular inflammation is

 FIGURE 9-1 Fibrinoid degeneration. Fibrinoid material is deposited within a vessel. There is also a polymorphonuclear infiltrate.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

This chapter discusses a group of conditions whose common denominator is damage to cutaneous blood vessels. Emphasized is the concept that vascular injury is a dynamic process with a limited spectrum of clinical and histologic reaction patterns.

Table 9-1 Definitions of Vascular Injury

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accompanied by fibrinoid alterations of the vessel wall. Is the presence of fibrinoid necrosis an absolute prerequisite for the pathologist to render a diagnosis of vasculitis? For didactic purposes, it is tempting to answer the question with an unambiguous “yes.” Yet in some cases other features of vascular damage, such as leukocytoclasis or intraluminal thrombi, are developed to such a degree that the constellation of findings favors vasculitis despite the lack of clear-cut fibrinoid necrosis. As a general rule, however, we advise the application of strict criteria for the diagnosis of vasculitis and caution in diagnosing vasculitis in the absence of fibrinoid necrosis. The term vasculopathy or pseudovasculitis is used to describe evidence of vascular damage in the absence of inflammation. The degree of vascular damage is variable. The spectrum of clinical settings in which noninflammatory vascular injury commonly occurs includes mainly coagulopathies and other vascular occlusive conditions. Hemmorrhage, intraluminal thrombi, or emboli are histologic findings in these disorders (Fig. 9-2). There is a third group of reactions in which inflammation is present, but the extent of vascular injury usually is limited and appears insufficient for vasculitis. This group of disorders encompasses a great number of heterogeneous inflammatory conditions, which may regularly or occasionally manifest vascular injury. Accordingly, including these entities in a chapter on vasculitis is a somewhat arbitrary decision. We have included those diseases whose histologic or clinical presentation warrants distinction from “true” vasculitis. Since the only common denominator for these disorders is the presence of an inflammatory infiltrate and some limited vascular damage, we designate them inflammatory vascular reactions (Fig. 9-3). This term is an adaptation and generalization of the more established term neutrophilic vascular reactions, which was coined to define a group of inflammatory disorders that showed histologic overlap with neutrophilic smallvessel vasculitis.1 An important step in evaluating vascular injury is to determine whether the vascular damage is a primary or secondary process. Primary vascular injury implies that the vascular insult is the predominant disease process. Secondary vascular injury indicates that another disease process outside the vessels is the primary pathologic process. An example of the latter would be vessels engulfed by the necrotizing inflammation around an ulceration initiated by external insult

 FIGURE 9-2 Vasculopathic reaction. Fibrin thrombi in small dermal vessels are seen with a minimal inflammatory cell infiltrate.

 FIGURE 9-3 Inflammatory vascular reaction. Occasional perivascular karyorrhectic debris and endothelial cell swelling are noted. However, no fibrinoid necrosis is present.

or infection. Usually, the primary disease process is evident microscopically. However, occasionally, secondary vascular changes can be misleading when noted on evaluation of shallow tissue sections before the primary process becomes visible. Secondary vascular injury often is variable, with sparing of

some vessels in the zone of tissue injury. Other indications of secondary vascular injury include deposition of fibrinoid material at the periphery of the vessel wall, focal thrombosis without significant infiltration by inflammatory cells, and extensive inflammation or granulation tissue between blood vessels.

VASCULITIS

CONDITION Giant cell (temporal) arteritis

Takayasu arteritis

Polyarteritis nodosa (classic polyarteritis nodosa) Kawasaki disease

Wegener granulomatosisc,d

Churg-Strauss syndromec,d

Microscopic polyangiitis (microscopic polyarteritis)c,d

Henoch-Schönlein purpurad

Essential cryoglobulinemic vasculitisd

Cutaneous leukocytoclastic angiitis

DEFINITION

Large-Vessel Vasculitisb (>10 mm in diameter) Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery; often involves the temporal artery; usually occurs in patients older than 50 years and often is associated with polymyalgia rheumatica Granulomatous inflammation of the aorta and its major branches; usually occurs in patients younger than 50 years Medium-Sized Vessel Vasculitisb (about 0.3-10 mm) Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules Arteritis involving large, medium-sized, and small arteries, and associated with mucocutaneous lymph node syndrome; coronary arteries are often involved; aorta and veins may be involved; usually occurs in children Small-Vessel Vasculitisb (10-20 um to 300 um) Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small-to medium-sized vessels, eg, capillaries, venules, arterioles, and arteries; necrotizing glomerulonephritis is common Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small- to medium-sized vessels, and associated with asthma and blood eosinophilia Necrotizing vasculitis with few or no immune deposits affecting small vessels, ie, capillaries, venules, or arterioles; necrotizing arteritis involving small- and medium-sized arteries may be present; necrotizing glomerulonephritis is very common; pulmonary capillaritis often occurs Vasculitis with IgA-dominant immune deposits affecting small vessels, ie, capillaries, venules, or arterioles; typically involves skin, gut, and glomeruli, and is associated with arthralgias or arthritis Vasculitis with cryoglobulin immune deposits affecting small vessels, ie, capillaries, venules, or arterioles, and associated with cryoglobulins in serum; skin and glomeruli are often involved Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

The classification of vasculitis is difficult for a number of reasons.2-5 The various vasculitic disease entities do not have specific histologic features, and the same disease process may show a spectrum of histologic changes depending on the stage of the disease, the level of activity, and treatment that might have modified its course. Moreover, advances in research have redefined or expanded the definitions of certain disease processes with subsequent loss of histologic criteria previously thought to be specific. Considerable, overlap between vasculitis syndromes exists with many case reports describing patients with hybrid disease states. In an attempt to standardize nomenclature for the vasculitides, an international conference has proposed a system based primarily on the size of the involved vessels4 (Table 9-3). A second international conference has proposed a similar classification tailored to the childhood vasculitides.5 Classification based on vessel size is helpful because there is some correlation with the clinical presentation. Purpura, palpable purpura, urticaria, vesicles and bullae, and splinter hemorrhages typically reflect small-vessel injury. Cutaneous nodules, ulcers, livedo reticularis, and racemosa and digital gangrene suggest the involvement of medium-sized arteries. However, classification based on vessel size alone is of limited value in dermatopathology because most cutaneous vasculitides affect primarily small dermal vessels. In addition, medium-sized-vessel vasculitis frequently will show some degree of small-vessel involvement and vice versa. Classification by etiology or pathogenetic mechanism is difficult because much remains to be learned about the causes of vasculitis. A practical approach (Table 9-4) to evaluating inflammed blood vessels is first to decide whether or not clear-cut vascular damage is present and is sufficient for a designation as vasculitis and then to assess the composition of the inflammatory infiltrate (neutrophilic/leukocytoclastic versus lymphocytic versus granulomatous) and its distribution (superficial, superficial and deep, or deep only) and to look for associated findings, such as microorganisms, that might narrow the differential diagnosis. The context of the histologic findings is important. Are the vasculitic changes merely secondary events in the setting of a herpetic ulcer? Lesions have a life span, and for example, a lesion that shows a leukocytoclastic vasculitis (LCV) at one

Table 9-3 Names and Definitions of Vasculitis Adopted by the Chapel Hill (NC) Consensus Conference on the Nomenclature of Systemic Vasculitisa

a

Modified from Jennette et al.4 Larger artery refers to the aorta and the largest branches directed toward major body regions (eg, to the extremities and the head and neck); medium-sized artery refers to the main visceral arteries (eg, renal, hepatic, coronary, and mesenteric arteries), and small artery refers to the distal arterial radicals that connect with arterioles (eg, renal arcuate and interlobular arteries). Note that some small- and large-vessel vasculitides may involve medium-sized arteries; but large- and medium-sized vessel vasculitides do not involve vessels smaller than arteries. c Strongly associated with antineutrophil cytoplasmic autoantibodies. d May be accompanied by glomerulonephritis and can manifest as nephritis or pulmonary-renal vasculitis syndrome.

b

point may show a predominantly lymphocytic or even granulomatous infiltrate at another point in time. The following sections discuss the histologic features and differential diagnoses

of vasculitides affecting the skin with emphasis on the small-vessel vasculitides. As suggested, classification of these disease entities into discrete categories is somewhat arbitrary because significant

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Table 9-4 Approach to Vasculitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Determine if vasculitis or vasculopathy is present or absent Determine if primary or secondary vascular injury, if possible Size of vessel and type Large Medium Small Composition of infiltrate Neutrophilic/leukocytoclastic Lymphocytic Histiocytic/granulomatous Evaluation for infection (special stains for microorganisms and cultures) Additional histologic clues: Intravascular PAS-positive bright red material (suspicious for cryoprecipitates) Viral cytopathic changes (eg, HSVaassociated vascular damage) Plasma cells (spirochetes) Presence of eosinophils (r/o drug, hypersensitivity reaction) Changes suggestive of connective tissue disease (eg, interface dermatitis; dermal mucin) Edema (urticarial reaction) Serologic and immunopathologic evaluation ANCA, ANA, rheumatoid factor, cryoglobulins immunofluorescence, and other studies for the detection of immune complexes, eg, IgA fibronectin aggregates Clinical context Cutaneous involvement only Extent of systemic involvement a

HSV: Herpes simplex virus.

overlap of features exists. A key concept is that some of the histologic entities discussed are not actual diseases per se but are reaction patterns to a wide variety of etiologic stimuli. As an organizing principle for discussing small-vessel vasculitides, we follow mainly morphologic criteria, that is, the composition of the inflammatory cell infiltrate (neutrophilic versus lymphocytic versus granulomatous). After reviewing small-vessel vasculitides and other inflammatory vascular reactions that need to be distinguished from vasculitis, we discuss systemic ANCA-associated vasculitides and vasculitides of mediumand large-sized vessels separately.

SMALL-VESSEL NEUTROPHILIC/ LEUKOCYTOCLASTIC VASCULITIS

182

A large number of different disease processes can be accompanied by smallvessel vasculitis with predominantly

Table 9-5 Differential Diagnosis of Cutaneous Neutrophilic Small Vessel Vasculitis Infection associated Bacterial Gram-positive/-negative organisms, mycobacteria, spirochetes Rickettsial Rocky Mountain spotted fever Scrub typhus Fungal Viral Immunologic-injury associated Immune-complex mediated Henoch-Schoenlein purpura Urticarial vasculitis Cryoglobulinemia Serum sickness Connective tissue diseases Autoimmune diseases Infection-induced immunologic injury (eg, hepatitis B or C, streptococcal) Drug-induced Paraneoplastic processes Behçet disease Erythema elevatum diutinum Antineutrophil-antibody associated Wegener granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Some drug-induced vasculitis No known association Polyarteritis nodosa

neutrophilic infiltrates. The main diseases to be considered are listed in Table 9-5.6 CLINICAL FEATURES The clinical manifestations are related to the depth of vascular involvement and degree of vascular injury. Vasculitis confined to the superficial dermis may exhibit lesions ranging from urticarial lesions to erythematous and purpuric macules, papules, and pustules (Fig. 9-4A). Involvement of the deep reticular dermal vascular plexus and subcutaneous fat by small-vessel vasculitis may result in hemorrhagic bullae, livedo reticularis, erythematous nodules, and cutaneous infarcts and necrosis. The single most common manifestation of this form of vasculitis is palpable purpura, that is, small papules associated with purpura (Fig. 9-4A). The distal lower extremities are the most common location, although any site may be involved. HISTOPATHOLOGIC FEATURES Neutrophilic small-vessel vasculitis is a reaction pattern of small dermal vessels, almost exclusively postcapillary venules, characterized by a combination of vascular

damage and an infiltrate composed largely of neutrophils (Fig. 9-4). Since there is often fragmentation of nuclei (karyorrhexis or leukocytoclasis), the term leukocytoclastic vasculitis (LCV) is used frequently. Depending on its severity, this process can be subtle and limited to the superficial dermis or pandermal and florid and associated with necrosis and ulceration. If edema is prominent, a subepidermal blister may form. In a typical case of LCV, the dermal vessels show swelling of the endothelial cells and deposits of strongly eosinophilic strands of fibrin within and around their walls. The deposits of fibrin and the marked edema together give the walls of the vessels a “smudgy” appearance referred to as fibrinoid degeneration (see Fig. 9-1). Actual necrosis of the perivascular collagen, however, is seen primarily in conjunction with lesions of vasculitis showing ulceration. Luminal occlusion of vessels by an expanded, inflamed, edematous vessel wall or by microthrombi may be observed. The cellular infiltrate is present predominantly around or within dermal blood vessels, blurring the vascular outlines. Neutrophils and varying numbers of eosinophils and mononuclear cells are found in the infiltrate. Karyorrhectic nuclear debris, or nuclear dust, gives these infiltrates a dirty appearance. If neutrophils are numerous and densely packed, micropustules are formed. If large pustules are found, the process can be termed pustular vasculitis (Fig. 9-5). Inflammatory cells also may be scattered throughout the upper dermis in association with fibrin deposits between and within collagen bundles. Extravasation of erythrocytes is almost invariably present. As with any inflammatory process, the appearance of the reaction pattern depends on the stage at which the biopsy is taken. In older lesions, the number of neutrophils may be decreased and the number of mononuclear cells increased so that mononuclear cells may predominate, and a designation of a lymphocytic or even granulomatous vasculitis or vascular reaction might be made. Many infectious and immunologically mediated processes are associated with vasculitis (see Table 9-5). In many cases the pathogenesis is unknown. The final common pathway typically involves neutrophils and monocyte activation with adherence to endothelial cells, infiltration of the vessel wall, and release of lytic enzymes and toxic radicals. The cascade leading to vascular injury may be initiated by (1) the deposition of immune complexes, (2) direct binding of antibodies to antigens in vessel walls, and (3) activation

B

 FIGURE 9-4 Leukocytoclastic vasculitis. (A) Erythematous and violaceous purpuric macules and papules (“palpable purpura”) characertistically involving the distal lower extremities. In addition necrotic, eroded, and ulcerated lesions are present. (B) Vascular damage with fibrinoid necrosis (red material at arrow head) and a perivascular neutrophilic infiltrate and nuclear debris are seen.

of leukocytes by antibodies with specificity for leukocyte antigens (ANCAs).

Diagnostic Approach to Neutrophilic Small-Vessel Vasculitis The cutaneous and histologic manifestations are largely nonspecific for the small-vessel vasculitides. Palpable purpura

may be the clinical appearance of dermal leukocytoclastic small-vessel vasculitis secondary to any of the entities listed in Table 9-5. Therefore, to reach an appropriate diagnosis, additional histologic clues (see Table 9-4) must be sought, and the histologic findings should only be interpreted in the context of clinical information. Often additional

 FIGURE 9-5 Pustular vasculitis. Intraepidermal pustule formation with many polymorphonuclear cells and vascular damage are present.

laboratory data, such as from microbiologic cultures, special stains for organisms, immunofluorescence, or serologic studies, are needed. One of the most important diagnostic steps in the evaluation of a vasculitis is to rule out an infectious process. If noninfectious vasculitis is suspected, evidence for systemic vasculitis must be sought. Clinical findings, such as hematuria, arthritis, and myalgia, and laboratory findings, such as enzymatic assays for muscle or liver enzymes, serologic analysis for ANCAs, antinuclear antibodies, cryoglobulins, hepatitis B and C antibodies, IgAfibronectin aggregates, and complement levels, are important to further delineate the disease process. Exposure to a potential allergen, such as a drug, that might have elicited a hypersensitivity reaction should be sought. Evidence of an allergic pathogenesis reassuringly suggests that the vasculitic process may be self-limited and not associated with systemic vasculitis. As mentioned previously, the possibility that the vasculitislike histologic findings are a secondary phenomenon should be excluded. The following paragraphs discuss the main clinical settings in which LCV occurs. INFECTIOUS VASCULITIS An infectious process needs to be ruled out early in the evaluation of an LCV.2,4 Clinically, the spectrum of findings ranges from small macules to papules, pustules, and purpura. Histologically, infection-related vasculitis probably shows a greater frequency of the following changes: subcorneal, intraepidermal, and subepidermal neutrophilic pustules and abscesses, that is, pustular vasculitis; dermal infiltrates with more

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

A

183

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 184

neutrophils relative to other cell types, such as eosinophils and lymphocytes; and intravascular fibrin thrombi, some of which will contain microorganisms on occasion. On the other hand, infectionrelated vasculitis may show a lesser degree of vascular damage compared with noninfectious vasculitides. Microorganisms may invade vessels directly or damage them by an immune-mediated mechanism. Neisseria meningitidis is a common cause of infectious cutaneous leukocytoclastic vasculitis. Meningococci may be found within endothelial cells and neutrophils at sites of vascular inflammation. However, other gram-positive or gramnegative bacteria and fungi also may cause cutaneous small-vessel vasculitis. Staphylococcal sepsis can lead to neutrophilic vasculitis with purpura or nodular lesions that may contain microabscesses (Fig. 9-6). Acid-fast organisms also cause vasculitis. Lucio phenomenon (erythema necroticans) and erythema nodosum leprosum (ENL) are syndromes that may arise during the course of lepromatous leprosy. These entities are discussed in Chap. 19. In both cases, biopsies show vascular damage, including LCV. Histologically, Lucio phenomenon shows necrotizing small-vessel vasculitis, and Fite-Faraco staining reveals large

aggregates of acid-fast bacilli within the vascular walls and endothelium and throughout the dermis. Ischemia and necrosis of the epidermis, dermis, and adnexal structures often with ulceration are seen. Some researchers have suggested that the massive endothelial mycobacterial burden in Lucio phenomenon may lead directly to vascular damage.7 Rickettsial infections, such as Rocky Mountain spotted fever (RMSF), are characterized by invasion of endothelial cells by organisms causing vascular damage. Inflammation, however, often is minimal in RMSF. The Brown-Hopp stain and direct immunofluorescence microscopy may demonstrate the organism. Many viral organisms such as hepatitis C, herpesvirus, and parvovirus B198 may result in LCV on occasion. ANCA-ASSOCIATED VASCULITIDES Microscopic polyarteritis (MPA) nodosa, Wegener granulomatosis (WG), and Churg-Strauss syndrome (CSS) may be associated with LCV and are discussed at length under ANCA-associated vasculitides. HENOCH-SCHÖNLEIN PURPURA HenochSchönlein purpura (HSP) is characterized clinically by palpable purpura of the buttocks and lower extremities, abdominal

 FIGURE 9-6 Septic vasculitis. Small dermal vessel filled with coccal forms and surrounded by a neutrophilic infiltrate.

pain, and hematuria. Retiform or patterned purpura is considered characteristic of HSP. Occasionally, hemorrhagic bullae may be seen.9 Typically, but not exclusively, children are affected after a streptococcal upper respiratory tract or other infection. However, the clinical picture of HSP is often incomplete. A diagnostic skin biopsy can clarify such cases before significant renal injury occurs. In adults, HSP is less common and histologic confirmation is also important to exclude mimics including serious underlying illnesses such as malignancy.10 Acute infantile hemorrhagic edema (AHE) is an uncommon benign form of cutaneous vasculitis occurring in children less than 2 years of age and is considered by some to be a variant of HSP. AHE often presents with striking inflammatory edema and ecchymotic purpura with a targetoid or cockade appearance. Recently rotavirus infection has been implicated in one case.11 Theoretically, abnormalities in the production of IgA follow stimulation of the mucosal immune system. A selflimited syndrome results and usually resolves within 6 to 16 weeks after onset. Complications generally arise from renal involvement that may even necessitate kidney transplantation. Various genetic polymorphisms may lead to a predisposition to or protection from these complications.12 IgA myeloma also has resulted in HSP-like manifestations.13 Familial Mediterranean fever is also associated with HSP, and occult cases of this genetic disease may be uncovered in patients presenting with HSP.14 HSP cannot be distinguished histologically from other forms of LCV, although the vascular damage in HSP often is more subtle. The limited extent of vascular damage is similar to that observed in some cases of infectious vasculitis or urticarial vasculitis (see the following section). However, in HSP, immunofluorescence studies typically demonstrate deposition of IgA in capillaries. IgA-associated vasculitis may occur outside the symptom complex of HSP.15 However, serologic detection of IgA-fibronectin aggregates may be associated with greater likelihood of renal or systemic disease in patients with cutaneous LCV.16 URTICARIAL VASCULITIS Urticarial vasculitis is not a specific disease but is a pattern of often minimal vasculitis associated with increased vascular permeability. Persistent wheals (lasting more than 24 hours by convention) with faint purpura are a typical clinical finding. Often,

CRYOGLOBULINEMIAS AND OTHER SMALLVESSEL VASCULITIDES ASSOCIATED WITH PARAPROTEINS Small-vessel vasculitis may be associated with paraproteins, that is, abnormal serum proteins, including cryoglobulins, cryofibrinogens, macroglobulins, and gamma heavy chains.2,19 Type I cryoglobulinemia most commonly leads to an occlusive vasculopathy, as discussed later in this chapter, but also can be associated with LCV. Examples include the hyperglobulinemic purpura of Waldenström hyperglobulinemia and Schnitzler syndrome, which manifests as chronic urticaria with macroglobulinemia (usually monoclonal IgM) and other paraproteinemias. Types II and III or mixed cryoglobulinemia frequently are associated with connective tissue disorders or infection, in particular, hepatitis C (HCV) infection. Idiopathic cases are referred to as essential cryoglobulinemia. The cryoprecipitates in mixed cryoglobulinemias are typically a composite of polyclonal IgG and an IgM rheumatoid factor that may be monoclonal. Clonal expansion of the rheumatoid factor-synthesizing B lymphocytes is fundamental to the development of mixed cryoglobulinemia. In the case of cryoglobulinemia associated with HCV, HCV particles and nonenveloped nucleocapsid protein participate in the formation of immune complexes.20 The rheumatoid factor Bcell clonal expansion primarily takes place in the liver and correlates directly with

 FIGURE 9-7 Urticarial vasculitis.There is dermal edema and a sparse predominantly polymorphonuclear vascular reaction.

intrahepatic HCV viral load, indicating the critical role of HCV the pathogenesis of such B-cell clonality. In any case, mixed cryopercipitates commonly trigger a cutaneous LCV but occasionally form periodic

acid-Schiff (PAS)-positive intramural and intravascular deposits (Fig. 9-8). SERUM SICKNESS This self-limited syndrome is typified by a morbilliform

 FIGURE 9-8 Cryoglobulinemia. PAS-positive bright red cryoprecipitates (arrow) are seen in small superficial dermal vessels.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

residual purpura are seen after resolution of the urticarial lesions.17 The clinical course generally is benign and episodic, lasting several months. However, urticarial vasculitis occurs with some frequency in lupus erythematosus and may be the initial clinical manifestation of the disease. The histology of urticarial vasculitis ranges from mild vascular damage with swollen endothelial cells and a sparse infiltrate composed of neutrophils, eosinophils, and lymphocytes to fully developed LCV (Fig. 9-7). The minimal essential criteria for UV include nuclear debris or fibrinoid alteration of microvessels, with or without extravasation of erythrocytes. Approximately one-third of patients with vasculitic urticaria have decreased complement levels (hypocomplementemic vasculitis). These patients may have systemic findings, such as arthralgias and adenopathy, and may be more likely to have underlying systemic lupus erythematosus.18 Low complement levels and positive anti-C1q antibodies may indicate greater likelihood of more severe systemic disease.

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Table 9-6 Drugs and Sera Associated with SerumSickness Reactionsa

Table 9-7 Common Examples of Drugs Associated with Vasculitisa

Cefaclor Minocycline Penicillins Propranolol Streptokinase Horse serum diphtheria antitoxin Horse serum antithymocyte globulins Human diploid cell rabies vaccine

Allopurinol Penicillin and aminopenicillins Sulphonamides Thiazide diuretics Pyrazolones Hydantoins Propylthiouracil a

Data from Wollenstein and Revuf, 1995.23

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

a

urticarial eruption, fever, arthralgias-myalgias, and lymphadenopathy occurring 7 to 10 days after a primary antigen exposure or 2 to 4 days after a repeat exposure. The offending antigen may be a drug, an arthropod sting, an antecedent infection, or therapeutic serum globulins.21 The LCV of serum sickness is not distinctive. Drugs and sera commonly associated with serum sickness are listed in Table 9-6. CONNECTIVE TISSUE DISEASE Rheumatoid arthritis, lupus erythematosus, dermatomyositis, and other diseases in the spectrum of connective tissue disease may develop LCV. Leukocytoclastic vasculitis may also occur in patients with antiphospholipid antibody syndrome.22 Clinical and serologic information is critical to arrive at the correct interpretation of the cutaneous findings in these clinical settings. AUTOIMMUNE DISEASES Primary Sjögren syndrome not associated with connective tissue disease may present with purpura in addition to ocular and glandular involvement.2 Skin biopsy commonly shows an LCV or lymphocytic vasculitis.

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DRUG-INDUCED VASCULITIS A hypersensitivity reaction to a drug or immunotherapeutic agent may result in an LCV or even a pustular vasculitis.2,6,23,24 Penicillin, thiazides, and sulfonamides are the most common drugs to induce LCV (Table 9-7). Increased tissue eosinophil counts (5.2 vs 1.05 per 10 high-power fields) have recently been shown to correlate with drug-induced versus non-drug-induced LCV.25 Vasculitic hypersensitivity may also result from the ingestion of nondrug chemicals, such as food additives, or allergenic foodstuffs.

Data from Wollenstein and Revuf, 1995.23

PARANEOPLASTIC VASCULITIS A wide spectrum of vasculitic processes has been associated with neoplastic disorders.26 The most common associations include polyarteritis nodosa with hairy cell leukemia and cutaneous smallvessel vasculitis with lympho or myelo proliferative disorders. Solid tumors are less commonly implicated. Occasional cases of Wegener granulomatosis, microscopic polyarteritis nodosum, and HenochSchönlein purpura have been reported.27,28 VASCULITIS INDUCED BY PHYSICAL FACTORS Leukocytoclastic vasculitis and urticarial vasculitis are not uncommon, occur in long-distance runners, and/or in females after long walks, especially in hot weather. The skin compressed by socks may be spared. No clear relation with chronic venous disease or underlying medical conditions has been established.29,30 Occasional reports of solar induced urticaria with leukocytoclastic vasculitis have been reported.31

Behçet Disease CLINICAL FEATURES Behçet disease is a multisystem disease characterized by oral aphthous lesions and at least two of the following criteria: genital aphthae, synovitis, posterior uveitis, superficial thrombophlebitis (STP), cutaneous pustular vasculitis, and meningoencephalitis (Table 9-8). Exacerbations and remissions are unpredictable. The skin pathergy reaction, a nonspecific hyperreactive lesion in response to a needle-prick, has been used in the diagnosis of Behçet disease. This reaction is similar to the erythematous papules or pustules that appear spontaneously in these patients. Behçet disease is most common from the Middle East through Asia, but is rare in northern Europe and the United States. An association with HLA-B51 has been reported. The clinical presentation is

Table 9-8 Behçet Syndrome

Clinical Features Oral and genital aphthae Synovitis Posterior uveitis Meningoencephalitis Vascular lesions: cutaneous pustular vasculitis, aneurysms, arterial or venous occlusions, varices Middle East and Japan, rare in Northern Europe and the United States HLA-B51 associated Histopathologic Features Early: neutrophilic, fully developed necrotizing leukocytoclastic vasculitis or pustular vasculitis Late: lymphocytic and granulomatous vascular reactions Differential Diagnosis Infection and infectious vasculitis Vasculitis in connective tissue disease Paraneoplastic vasculitis Neutrophilic vascular reactions Sweet syndrome Pyoderma gangrenosum Inflammatory bowel disease Other pustular vasculitides Bowel bypass–associated process

extremely variable and so is the vascular involvement. Vascular lesions include not only active inflammatory lesions but also aneurysms, arterial or venous occlusions, and varices.32 The etiology of Behçet disease remains unknown. Enhanced inflammatory response to minor stimuli and the possibility of a genetic susceptibility suggest that Behçet disease may be an autoinflammatory disorder, similar to familial Mediterranean fever.33 HISTOPATHOLOGIC FEATURES The histopathologic spectrum of mucocutaneous inflammatory vascular lesions, depending on the stage and activity of the lesion, includes neutrophilic, lymphocytic, and granulomatous vascular reactions. Biopsy specimens of early lesions typically show a neutrophilic vascular reaction, and Behçet disease is sometimes classified as a neutrophilic dermatosis/neutrophilic vascular reaction. However, unlike in the neutrophilic dermatoses, fully developed necrotizing leukocytoclastic vasculitis, pustular vasculitis, or lymphocytic vasculitis may develop (see Figs. 9-4, 9-5, 9-12).

LOCALIZED FIBROSING SMALL-VESSEL VASCULITIS Erythema elevatum diutinum (EED) and granuloma faciale (GF) and some examples of cutaneous inflammatory pseudotumor are very similar chronic fibrosing conditions that show evidence of vascular damage. Sometimes, these entities are classified with the neutrophilic dermatoses. All are hypothesized to be reactions to localized persistent immune-complex deposition or hypersensitivities to a persistent antigen. EED- and GF-like reactions may be seen occasionally in clinical settings atypical for either entity.34

EED probably is not a distinct disease entity but rather a clinicopathologic reaction pattern most often developing in association with either a monoclonal or polyclonal gammopathy and in particular IgA hyperglobulinemia. Inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus also may be associated with EED. HIV-infected patients also develop EED, which can mimic Kaposi sarcoma clinically.36 HISTOPATHOLOGIC FEATURES In the early stage of EED, LCV is observed. In later stages, granulation tissue and fibrosis

develop with a diffuse mixed-cell infiltrate showing a predominance of neutrophils (Fig. 9-9). The capillaries may still show deposits of fibrinoid material or merely fibrous thickening. Vertically oriented vessels, as noted in scars, suggest EED. In the late fibrotic stage, lipid material also may be present as cholesterol clefts. Serial sections may be required to demonstrate vascular damage in late lesions. DIFFERENTIAL DIAGNOSIS Early lesions of EED show nonspecific LCV. Fully developed lesions of EED may be indistinguishable from Sweet syndrome,

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

Erythema Elevatum Diutinum CLINICAL FEATURES This rare condition is characterized by persistent, initially redto-violaceous and later brown-to-yellow papules, nodules, and plaques.35 The lesions, typically distributed symmetrically on the extensor surfaces of the extremities, initially are soft and then evolve into fibrous nodules (Table 9-9).

Table 9-9 Erythema Elevatum Diutinum

Clinical Features Red to violaceous, soft papules Nodules and plaques evolving into brown to yellow fibrous nodules primarily on the extensor surfaces of the extremities Histopathologic Features Early: LCV Mature: Granulation tissue Fibrosis with vertical vessels A diffuse mixed-cell infiltrate with neutrophils Capillaries with fibrinoid necrosis or fibrous thickening Late: Fibrosis Lipid material may also be present as cholesterol clefts Active vasculitis may still be observed Differential Diagnosis Early: Sweet syndrome Other causes of LCV Rheumatoid neutrophilic dermatitis Bowel bypass–associated dermatosis Neutrophilic drug reaction Behçet syndrome Mature: Granuloma faciale Late: Kaposi sarcoma Dermatofibroma Granuloma annulare

A

B  FIGURE 9-9 Erythema elevatum diutinum. (A) A mixed infiltrate is noted in the dermis with a Grenz zone (arrow). (B) Higher magnification shows neutrophilic infiltrates and fibroplasia.

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rhe-umatoid neutrophilic dermatitis, bowel bypass-associated dermatosis, neutrophilic drug reaction, and Behçet syndrome. GF also may resemble EED but is distinguished by clinical localization to the face, sparing of the superficial papillary dermis (a grenz zone), and prominence of eosinophils and plasma cells in addition to neutrophils. Occasional cases show neutrophilic microabscesses in the tips of dermal papillae that might suggest dermatitis herpetiformis.37 Older lesions of EED must be differentiated from Kaposi sarcoma, dermatofibroma, or granuloma annulare. In old, fibrotic lesions of EED there is an orderly array of spindle cells and collagen bundles often parallel to the skin surface with vertically arranged capillaries similar to a scar. Many of the spindle cells have the immunohistochemical and electron microscopic features of macrophages. Neutrophils, nuclear dust, and fibrin owing to persistent vascular damage may be present, helping to distinguish these lesions from dermatofibromas or scars. The irregularly arranged, jagged vascular spaces of Kaposi sarcoma are absent. Focal areas of basophilic collagen caused by nuclear dust in EED can resemble the mucin seen in granuloma annulare but do not stain with alcian blue.

Granuloma Faciale CLINICAL FEATURES Clinically, GF presents as one or several asymptomatic, soft, brown-red, slowly enlarging papules or plaques, almost always on the face of older individuals (Table 9-10).

A

188

Table 9-10 Granuloma Faciale

Clinical Features Asymptomatic, soft, brown-red, slowly enlarging papules or plaques usually on the face Histopathologic Features Dense polymorphous dermal infiltrate primarily of neutrophils but also eosinophils, plasma cells Grenz-zone beneath epidermis and around pilosebaceous appendages Intact pilosebaceous structures Subtle evidence of vascular damage Nuclear dust Fibrinoid material within and around vessels Foam cells and fibrosis in older lesions Differential Diagnosis Infections Erythema elevatum diutinum Acne vulgaris or rosacea Acute folliculitis Other neutrophilic dermatoses Sweet syndrome

Rare upper respiratory tract forms have been described.38 HISTOPATHOLOGIC FEATURES A dense polymorphous infiltrate is present (see Table 9-10) mainly in the upper half of the dermis, but it may extend into the lower dermis and occasionally even into the subcutaneous tissue. Quite characteristically, the infiltrate does not

invade the epidermis or the pilosebaceous appendages but is separated from them by a narrow grenz zone of normal collagen (Fig. 9-10A). The pilosebaceous structures tend to remain intact. The polymorphous infiltrate consists primarily of neutrophils and eosinophils, but mononuclear cells, plasma cells, and mast cells also are present. Vascular damage in GF is seen but often is limited, and thus perhaps GF is best termed a neutrophilic vascular reaction39 (see Fig. 9-10B). However, vascular damage may be important to the pathogenesis of this lesion because direct immunofluorescence data suggest an immune complex–mediated event with deposition of mainly IgG in and around vessels. Frequently, the nuclei of some of the neutrophils are fragmented, especially in the vicinity of the capillaries, thus forming nuclear dust. Often there is some evidence of vasculitis with deposition of fibrinoid material within and around vessel walls. Occasionally, some hemorrhage is noted. Foam cells and fibrosis are observed frequently in older lesions. DIFFERENTIAL DIAGNOSIS GF can appear similar to EED, although a grenz zone and prevalence of eosinophils and plasma cells favor GF. Other neutrophilic dermatoses can be distinguished from GF by the lack of a grenz zone and clinical features. Frank leukocytoclastic vasculitis should not be seen in GF. In acneiform lesions and folliculitides, pilosebaceous units are invaded by inflammatory cells and may be destroyed or disrupted.

B

 FIGURE 9-10 Granuloma faciale. (A) There is a small grenz zone between the epidermis and the dermal mixed inflammatory cell infiltrate. (B) The infiltrate is composed of neutrophils, eosinophils, lymphocytes, and histiocytes.

NEUTROPHILIC VASCULAR REACTIONS

Acute Febrile Neutrophilic Dermatosis (Classic Sweet Syndrome) CLINICAL FEATURES In 1964, Sweet described a disease process that he termed acute febrile neutrophilic dermatosis that was characterized by acute onset of fever, leukocytosis, and erythematous plaques infiltrated by neutrophils.42-43 This condition classically occurs in middle-aged women after a nonspecific infection of the respiratory or gastrointestinal

 FIGURE 9-11 Bowel-associated dermatosis arthritis syndrome. In addition to a dense superficial dermal infiltrate composed of neutrophils and mild vascular damage, there is an intraepidermal pustule.

Table 9-11 Differential Diagnosis of Neutrophilic Dermatoses Neutrophilic dermatoses Granuloma faciale Sweet syndrome Inherited autoinflammatory syndromes Bowel-associated neutrophilic dermatosis Pyoderma gangrenosum Infection Neutrophilic vesicular dermatoses Linear IgA disease Dermatitis herpetiformis Leukocytoclastic vasculitis Leukemia cutis Neutrophilic drug reaction

tract (Table 9-12). Abrupt onset of painful or tender erythematous plaques, nodules, vesicles, and pustules on the face, extremities, and rarely, the trunk is characteristic. Occasional cases are limited to the hands.44,45 Involvement of noncutaneous sites, such as the eyes, joints, and oral mucosa, as well as visceral sites (eg, lung, liver, brain, and kidney), has been reported. A number of disorders have been associated with neutrophilic dermatoses similar to those seen in Sweet syndrome, as listed in Table 9-12. About 20% of cases are associated with malignancy. The etiology of Sweet syndrome is unknown. Current hypotheses include altered T-cell activation and altered function of neutrophils. The neutrophils within the lesions may be clonal whether or not associated with myelodysplasia. The vascular alterations seen in Sweet syndrome may be secondary to the massive extravasation of activated neutrophils. Direct immunofluorescence studies generally are negative in Sweet syndrome.46 HISTOPATHOLOGIC FEATURES A dense, bandlike, and perivascular infiltrate composed largely of neutrophils occupies the superficial dermis (Fig 9-12B). Some of the neutrophils may show leukocytoclasis. Lymphocytes, histiocytes, and occasionally eosinophils may be included in the infiltrate. The density of the infiltrate varies and may be limited in a small proportion of patients. Although extensive vascular damage is not a feature of Sweet syndrome, common vascular alterations include vasodilation, swelling of endothelium, erythrocyte extravasation, and occasional karyorrhectic debris. Frank fibrinoid

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

In many clinical conditions there are reactions characterized by a neutrophilic infiltrate with variable leukocytoclasis and some vascular damage1 (Fig. 9-11). However, the extent of vascular damage is insufficient for necrotizing vasculitis; that is, fibrinoid necrosis is lacking. This histologic pattern needs to be distinguished from necrotizing vasculitis. However, occasionally a neutrophilic vascular reaction may be a precursor to or associated with full-blown necrotizing vasculitis. Conditions with a neutrophilic vascular reaction that rarely develop necrotizing vasculitis generally are categorized as neutrophilic dermatoses. The term neutrophilic dermatosis includes a number of conditions characterized (1) histologically by a neutrophilic infiltrate, which may be clonal even if unassociated with myelodysplasia,40 (2) by the lack of microorganisms on special stains and cultures, and (3) by clinical improvement on systemic steroid treatment. The lesions are most commonly associated with hematologic, gastrointestinal, or rheumatologic diseases. A relationship

between these entities is suggested by their occasional co-occurrence in patients with predisposing conditions. The differential diagnosis of these lesions is outlined in Table 9-11. The stimulus for the aggregation of neutrophils is unclear. However, as more is understood about the inherited disorders associated with neutrophilic aggregates, termed autoinflammatory disorders, revelations regarding the etiology of acquired neutrophilic dermatoses may be around the corner. Vascular damage has been observed in these conditions, but is likely secondary to the dense neutrophilic infiltrate.41

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Table 9-12 Sweet Syndrome

Clinical Features Women greater than men Adults, but patients of any size Fever Leukocytosis Elevated erythrocyte sedimentation rate Erythematous plaques Vesicles and pustules of the face or extremities, rarely trunk Response to systemic steroids or potassium iodide Involvement of noncutaneous sites: eye, joints, oral mucosa, visceral sites Associations: Gastrointestinal or upper respiratory tract infection (classic Sweet syndrome) Malignancy, especially myeloproliferative disorders Sjögren syndrome Pustular psoriasis Rheumatoid arthritis Subacute lupus erythematous Subacute thyroiditis Pregnancy Histopathologic Features Superficial dermal neutrophilic infiltrate with some leukocytoclasis Vascular alterations, including vasodilation and swelling of endothelium Erythrocyte extravasation Prominent edema with subepidermal blister formation Differential Diagnosis Infection Vasculitis Other neutrophilic dermatoses Dermatitis herpetiformis or linear IgA disease Neutrophilic drug reaction Leukemia cutis Suppurative panniculitides Neutrophilic arthropod bite Secondary syphilis

necrosis may occur but is rare.46 Prominent edema of the upper dermis may result in subepidermal blister formation (Fig. 9-12A). As expected, the histologic appearance varies depending on the stage of the process. In later stages, lymphocytes and histiocytes may predominate.

190

DIFFERENTIAL DIAGNOSIS Infection (bacterial or fungal especially) must be excluded by special stains and tissue cultures. Vasculitis should be considered, but necrotizing vasculitis, that is, fibrinoid

A

B  FIGURE 9-12 Sweet Syndrome. (A) Prominent subepidermal edema is noted above a dense infiltrate. (B) The infiltrate is mostly neutrophilic.

necrosis, should not be observed in Sweet or Sweet-like lesions. The findings overlap with other neutrophilic dermatoses such as early or bullous pyoderma gangrenosum, bowel-associated dermatosisarthritis, periodic fever syndromes, and EED. Clinical features should distinguish these entities. A neutrophilic vesicular disease such as dermatitis herpetiformis or linear IgA disease may be suspected in cases of Sweet syndrome with vesicle formation. In addition, some cases of lupus erythematosus or polymorphous light eruption with an unusual neutrophilic component may resemble Sweet syndrome. Clinicopathologic and immunofluorescence studies should distinguish these entities. Secondary syphilis also may mimic Sweet syndrome. Other considerations include a neutrophilic drug reaction. Leukemia cutis must be excluded in the appropriate clinical setting.

Inherited Autoinflammatory Syndromes Synonyms: Hereditary periodic fever syndromes. The inherited autoinflammatory syndromes are characterized by bouts of inflammation, unprovoked by infection or autoimmunity. Many are characterized by mutations in genes involved in the system of innate immunity that provides rapid host defense against microbes and rapid response to cellular injury. The end result of many of these molecular lesions is deregulated production of proinflammatory cytokines.47 Cutaneous neutrophilic eruptions which resemble the neutrophilic dermatoses or frank vasculitis may occur. The familial fever syndromes, such as familial Mediterranean fever (FMF), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS),

Bowel-Associated DermatosisArthritis Syndrome CLINICAL FEATURES Initially described in patients after jejunoileal bypass surgery, this syndrome has been expanded to include neutrophilic cutaneous lesions associated with many bowel diseases.1 Patients may have inflammatory bowel disease or a blind loop after peptic ulcer surgery (Table 9-14). The cutaneous

Table 9-14 Bowel-Associated Dermatosis-Arthritis Syndrome

Clinical Features Status post-jejunoileal bypass Inflammatory bowel disease Blind loop syndrome Associated fever, myalgias, and arthralgias Episodic, recurrent crops of cutaneous lesions on upper body, especially arms Initial small macules developing into papules, then pustules on a purpuric base Histopathologic Features Neutrophilic dermal infiltrate with minimal or no vascular injury Occasional frank necrotizing small vessel vasculitis Papillary dermal edema with subepidermal pustule formation Differential Diagnosis As for Sweet-like neutrophilic dermatoses

lesions are characterized by initial small macules that develop through a papular phase into pustules on a purpuric base. This evolution usually occurs within a 2-day period. The lesions commonly reach a size of 0.5 to 1.5 cm. They are typically distributed on the upper part of the body, especially the arms, rather than the dependent sites of the legs and often occur in episodic, recurrent crops. Fever, myalgias, and arthralgias may accompany the disease process. An immune complex–mediated reaction triggered by intestinal bacteria-derived antigens may lead to the initiating vascular insult. HISTOPATHOLOGIC FEATURES The histopathologic changes are usually those of a neutrophilic vascular reaction with minimal or no vascular damage, as seen in Sweet syndrome and the other neutrophilic dermatoses (see Fig. 9-11, 9-12). However, frank, necrotizing, small-vessel vasculitis may be noted occasionally. In fully developed lesions, the neutrophilic infiltrate and papillary dermal edema may be florid, and subepidermal pustules form. If vascular damage is observed in such a context, the term pustular vasculitis is applied.

Pyoderma Gangrenosum Pyoderma gangrenosum (PG) is included in this chapter because in these and other authors’ opinions it falls within the spectrum of neutrophilic dermatoses.1 As with other neutrophilic dermatoses, an infection must be excluded to arrive at the correct diagnosis.

CLINICAL FEATURES Several clinical types have been described: ulcerative PG with an undermined border; pustular PG with discrete, painful pustules; painful bullae with progression to a superficial ulceration; and vegetative PG with a painless ulcer and a nonundermined exophytic border.50 Classically, lesions begin as tender papulopustules or folliculitis that eventually may ulcerate. Again, as with other neutrophilic dermatoses, pyoderma gangrenosum, especially the vegetative form, may occur as an isolated cutaneous phenomenon or may be a cutaneous manifestation associated with a number of systemic disease processes, such as inflammatory bowel disease, connective tissue disease, or a lymphoproliferative disorder (Table 9-13). Bullous PG, when associated with leukemia, is an indicator of poor prognosis.50

Table 9-13 Pyoderma Gangrenosum

Clinical Features Tender papulopustules or folliculitis Ulcerated lesions with bluish borders Vegetating lesions Associated diseases: Inflammatory bowel disease Malignancy (especially leukemia) Connective tissue disease Immunologic abnormalities Monoclonal gammopathy (hypogammaglobulinemia, hyperimmunoglobulin E, iatrogenic immunosuppression) Histopathologic Evaluation Possible lymphocytic infiltrates early Extensive neutrophilic infiltrates often involving follicular structures Neutrophilic vascular reaction with variable vascular damage Pustular vasculitis Ulceration Necrosis Occasional granulomatous inflammation Differential Diagnosis Deep fungal infection Mycobacterial lesions Traumatic deep ulceration (factitial diseases) Sweet and Sweet-like dermatosis Subcorneal pustular dermatosis Erythema elevatum diutinum Bowel-associated dermatosis Spider bite Pustular drug reactions Blastomycosis-like pyoderma (from vegetative PG)

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

and tumor necrosis factor receptor superfamily 1A-associated periodic syndrome (TRAPS), and the rare cryopyrin-associated familial cold autoinflammatory syndrome (CAFCA, subsuming Muckle-Wells syndrome, familial cold urticaria, and chronic infantile neurological cutaneous articular syndrome), are a subset of the inherited autoinflammatory syndromes.48 The skin lesions of FMF typically have an erysipelas-like appearance and occur on the shins or feet. Neutrophilic infiltration is seen histologically. Leukocytoclastic vasculitis, including polyarteritis nodosa and Henoch-Schönlein purpura, has been reported. Amyloid deposits are a major complication of the disease. In HIDS, erythematous macules and papules, and even petechiae and purpura, may occur. Aphthous ulcers can be seen in the oral mucosa. Neutrophilic infiltrates and leukocytoclastic vasculitis have been reported. TRAPS was first described in a large Irish family and had been called familial Hibernian fever. Recurrent fevers associated with myalgia and painful erythema are common. During febrile attacks, painless erythematous macules and plaques may develop on the trunk and extremities and may migrate distally. Leukocytoclastic vasculitis of small vessels, nonspecific, perivascular, and interstitial mononuclear cell infiltrates and panniculitis have been reported. Amyloidosis is also a complication in some patients. CAFCA is associated with an urticarial rash and sometimes with amyloidosis.49 Other rare hereditary diseases with neutrophilic or granulomatous inflammation, such as pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome, Blau syndrome (early-onset sarcoidosis), and chronic recurrent multifocal osteomyelitis have also been grouped under the umbrella of autoinflammatory disease. Idiopathic diseases with a genetic predisposition and symptoms suggesting dysregulated innate inflammation such as Behçet disease, Crohn disease, sarcoidosis and psoriatic arthritis may be placed in this category, depending on future research.

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HISTOPATHOLOGIC FEATURES The histologic findings are nonspecific and depend on the type of lesion and timing of the biopsy. The diagnosis primarily is clinical. Most authors studying early lesions have reported a primarily neutrophilic infiltrate that frequently involves follicular structures. Other authors, however, have stated that the lesions begin with a lymphocytic reaction. Degrees of vessel involvement range from none to fibrinoid necrosis. In the majority of biopsied lesions, a neutrophilic vascular reaction is present with limited vascular damage. The infiltrate tends to be deeper and more extensive than in classic Sweet syndrome. The pattern of pustular vasculitis may be present. Fully developed lesions show ulceration, necrosis, and a mixed inflammatory cell infiltrate. Involvement of the deep reticular dermis and subcutis may exhibit primarily mononuclear cell and granulomatous inflammatory reactions.

LYMPHOCYTIC VASCULITIDES AND VASCULAR REACTIONS A histologic diagnosis of a lymphocytic vasculitis may be made if there is sufficient evidence of vascular damage and the inflammatory infiltrate is predominantly lymphocytic (Fig. 9-13). Often the vascular damage is subtle, and in many cases there may be disagreement among

dermatopathologists on whether the term vasculitis is warranted or not.51 Clear-cut evidence of vasculitis again is indisputable if an inflammatory infiltrate is present together with fibrinoid necrosis of the vascular wall. A diagnosis of lymphocytic vasculitis may still be rendered in the absence of fibrinoid necrosis if the constellation of findings suggests clear-cut vascular damage. Features indicative of vascular damage include lamination of the adventitia of venules by concentrically arranged pericytes and basement membrane material, lymphocytic nuclear fragmentation, and subendothelial or intramural infiltration of arterioles by lymphocytes. Lymphocytic vasculitis, if rigidly defined as here, is rare. However, in the majority of conditions to manifest lymphocytic vasculitis, “true vasculitis” is the exception rather than the rule. In instances one might use the term lymphocytic vascular reaction to indicate that a lymphocytic infiltrate is accompanied by some, albeit limited, vascular injury. The disease processes in which lymphocytic vasculitis is seen commonly include a variety of hypersensitivities and reactive processes, autoimmune and connective tissue diseases, infections, and idiopathic conditions as listed in Table 9-15. The histologic picture of lymphocytic vasculitis or lymphocytic vascular reaction

Table 9-15 Differential Diagnosis of Lymphocytic Vasculitis and Lymphocytic Vascular Reactions Pernio (chilblains) Arthropod bites Drug-induced or other hypersensitivity reactions Infection-associated reactions (eg, viral) Connective tissue diseases Behçet disease Pigmented purpuric dermatitides Pityriasis lichenoides (acute and chronic) Lymphomatoid papulosis Cutaneous lymphoma Autoimmune diseases Polymorphous light eruption Atrophie blanche Malignant atrophic papulosis (Degos disease) Infestations (eg, scabies)

also may occur in other situations. Leukocytoclastic vasculitides (eg, drug reactions), neutrophilic vascular reactions (eg, pyoderma gangrenosum), or usually noninflammatory vasculopathies (eg, atrophie blanche) may show a lymphocytic vasculitis-like picture at some stages. Clinical information and other histologic features are needed to determine the significance of lymphocytic vasculitis. Most of these entities are discussed at greater length elsewhere in this text.

Perniosis Pernio (chilblains) is perhaps the most commonly biopsied condition in which lymphocytic vasculitis is observed. Most patients are young or middle-aged women. The acral surfaces and less commonly the thighs and buttocks are involved. Erythematous to purpuric lesions develop in response to cold damp air or cold water.52 Histologically, a biopsy typically shows a superficial and possibly deep dermal perivascular and perieccrine lymphocytic infiltrate accompanied by variable degrees of vascular damage, most commonly in the form of fibrin in the walls of venules. There may be associated papillary dermal edema or interface dermatitis (Fig. 9-14).

192

 FIGURE 9-13 Lymphocytic vasculitis. A dermal vessel infiltrated by lymphocytes with red cell extravasation.

DIFFERENTIAL DIAGNOSIS Acral erythematous and violaceous papular and nodular lesions can be associated with a number of systemic disease states, most importantly systemic lupus erythematosus but also chronic viral infection and clotting abnormalities.53 Significant histologic

B

 FIGURE 9-14 Pernio. (A) A superficial and deep, mostly perivascular lymphocytic infiltrate is present with (B) superficial edema.

overlap can occur, and clinical information, direct immunofluorescence, and serologic studies may be needed to differentiate these entities.

Pigmented Purpuric Dermatitis Synonyms: Purpura pigmentosa chronica, pigmented purpura, capillaritis, pigmented purpuric dermatitis, chronic purpuric dermatitis, or purpura pigmentosa chronica. Four clinical presentations of these entities have been described and named: purpura annularis telangiectoides of Majocchi (Majocchi disease), progressive pigmentary dermatosis of Schamberg (Schamberg disease), pigmented purpuric dermatitis of Gougerot and Blum, and eczematid-like purpura of Doucas and Kapetanakis (Table 9-16).54 However, they are closely related and often cannot be reliably distinguished on clinical and histologic grounds.55 Precise subclassification may not be necessary in dermatopathologic practice, but some knowledge of the spectrum of their various appearances is helpful. Lichen aureus is a closely related entity because the clinical lesion has a purpuric component and the histologic findings are similar to the other four variants of pigmented purpuric dermatitis (PPD).56 The etiology of PPD is essentially unknown, and there are probably a number of different factors involved. Some degree of venous insufficiency or stasis is present in most or many patients with PPD. In some instances PPD also may be related to drug or contact hypersensitivity. Eruptions with the clinical and histologic appearance of a PPD also have been associated

with subsequent development of a T-cell lymphoproliferative disorder. Thus it is possible that some PPD may be the initial manifestation of T-cell lymphoproliferative disease.55 CLINICAL FEATURES Clinically, the primary lesion consists of discrete puncta and pigmentation. Telangiectatic puncta may appear as a result of capillary dilatation and pigmentation as a result of hemosiderin deposits. In some cases, telangiectasia predominates (Majocchi disease), and in others, pigmentation (Schamberg disease). In Majocchi disease, the lesions usually are irregular in shape and occur predominantly on the lower legs. In some cases the findings may mimic those of stasis. Frequently, clinical signs of inflammation are present, such as erythema, papules, and scaling (Gougerot-Blum disease) or papules, scaling, and lichenification (eczematid-like purpura). The disorder often is limited to the lower extremities, but it may be extensive. Mild pruritus may be present, but usually there are no systemic symptoms. Lichen aureus, a localized, persistent variant of PPD, most commonly involves the lower extremities but may occur anywhere.57 One or a few patches are composed of closely set, flat papules of rust, copper, or orange color. In some cases petechiae are present within the patches. Lichen aureus shows a male predilection, and its peak incidence is in the fourth decade. HISTOPATHOLOGIC FEATURES The principal histologic finding is a lymphocytic perivascular infiltrate limited to the papillary dermis (Fig. 9-15). The pattern of

the infiltrate often is not strictly confined to the perivascular area and may infiltrate the adjacent papillary dermis between vessels. In some instances the infiltrate may assume a bandlike or lichenoid pattern (Fig. 9-16), particularly in the lichenoid variant of Gougerot-Blum, and may involve the reticular dermis in a perivascular distribution. Epidermal alterations are variable and include parakeratosis, slight acanthosis, spongiosis, exocytosis, and basal layer vacuolopathy. Evidence of vascular damage may be present, and the reaction pattern then may be termed lymphocytic vasculopathy or vasculitis. However, the extent of vascular injury usually is mild and often insufficient to justify the term vasculitis. Vascular damage commonly consists only of endothelial cell swelling and dermal hemorrhage. Extravasated red blood cells and often subtle hemosiderin deposits usually are found in the vicinity of the capillaries. However, less commonly one may observe deposition of fibrinoid material in vessel walls. This may be observed particularly in pigmented purpuric lichenoid dermatitis of Gougerot and Blum and eczematid-like purpura of Doucas and Kapetanakis. In older lesions the capillaries often show dilatation of their lumen and proliferation of their endothelium. Extravasated red blood cells may no longer be present, but one frequently finds hemosiderin deposition. An iron stain may aid in the diagnosis in these cases. The inflammatory infiltrate is less pronounced than in the early stage. Lichen aureus is characterized by a dense mononuclear cell infiltrate in the papillary dermis, typically distributed in

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

A

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Table 9-16 Pigmented Purpuric Dermatoses

Clinical Features Orange/brown pigmentation Interspersed pinpoint (cayenne pepper-like) purpura Histological Features Superficial dermal perivascular lymphocytic infiltrate Vascular damage (usually limited, eg, endothelial cell swelling, focal karyorrhectic debris) Extravasation of red blood cells Hemosiderin Occasional epidermal changes: Spongiosis Basal layer vasculopathy Clinicopathological Patterns Schamberg disease Clinical: Male predominance Ill-defined lesions, pinhead-sized reddish purpura Predilection for lower leg Histological: usually moderately dense perivascular lymphocytic infiltrate and hemorrhage Majocchi disease Clinical: Discrete annular lesions Associated telangiectasia Often symmetric involvement beginning on lower extremities Histological: telangiectasia may be prominent Lichenoid dermatitis of Gougerot and Blum Clinical: Male predominance Purpuric lesions with lichenoid papules, erythema Predilection for legs Histological: lichenoid, more densely cellular infiltrate Eczematid-like purpura of Doucas and Kapetanakis Clinical: papules, scale, lichenification Histological: spongiosis, parakeratosis more prominent Lichen aureus Clinical: Male predominance Younger individuals Discrete confluent macules and papules (golden yellow, dark brown, or bruise-like) Variable purpura Persistent clinical course Predilection for lower legs Usually unilateral * Histological: Band-like lymphocytic infiltrate Increase in vascularity Prominent hemosiderin-laden macrophages Usually no or minimal vascular damage Differential Diagnosis Stasis dermatitis Eczematous dermatitis Drug eruptions Cutaneous T-cell lymphoproliferative disorders

a bandlike fashion. Scattered within the infiltrate are hemosiderin-laden macrophages. The epidermal changes are variable, as in the other forms of PPD.

194

DIFFERENTIAL DIAGNOSIS PPD may resemble stasis dermatitis because inflammation,

dilatation of capillaries, extravasation of erythrocytes, and deposits of hemosiderin occur in both. However, stasis dermatitis usually extends much deeper into the dermis and exhibits more pronounced epidermal changes and fibrosis of the dermis than PPD. In addition,

intravascular sludging of erythrocytes and fibrin is indicative of stasis. PPD also may resemble an atypical T-cell process. Careful evaluation of the lesion for epidermotropism and lymphoid atypia and clinicopathologic correlation are needed to arrive at the correct diagnosis. Patients with suspicious or equivocal lesions require monitoring and possibly further evaluation to exclude a cutaneous T-cell lymphoproliferative disorder. However, evidence of T-cell clonality may even be demonstrated in some examples of PPD that otherwise lack sufficient criteria for T-cell lymphoma. The scarcity of Civatte bodies or basal layer vacuolopathy facilitates the differential diagnosis of lichen aureus from lichenoid dermatitides, such as lichen planus or lichen striatus.

Lymphomatoid Vasculitis and Vascular Reactions The terms lymphomatoid vasculitis and lymphomatoid vascular reaction may be used if there is a lymphocytic vasculitis or lymphocytic vascular reaction with significant cytologic atypia of the lymphoid cells. Although lymphoid nuclear irregularities of some degree may be present in many lymphocytic vascular reactions, probably as a reflection of an activated state of the lymphocytes, lymphoid atypia tends to be particularly well developed in lymphomatoid papulosis (LYP) and some viral processes (Table 9-17). The differential diagnosis includes vascular damage in the context of cutaneous or systemic lymphoma, such as angiocentric T-cell lymphoma.57 Marked lymphocytic hyperchromasia, nuclear atypia, and exaggerated nuclear fragmentation are clues to lymphomatous destruction of blood vessels.

Vasculitis with Granulomatosis In the life span of many inflammatory reactions involving blood vessels, histiocytes may predominate at a certain stage and form granulomas58 (Fig. 9-17). At that point, little or no vascular wall damage or associated fibrinoid degeneration of the vessel wall may be observed. In the latter situation, a granulomatous vasculitis is present. Granulomatous vasculitis is seen only rarely in a cutaneous biopsy. Some cases of leukocytoclastic vasculitis, such as that associated with rheumatoid papules can show necrobiotic change in the surrounding collagen or associated palisading granulomas, but granulomatous destruction of vessel walls is not seen.59 In several diseases (eg, Takayasu arteritis, Wegener granulomatosis, Churg-Strauss

Table 9-17 Differential Diagnosis of Lymphomatoid Vasculitis and Vascular Reaction

 FIGURE 9-15 Pigmented purpuric dermatitis. There is a papillary dermal lymphocytic perivascular infiltrate and extravasation of red blood cells.

syndrome), a granulomatous vasculitis can be found in large visceral vessels, whereas cutaneous biopsies show extravascular granulomas, leukocytoclastic vasculitis, or ulcerative lesions. Adequate clinical information is essential to an accurate assessment of the skin biopsy in such situations. The main disease processes that need to be considered in the differential diagnosis of a granulomatous vascular reaction are listed in Table 9-18.

NCA-ASSOCIATED SYSTEMIC VASCULITIDES

A

B  FIGURE 9-16 Pigmented purpuric dermatitis. (A) A lichenoid infiltrate of lymphocytes and hemorrhage are seen. (B) Iron stain shows positivity (blue) in the superficial dermis.

Antineutrophil cytoplasmic antibodies (ANCAs) are important serologic markers of certain vasculitides.58,60,61 ANCAs may be demonstrated by a combination of indirect immunofluorescence of normal peripheral blood neutrophils followed by enzyme-linked immunosorbent assay (ELISA) to detect specific autoantibodies. Indirect immunofluorescence assays reveal two staining patterns: cytoplasmic (c-ANCAs) and perinuclear (p-ANCAs). ELISAs show that the majority of cANCAs are autoantibodies to proteinase 3, and most p-ANCAs are specific for myeloperoxidase (MPO). These antibodies are especially helpful, in combination with clinical features, in the differential diagnosis of three primarily small-vessel vasculitides: Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyarteritis. WG is usually associated with c-ANCAs, MPA with either p- or c-ANCAs, and CSS with p-ANCAs (Table 9-19). However, these syndromes cannot be discriminated by ANCA subtype alone as exceptional cases and population differences are seen.62

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

T-cell lymphoproliferative disorders Peripheral T-cell lymphoma Angiocentric T-cell lymphoma Lymphomatoid papulosis Lymphomatoid granulomatosis Angioimmunoblastic lymphadenopathy Pigmented purpuric dermatitis-like eruptions Lymphomatoid drug eruptions Lymphomatoid contact dermatitis Connective tissue disease Viral processes Florid hypersensitivity reactions Arthropod bite Scabies infestation

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 FIGURE 9-17 Granulomatous vasculitis. There is a perivascular histiocytic/granulomatous infiltrate and focal vascular damage.

These three syndromes are termed pauci-immune vasculitides because vascular injury is not associated with immunoglobulin deposition in vessel walls, in contrast to the immune-complex-mediated

Table 9-18 Differential Diagnosis of Vasculitides Associated with Granulomatous Inflammation Temporal arteritis Infection Wegener granulomatosis Churg-Strauss syndrome Polyarteritis nodosa Cutaneous Crohn disease Drug reaction Connective tissue disease Granuloma annulare Necrobiosis lipoidica Paraneoplastic phenomena Angiocentric T-cell lymphoma (lymphomatoid granulomatosis) Erythema nodosum and erythema nodosumlike reactions

small-vessel injury seen in entities such as Henoch-Schönlein purpura. The pathogenesis of the vascular injury and the role of ANCAs in these disease processes are still unclear although there is evidence for a direct role.63,64 ANCAs may play a role in inducing vasculitis by activating circulating neutrophils and monocytes, causing them to adhere to vessels, degranulate, and release toxic metabolites, thereby causing vascular injury. Another possibility is that immune deposits are present at an early stage of vasculitis but are degraded rapidly, resulting in pauci-immune lesions.65 Both environmental insult and genetic predisposition have been implicated in the pathogenesis of WG. A recessive genetic defect completely unrelated to ANCAs has been shown to lead to a vasculitis/granulomatosis syndrome similar to WG. This inherited syndrome differs from WG, though, showing familial clustering and not responding to immunosuppression. Recurrent bacterial infection is also a feature. A mutation in the transporter associated with antigen processing (TAP) leads to a decreased cell surface

Table 9-19 ANCA-Positive Vasculitides

196

DISEASE PROCESS

ANTI-MYELOPEROXIDASE (PANCA)

ANTI-SERINE PROTEINASE (CANCA)

Wegener granulomatosis Microscopic polyarteritis Churg-Strauss syndrome

Rare (5%) Common (50%-60%) Common (70%)

Common (80%) Common (45%) Rare (7%)

expression of HLA class I molecules and possibly increased self-reactivity.66 Novel immunologic defects may await detection in patients with systemic vasculitis. A number of cases of ANCA-associated vasculitis have been reported in patients with Grave disease receiving treatment, most commonly with propylthiouracil.67 CSS and WG most often are classified as granulomatous vasculitides in textbooks. However, the most common cutaneous histologic finding in both diseases is leukocytoclastic vasculitis. The granulomatous inflammation seen in the skin usually is not angiodestructive. Although MPA does not have a significant granulomatous component, it is discussed here because there is significant overlap, histologically and clinically, with WG and CSS patients who show an extensive vasculitic diathesis. In fact, significant overlap between these three syndromes as well as polyarteritis nodosum is well recognized. Over time, particular patients may shift from one disease category to another.

Churg-Strauss Syndrome Synonym: Allergic granulomatosis. The classic clinicopathologic syndrome of Churg-Strauss is characterized by asthma, fever, hypereosinophilia, eosinophilic tissue infiltrates, necrotizing vasculitis, and extravascular granuloma formation (Table 9-20). Short of an autopsy, the classic pathologic triad of necrotizing vasculitis, eosinophilic tissue

Table 9-20 Churg Strauss Syndrome

Clinical Features Men and women equally affected 20-40 years of age Asthma Allergic rhinitis Eosinophilia Petechiae, extensive ecchymoses Necrotic ulcers Cutaneous-subcutaneous nodules Histopathologic Features Leukocytoclastic vasculitis Tissue eosinophilia Churg-Strauss granulomata (extravascular granulomas with numerous eosinophils) Differential Diagnosis Infection Connective tissue disease Wegener granulomatous Microscopic polyarteritis nodosa

infiltration, and extravascular granulomas is extremely difficult to demonstrate because of the focality of the process.68 A broader definition of CSS requiring asthma, hypereosinophilia greater than 1.5 × 109/L, and systemic vasculitis involving two or more extrapulmonary organs has been suggested. Considerable overlap with other systemic vasculitides and with other inflammatory disorders associated with eosinophils, such as eosinophilic pneumonitis, has brought the legitimacy of the CSS into question.

bundles with eosinophilic granules (flame figures).73,74 DIFFERENTIAL DIAGNOSIS CSS is a clinicopathologic entity whose diagnosis depends on the presence of respiratory disease, in particular a history of asthma, p-ANCA positivity, and particular histologic features such as extravascular granulomas described earlier, necrotizing vasculitis, and eosinophilia. The differential diagnosis includes all varieties of smallvessel LCV but in particular, PAN, MPA, and WG, and the conditions mentioned earlier that may show extravascular necrotizing granulomas. Although Churg and Strauss initially characterized allergic granulomatosis as a “strikingly uniform clinical picture,” there is less clarity today about its distinction from other vasculitic processes, particularly WG and PAN.75

Wegener Granulomatosis WG was first recognized as a distinct clinicopathologic disease process in 1936, when Wegener reported three patients with a “peculiar rhinogenic granulomatosis.”76 Godman and Churg summarized postmortem studies in 1954, from which the classic triad of this clinicopathologic complex evolved: (1) necrotizing and granulomatous inflammation of the upper and lower respiratory tracts, (2) glomerulonephritis, and (3) systemic vasculitis.77 Limited variants of the disease involving the respiratory tract only have been described. In the protracted superficial variant, ulcerated, necrotizing lesions remain localized to the mucosa and skin for many years,

 FIGURE 9-18 Palisading necrotizing granuloma. A blue-tinted area of fibrinoid dermal necrosis is surrounded by epithelioid histiocytes.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

CLINICAL FEATURES Despite multiple reports, CSS appears to be rare. Between 1950 and 1995, only 120 cases were identified at the Mayo Clinic.69 The incidence of CSS is similar in males and females. It typically presents in the third and fourth decades of life. Patients tend to move through several phases of disease development from nonspecific signs and symptoms such as asthma and allergic rhinitis (prodromal phase), to a phase of hypereosinophilia with eosinophilic pneumonitis or gastroenteritis (second phase), and finally, to systemic vasculitis (third phase). The three disease phases are not always sequential and on occasion may occur simultaneously. The internal organs most commonly involved are the lungs, the gastrointestinal tract, and less commonly, the peripheral nerves and heart. In contrast to polyarteritis nodosa, renal failure is rare. A limited form of allergic granulomatosis is characterized by preexisting asthma and lesions confined to the conjunctiva, skin, and subcutaneous tissue. Two types of cutaneous lesions occur in about two-thirds of patients: (1) hemorrhagic lesions varying from petechiae to palpable purpura to extensive ecchymoses, sometimes accompanied by necrotic ulcers and often associated with areas of erythema (similar to HenochSchönlein purpura), and (2) cutaneoussubcutaneous nodules. The most common sites of skin lesions are the extremities, followed by the trunk. In some instances the petechiae and ecchymoses are generalized. Other skin manifestations include urticaria, erythematous macules, and livedo reticularis. Diagnostically helpful laboratory findings include an elevated peripheral eosinophil count. Patients with active CSS have anti-MPOs (p-ANCAs) in most cases (see Table 9-19). The levels of antiMPOs have been found to correlate with disease activity. Anti-MPOs are found less often in patients with limited forms of the disease. Anti-serine proteinase antibodies (c-ANCAs) are uncommon in patients with CSS (see Table 9-19).

HISTOPATHOLOGIC FEATURES The areas of cutaneous hemorrhage typically show small-vessel LCV often with numerous eosinophils. Granulomatous arteritis may also be occasionally observed.70 In some instances the dermis shows a distinctive granuloma typified by radially arranged histiocytes and multinucleated giant cells centered around degenerated collagen fibers (Fig. 9-18). The central portion of these so-called “red” palisading granuloma contains not only degenerated collagen fibers but also disintegrated cells, particularly eosinophils, in great numbers.71 These granulomas initially were thought to be characteristic and were referred to as Churg-Strauss granulomas. However, they are not always present and are not a prerequisite for the diagnosis. The “Churg-Strauss granuloma” can also can be observed in other disease processes, such as connective tissue disease (rheumatoid arthritis and lupus erythematosus), WG, PAN, lymphoproliferative disorders, subacute bacterial endocarditis, chronic active hepatitis, and inflammatory bowel disease (Crohn disease and ulcerative colitis).72 The extravascular granulomas may involve subcutaneous fat, where they may attain considerable size through expansion and confluence, thus giving rise to the clinically apparent cutaneoussubcutaneous nodules. These palisading granulomas are embedded in a diffuse inflammatory exudate rich in eosinophils. Erythematous plaques, sometimes annular or bullous lesions can show the histopathology of eosinophilic cellulitis or Wells syndrome with an intense dermal eosinophilic infiltrate encrusting collagen

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with pulmonary and renal involvement eventually developing in some of these patients. With the recognition of an association between ANCAs and WG, the concept of WG has been modified, and the need for demonstrating granulomatous inflammation as a prerequisite for the diagnosis of WG has been challenged. A less restrictive definition has been proposed; Wegener vasculitis.4 Subsumed under this less restrictive category are ANCA-positive patients with clinical presentations of WG, such as sinusitis, pulmonary infiltrates, and nephritis, and documented necrotizing vasculitis but without biopsyproven granulomatous inflammation. Wegener syndrome, a more generic term can include both classic WG and Wegener vasculitis. CLINICAL FEATURES Two-thirds of patients with WG are male, and the mean age of diagnosis is 35 to 54 years.78 The vast majority of patients are Caucasians. The clinical presentation is extremely variable, ranging from an insidious course with a prolonged period of nonspecific constitutional symptoms and upper respiratory tract findings to abrupt onset of severe pulmonary and renal disease (Table 9-21).

Table 9-21 Wegener Granulomatosis

Clinical Features Sinusitis Recurrent pneumonitis Glomerulonephritis Myalgia, arthralgia, fever Palpable purpura, nodules, and ulcers Histopathologic Features LCV Granulomatous inflammation with suppuration and necrosis Cutaneous extravascular necrotizing granuloma Erythema elevatum diutinum, granuloma annulare, or erythema nodosum Nonspecific acute or chronic inflammatory lesions and ulcerations Differential Diagnosis Vasculitic component MPA, CSS, other causes of LCV Metastatic Crohn disease Granulomatous component Granulomatous infections CSS Sarcoidosis Granulomatous rosacea Foreign body reactions Ruptured cysts

The most commonly involved anatomic sites include the upper respiratory tract, lower respiratory tract, and kidney. Other organ systems that are commonly affected include the joints and skin. Migratory polyarticular arthralgia of large and small joints is found in up to 85% of patients with WG. Cutaneous involvement is extremely variable in different series, ranging from less than 20% to over 50% of patients. The most common presentation is palpable purpura. Other cutaneous manifestations include macular erythematous eruptions, papulonecrotic lesions, subcutaneous nodules with and without ulceration, and pyoderma gangrenosum. Occasionally, cutaneous lesions are the first indication of WG. However, because of their nonspecific appearance, they are infrequently recognized as presentations of WG. HISTOPATHOLOGIC FEATURES The majority of skin biopsies in patients with WG are nonspecific, such as, perivascular lymphocytic infiltrates.79 However, in about 25% to 50% of patients the histopathologic findings are fairly characteristic. The most frequent reaction patterns that are distinctive include necrotizing/leukocytoclastic small-vessel vasculitis and granulomatous inflammation. The small-vessel vasculitis is characterized by neutrophilic infiltrates and is indistinguishable from LCV secondary to many other processes (Fig. 9-19). Eosinophils can be as numerous

in LCV lesions from patients with WG, as in those with CSS. The granulomatous reactions contain histiocytes, lymphocytes, and giant cells and show suppurative necrosis. Microgranulomas, minute foci of tissue necrosis surrounded by histiocytes, are characteristic and are similar to lesions described in open lung biopsies from WG patients. True granulomatous vasculitis (see Fig. 9-17), acneiform perifollicular granulomatous inflammation, EED, and erythema nodosum-like reaction patterns have been described.80 The palisading granulomas of WG resemble those of CSS, except that the center of the WG granuloma contains necrobiotic collagen and basophilic fibrillar necrotic debris admixed with neutrophils, the so-called “blue” pallisading granuloma (Fig. 9-18).81 Tissue eosinophilia and eosinophilic debris are observed less frequently in the granulomata of WG. These lesions, also referred to as cutaneous extravascular necrotizing granuloma, are not specific for WG and may be associated with systemic vasculitis, connective tissue disease, or lymphoproliferative disease.72 Cutaneous ulcerations in WG may show granulomatous inflammation and necrotizing vasculitis and also secondary nonspecific vascular damage. DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of WG includes numerous entities causing LCV and palisading granulomas. Infective processes

 FIGURE 9-19 Wegener granulomatosis. A subcutaneous small artery shows fibrinoid necrosis and a florid inflammatory cell infiltrate.

Microscopic Polyarteritis Nodosum Synonyms: Microscopic polyangiitis, ANCA-positive leukocytoclastic angiitis, MPA. Microscopic polyarteritis nodosa is a systemic small-vessel vasculitis that is typically associated with focal necrotizing glomerulonephritis with crescents and serum myeloperoxidase-antineutrophil cytoplasmic autoantibodies. Involvement of the small vessels of the kidneys, lungs, and skin gives MPA a particular clinical picture and separates MPA from “classic” polyarteritis nodosum, which is to a greater degree a disease of medium-sized vessels. CLINICAL FEATURES Most patients with MPA are male and over 50 years of age (Table 9-22). Prodromal symptoms include fever, myalgias, arthralgias, and sore throat. The most common clinical feature is renal disease, manifesting as microhematuria, proteinuria, or acute oliguric renal failure. Although cutaneous involvement is rare in classic PAN, at least 30% to 40% of patients with MPA have skin changes. These include erythematous macules (100% in one study), livedo reticularis, palpable purpura, splinter hemorrhages, and ulcerations. Tender erythematous nodules typical of classic PAN are exceedingly rare in MPA. Pulmonary involvement without granulomatous tissue reaction occurs in approximately one-third of patients. Other organ systems (eg, gastrointestinal tract, central nervous system, serosal and articular surfaces) also may be affected, but this is less common. Serious clinical

Table 9-22 Microscopic Polyarteritis Nodosa (MPA)

Clinical Features Males over 50 years of age Viral-like prodrome Renal disease: Microhematuria, proteinuria, or acute oliguric renal failure Cutaneous symptoms: Palpable purpura, splinter hemorrhages, and ulcerations Pulmonary involvement without granulomas Histopathologic Features LCV Differential Diagnosis Wegener granulomatosus Churg-Strauss syndrome PAN Other causes of LCV

complications usually arise from renal and pulmonary disease. HISTOPATHOLOGIC FEATURES A leukocytoclastic vasculitis primarily affecting arterioles, venules, and capillaries is observed (see Fig. 9-20). Necrotizing vasculitis of medium-sized arteries typical of classic PAN is present on occasion (see Fig. 9-21). Cutaneous granulomatous inflammation is only rarely seen in MPA.

DIFFERENTIAL DIAGNOSIS MPA and classic PAN may not be distinguishable in every case, practically speaking. Glomerulonephritis, typical skin signs, ANCA positivity, and lack of arteriographic findings (aneurysms and stenoses reflecting medium-sized vessel involvement) favor MPA over classic PAN.82 MPA also tends not to be associated with viral hepatitis in contradistinction to some cases of classic PAN. Biopsy findings are less useful in distinguishing between these two syndromes because the size of diseased vessels detected is highly dependent on biopsy site, size of specimens, and number of tissue samples. Thus lack of medium-sized vessel involvement by no means excludes classic PAN. Detection of small-vessel involvement also does not exclude classic PAN, which may show small-vessel disease. A number of cases of vasculitis show overlapping features, leading to introduction of the term overlapping syndrome of vasculitis to encompass vasculitis affecting both small- and medium-sized arteries.83 The differential diagnosis also includes Wegener vasculitis and other small-vessel vasculitides that are occasionally ANCA-positive, such as certain drug reactions. The granulomatous inflammation of WG should be lacking in MPA; however, these two entities share many features, and some are of the opinion that the distinction between MPA and WG is largely artificial.84

 FIGURE 9-20 Microscopic polyarteritis nodosum. Florid inflammation and fibrinoid necrosis of a microvessel in the dermis.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

causing granulomatous inflammation and possibly vasculitis should be excluded; the list of such agents is large and includes mycobacteria, deep fungi, viruses, and syphilis, among others. Other conditions causing LCV and granulomatous reactions include CSS, metastatic Crohn disease, rheumatoid arthritis, and sarcoidosis. Granulomatous vascular reactions also may be a manifestation of Tcell lymphomas such as angiocentric T-cell lymphoma or panniculitic T-cell lymphoma. Tightly packed, nonnecrotizing granulomas characteristic of sarcoid are not typical of WG. The distinction between WG and these other diseases relies primarily on clinical findings. In contrast to WG, CSS is associated with asthma, lacks lesions in the upper respiratory tract, rarely shows severe renal involvement, and typically is accompanied by eosinophilia or eosinophilic infiltrates and p-ANCA positivity.

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A

B

 FIGURE 9-21 Polyarteritis nodosum. (A) Erythematous papules and nodules are associated with a subtle pattern of livedo reticularis on the foot. (B) Fibrinoid necrosis and inflammation of a medium-sized vessel in the deep dermis.

VASCULITIS OF MEDIUM AND LARGE-SIZED VESSELS This section on vasculitides concludes with a brief review of conditions that preferentially affect medium- and largesized vessels. WG and CSS can affect medium-sized arteries, but they have been discussed previously as ANCAassociated vasculitis. The remaining entities to be discussed include PAN and processes that characteristically affect visceral vessels or large veins with rather nonspecific cutaneous findings.

Polyarteritis Nodosa

200

Synonyms: Periarteritis nodosa, PAN, classic polyarteritis nodosa. The first report of PAN in 1885 describes a 27-year-old man with fever, abdominal pain, muscle weakness, peripheral neuropathy, and renal disease.85 The fatal illness was termed periarteritis nodosa, referring to nodular protuberances along the course of medium-sized muscular arteries. Ferrari in 1903 emphasized the characteristic presence of inflammatory cells within all levels of the affected vessels (panarteritis) and suggested the term polyarteritis instead of periarteritis.86 The term PAN now subsumes three entities: (1) classic systemic PAN, (2) cutaneous PAN, and (3) microscopic polyarteritis.87,88 Classic PAN is a multisystem disorder characterized by inflammatory vasculitis involving arterioles and small and medium-sized arteries. Cutaneous PAN according to some authors is the only variety of PAN consistently involving the deep dermis and

subcutaneous fat with diagnostic features of arteritis. Some authors maintain that if there is no evidence of systemic involvement by (skin-limited) PAN at the time of initial diagnosis, then the condition will remain confined to the skin despite a potentially prolonged clinical course with multiple recurrences. MPA was discussed earlier in the chapter. The pathogenesis of PAN is poorly understood. Direct immunofluorescence testing of skin lesions of PAN shows some immune deposits in dermal vessels. However, these deposits may reflect a secondary event after vascular injury from another cause. As discussed earlier, there is some clinical overlap with microscopic PAN, although ANCAs generally are absent in patients with only medium-sized vessel involvement and thus not involved in the pathogenesis of these cases of PAN. CLINICAL FEATURES PAN is more common in men than in women, usually occurring between the ages of 20 and 60 years. Clinical manifestations may be dramatic and protean. Fever, malaise, weight loss, weakness, myalgias, arthralgias, and anorexia are common symptoms reflecting the systemic nature of the disease. Other findings may reflect infarction of specific organs (Table 9-23). Renal involvement, present in about 75% of patients, is the most common cause of death. Hematuria, proteinuria, hypertension, and azotemia may result from both infarction owing to disease of renal arteries or focal, segmental necrotizing glomerular lesions suggesting involvement of small vessels. Acute abdominal crises, strokes, myocardial

infarction, and mononeuritis multiplex result from involvement of the relevant arteries. Arteriography of visceral arteries often shows multiple aneurysms that are highly suggestive of PAN. Symptoms such as asthma, Löffler syndrome, and rashes may be related to the hypereosinophilia sometimes seen in these patients. Cutaneous manifestations

Table 9-23 Polyarteritis Nodosa

Clinical Features Fever, malaise, weight loss, weakness myalgias, arthralgias, and anorexia Hematuria, proteinuria, hypertension, and azotemia Acute abdominal crises, strokes, myocardial infarction, and mononeuritis multiplex Subcutaneous nodules which may pulsate or ulcerate Ecchymoses and gangrene of fingers and toes Livedo reticularis, bullae, papules, scarlatiniform lesions, and urticaria Histopathologic Features Early: leukocytoclastic vasculitis of small to medium-sized arteries Late: intimal proliferation and thrombosis, chronic inflammatory infiltrate, fibrosis Differential Diagnosis Infection (bacterial, eg, pseudomonas; viral, eg, hepatitis B or HIV) Connective tissue disease (lupus erythematosus, rheumatoid arthritis) Vasculitides with granulomatosis Wegener granulomatosis Churg-Strauss syndrome

include subcutaneous nodules that may pulsate or ulcerate, ecchymoses, and gangrene of fingers and toes. Livedo reticularis, bullae, papules, scarlatiniform lesions, and urticaria occur in some patients (Fig. 9-21A). A limited form of PAN without visceral involvement may exist, but this concept is controversial.87 So-called cutaneous PAN actually may show skin, muscle, peripheral nerve, and joint involvement. The course of disease is benign but protracted and shows steroid dependence.89

DIFFERENTIAL DIAGNOSIS Vasculitides indistinguishable from idiopathic PAN may be observed in infection (bacterial, eg, Streptococcus and Pseudomonas; viral, eg, hepatitis B or HIV), connective tissue disease (lupus erythematosus, rheumatoid arthritis), WG, CSS, and other settings without explanation, for example, acute myelogenous leukemia. Some cases of erythema induratum with limited septolobular panniculitis can mimic PAN histologically.90 In general, any panniculitis accompanying PAN should be limited to the area directly adjacent to the affected vessel. Widespread inflammation of the fat suggests panniculitis is the primary disease category. As with all vasculitides, the disease process should be defined by ruling out

occur in other processes, including nonspecific thrombosis and inflammation of intermediate-sized arteries and veins. Peripheral vascular disease from arteriosclerosis must be excluded.

Buerger Disease Synonym: Thromboangiitis obliterans. CLINICAL AND HISTOPATHOLOGIC FEATURES This distinctive but rare condition is observed most frequently in men ranging in age from 20 to 40 years of age who are tobacco smokers (Table 9-24). A similar condition effecting canabis smokers has also been reported.91 Painful segmental, thrombosis and inflammation effects intermediate- and small-sized arteries and sometimes veins, primarily of the upper and lower extremities. The clinical findings are manifestations of ischemic injury and include claudication, cyanosis, painful ulcers, and gangrene. Cessation of smoking is the most important therapeutic intervention. However, the ischemic injury often is so extreme that amputation is needed to control the process. Active lesions show luminal thrombotic occlusion, a mixed inflammatory cell infiltrate of the vessel wall, and luminal microabscesses that are thought to be characteristic. A granulomatous reaction may be present as well. Later, the thrombus is organized and its lumen may be recanalized. DIFFERENTIAL DIAGNOSIS The histologic findings in Buerger disease have been thought to be unique; however, they are likely to be nonspecific and probably

Table 9-24 Buerger Disease, Thromboangiitis Obliterans

Clinical Features Men greater than women, 20-40 years of age Smokers Lower extremities more than upper extremities Painful ulcers, gangrene Histopathologic Features Mixed inflammatory cell infiltrates of intermediate and small vessel walls with micro-abscesses +/– a granulomatous reaction Luminal thrombi Differential Diagnosis Infection

Superficial Thrombophlebitides Synonyms: Mondor disease, nonsclerosing lymphangitis of the penis. CLINICAL FEATURES Superficial thrombophlebitis of small- to medium-sized veins may be seen at many anatomic sites but especially the lower extremities. The usual presentation is a tender, erythematous cordlike structure or nodule. Affected individuals often have predisposing factors such as varicose veins, a hypercoagulable state, ingestion of oral contraceptives, or an underlying malignancy. Superficial septic thrombophlebitis is usually secondary to peripheral venous infusion. Mondor disease is a thrombophlebitis of the subcutaneous veins of the chest region and often is manifested clinically by a cordlike induration.92 It usually is not accompanied by general symptoms and tends to resolve within weeks. In most cases the etiology remains unknown; however, local interference with venous flow may be a factor as associations include trauma and surgical procedures. A variety of other conditions including connective tissue disease and, rarely, breast carcinoma have also occurred with Mondor disease. Nonvenereal sclerosing lymphangitis of the penis arises acutely and has features similar to Mondor disease. Despite the name, the involved vessel is most likely a vein, and some refer to this condition as Mondor phlebitis of the penis.93 Clinically, a firm, tender, wormlike cord lying just behind the corona of the glans penis in the coronary sulcus appears suddenly. Resolution usually occurs in 4 to 6 weeks regardless of therapy. Proposed etiologic factors include trauma during coitus and infectious agents such as viruses or chlamydiae. HISTOPATHOLOGIC FEATURES In early lesions, small and medium-sized veins of the lower dermis demonstrate dense inflammatory infiltrates, primarily composed of neutrophils, within the vessel wall. The venous wall is significantly thickened by this influx of leukocytes and edema. In later stages, the infiltrate is composed of lymphocytes, histiocytes, and multinucleate giant cells. However, most biopsied lesions show subcutaneous veins with organizing thrombi and

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

HISTOPATHOLOGIC FEATURES Although affected skin often shows only a smallvessel necrotizing vasculitis, the characteristic lesion of classic PAN is a panarteritis involving medium-sized and small arteries in visceral sites (Fig. 9-21B). A panarteritis of the larger arteries in deeper dermis or panniculus is observed most commonly in patients presenting with cutaneous nodules. Lesions typically are in different stages of development. Early lesions show degeneration of the arterial wall with deposition of fibrinoid material. There is partial to complete destruction of the external and internal elastic laminae. An infiltrate present within and around the arterial wall is composed largely of neutrophils showing evidence of leukocytoclasis, although eosinophils often are admixed. At a later stage, intimal proliferation and thrombosis lead to complete occlusion of the lumen with subsequent ischemia and possibly ulceration. The subacute infiltrate often contains lymphocytes, histiocytes, and some plasma cells. The healing stage is distinguished by a fibroblastic proliferation extending into the perivascular area. The small vessels of the middle and upper dermis often show a nonspecific lymphocytic perivascular infiltrate.

infection, searching for underlying systemic diseases, and then documenting the extent of systemic involvement and associated findings.

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fibrous, thickened walls, giving them a cordlike appearance at scanning magnification. Recanalization of the affected veins ultimately occurs with resolution of the process. A Gram stain is indicated for the assessment of septic STP. DIFFERENTIAL DIAGNOSIS Polyarteritis nodosa is the principal entity to be distinguished. PAN affects medium-sized arteries rather than veins, is more inflammatory and less thrombogenic than STP, that is, thrombi are usually absent in PAN, and finally PAN shows conspicuous fibrinoid necrosis whereas STP usually does not. An elastic tissue stain to demonstrate the presence of an internal elastic lamina in an arterial vessel versus its usual absence (not always) in a vein may facilitate the differentiation of PAN and STP.

Kawasaki Syndrome

Clinical Features Young Asian women Upper extremity claudication Visual symptoms and Raynaud phenomenon Arterial bruits and diminished arterial pulses Cutaneous findings: Erythema nodosum–like nodules Ulcers with features of pyoderma gangrenosum and papular lesions Histopathologic Features Necrotizing vasculitis of both small and large vessels Granulomatous vasculitis Sarcoidal noncaseating tuberculoid granulomas Acute panniculitis “Cutaneous extravascular granulomas” Differential Diagnosis Infection similar to that described under Wegener granulomatosis

Synonym: Mucocutaneous lymph node syndrome. CLINICAL FEATURES Kawasaki syndrome is a necrotizing arteritis that usually affects young children, with a peak age incidence at 1 year.94 The disease is most common in Japan and shows seasonal variations, hinting at an interplay between an infectious precipitant and a genetically predisposed host. Mucocutaneous findings are common and include a polymorphous exanthematous macular rash, conjunctival congestion, dry reddened lips, “strawberry tongue,” oropharyngeal reddening, and swelling of the hands and feet, especially the palms and soles. There is typically an associated nonpurulent cervical lymphadenopathy. Desquamation of the skin of the fingers typically occurs after 1 to 2 weeks, often followed by thrombocytosis. The most serious clinical complications are related to arteritis and thrombosis of coronary arteries. HISTOPATHOLOGIC FEATURES Cutaneous vasculitis is rare. The macular rash usually is accompanied by nonspecific histologic changes, such as a perivascular infiltrate of lymphocytes and histiocytes. Characteristic arteritis typically is seen in visceral sites, such as the coronary arteries.

Takayasu Arteritis Synonym: Pulseless disease.

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Table 9-25 Takayasu Arteritis

CLINICAL FINDINGS Takayasu arteritis primarily affects the aorta and has its

main branches in young Asian women (Table 9-25). Chronic granulomatous vascular inflammation with fibrosis and thickening of the vessel walls is the predominant pathologic feature. The resulting vascular stenosis leads to symptoms such as upper extremity claudication, visual symptoms, and Raynaud phenomenon. Arterial bruits and diminished arterial pulses are found. Cutaneous findings include erythema nodosum-like nodules and ulcers with features of pyoderma gangrenosum. HISTOPATHOLOGIC FEATURES Nodular cutaneous lesions potentially related to Takayasu arteritis have shown necrotizing vasculitis of both small and large vessels, granulomatous vasculitis, septal and lobular panniculitis, and sarcoidal noncaseating tuberculoid granulomas.95 The cutaneous extravascular granuloma discussed earlier in the section on WG also may be seen. DIFFERENTIAL DIAGNOSIS None of the pathologic findings in the skin are specific for Takayasu arteritis. A number of vasculitic or granulomatous diseases are included in the differential diagnosis of the lesions described earlier. Infection must be excluded. Sarcoidosis occasionally may be complicated by large-vessel vasculitis mimicking Takayasu arteritis.96 Clinically, Cogan syndrome may show a Takayasu-like arteritis, but interstitial keratitis and Meniere-like episodes are also features. Angiography and the

appropriate clinical context should differentiate Takayasu arteritis from other entities.

Temporal Arteritis Synonyms: Giant cell arteritis, giant cell arteritis of the elderly, cranial arteritis, Horton disease. CLINICAL FEATURES Temporal arteritis affects primarily large- or medium-sized arteries in the temporal region of elderly people. Other arteries of the head and neck, particularly retinal arteries, may be involved, and patients with generalized arterial involvement have been described. The clinical presentation may include pain and tenderness of the forehead or scalp and possibly sudden visual impairment. There may be systemic symptoms, such as fever and malaise. Erythema and edema of the skin overlying the involved arteries may be noted, and occasionally, ulcerations of the scalp occur.97 The involved artery may be palpable. Clinical laboratory findings include a significantly elevated erythrocyte sedimentation rate (ESR) and sometimes a normochromic, microcytic, or normocytic anemia. Although the clinical presentation strongly suggests the diagnosis, a biopsy often is performed for confirmation prior to initiation of systemic steroid therapy. Long segments of the artery, preferably nodular or tender areas, should be biopsied because skip lesions are common. Although the etiology of temporal arteritis is unknown, in some cases actinic degeneration of the internal elastic lamina may provoke the granulomatous inflammation in a reaction similar to actinic granuloma. HISTOPATHOLOGIC FEATURES Involved arteries show partial destruction by an inflammatory infiltrate composed mainly of lymphocytes and macrophages (Fig. 9-22). In some instances neutrophils may be present, but this finding should not dissuade one from the diagnosis. The inflammatory infiltrate may extend throughout the entire arterial wall but is unevenly distributed, and step sections often are needed for identification. Some of the macrophages are multinucleated and intimately associated with the internal elastic lamina. Fragmentation of the elastic lamina and elastophagocytosis by the multinucleated giant cells even may be observed. An elastica-van Gieson stain greatly facilitates evaluation of elastic fibers. Some find the CD68 marker for histiocytes helpful in the evaluation of the inflammatory infiltrate. Depending

 FIGURE 9-22 Giant cell arteritis. A biopsy of the temporal artery shows a panmural predominantly mononuclear infiltrate with giant cells and fragmentation of elastic fibers (arrow).

on the stage of the disease process or corticosteroid treatment history, giant cells may not be present.98 In late stages, there only may be thickening of the intima by deposits of fibrin-like material and myofibroblastic proliferation with subsequent luminal narrowing or obliteration. DIFFERENTIAL DIAGNOSIS Not all cases of arteritis involving the temporal artery represent examples of temporal arteritis. Biopsy of the temporal artery may show necrotizing vasculitis, such as PAN, hypersensitivity angiitis, or vasculitis associated with infection or connective tissue disease. However, the biopsy findings may not always discriminate between TA and other systemic vasculitities.99 Serologic studies, the exclusion of infection, and the appropriate clinical findings along with the histopathologic requisite features lead to the correct diagnosis.

VASCULOPATHIC REACTIONS AND PSEUDOVASCULITIS A vasculopathic reaction as defined in Table 9-1 refers to vascular damage without inflammation. As already mentioned, the term pseudovasculitis has been used to describe a closely related group of conditions that mimic or exhibit some attributes of vasculitis. Vasculopathies or pseudovasculitis may

be associated with vascular occlusive phenomena, including thrombi or emboli, pathologic alterations of the vessel wall or structural deficiencies of the perivascular connective tissue, and miscellaneous other disease processes including drug-induced vasospasm and repetitive vascular injury.

Vascular Occlusive Conditions In these conditions, thrombi are present in blood vessels of dermis and subcutis. Extensive infarctions and necrosis may be associated and are more characteristic of some coagulopathies, cryoglobulinemias, early livedoid vasculitis (atrophie blanche), cholesterol emboli, and calciphylaxis. Livedo reticularis and late atrophie blanche present a more fibrotic chronic picture. Usually, the various conditions can be distinguished by other distinctive pathologic findings, such as calcification in calciphylaxis, needleshaped crystals in cholesterol emboli, or the wedge-shaped dermal alteration of Degos syndrome. Characteristic clinical findings or serologic tests (eg, cryoglobulinemia, cryofibrinogenemia, coagulopathy) further narrow the differential diagnosis. A differential diagnosis is provided in Table 9-26A and 9-26B.

Coagulopathies Any coagulopathy may be accompanied by vasculopathic changes, although the

CLINICAL FEATURES In mild forms, the clinical manifestations may be subtle and limited to petechiae. Severe forms of coagulopathy may show palpable purpura or large areas of ecchymoses, often on the extremities. Large hemorrhagic bullae may overlie the ecchymoses, and in some instances, necrosis may supervene. Retiform purpura (a livedoid pattern of cutaneous hemorrhage) in palpable plaques is characteristic of antiphospholipid antibody syndrome, heparin-induced skin necrosis, coumadin/ warfarin-induced skin necrosis, and calciphylaxis.101 HISTOPATHOLOGIC FEATURES The histologic findings are nonspecific. In mild forms of coagulopathy, dermal hemorrhage with extravasation of red blood cells into perivascular connective tissue may be the only histologic manifestation. With increasing severity of the coagulopathic process, intravascular fibrin thrombi may be found (see Fig. 9-2). In the severe coagulopathies (eg, thrombotic thrombocytopenic purpura, coumarin necrosis, or purpura fulminans), thrombotic vascular occlusion may lead to hemorrhagic infarcts, epidermal and dermal necroses, or subepidermal bullae formation. Systemic intravascular coagulation with widespread thrombosis of the small vessels of internal organs leading to hemorrhagic necrosis also may develop.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

extent of vascular damage is variable. Vascular damage may occur in the setting of altered platelet counts, such as in idiopathic thrombocytopenic purpura, in coagulation factor deficiencies (eg, inherited or acquired protein C and S deficiencies), coagulopathies associated with connective tissue disease (eg, lupus anticoagulant, antiphospholipid antibody syndrome), and platelet thrombosis in heparin-induced skin necrosis. Extensive vascular damage with luminal occlusion by thrombotic material may develop in coumarin/warfarin-induced skin necrosis, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation, in particular in the setting of purpura fulminans.100

Cryoglobulinemia Cryoglobulins are serum immunoglobulins that precipitate when the serum is cooled and redissolve with rewarming. There are three major types of cryoglobulinemia (Tables 9-27A and 9-27B). In type I cryoglobulinemia, monoclonal IgG or IgM cryoglobulins are found. This type of cryoglobulinemia may be idiopathic but often is associated with lymphoma,

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Table 9-26A Vasculopathic Reactions and Pseudovasculitis MECHANISM

CONDITION

Coagulopathies

Idiopathic thrombocytopenic purpura Coagulation factor deficiencies (eg, protein C and S deficiencies) Antiphospholipid antibody syndrome Thrombotic thrombocytopenic purpura Coumadin/warfarin-induced skin necrosis Heparin-induced skin necrosis Calciphylaxis Purpura fulminans Disseminated intravascular coagulation Monoclonal gammopathy Sickle cell disease Livedo vasculopathy Calciphylaxis Primary hyperoxaluria Diabetes mellitus Amyloidosis Porphyria Radiation vasculopathy Cholesterol embolism Atrial myxoma Solar/senile purpura Scurvy Ergot derivatives Cocaine Methamphetamines Hypothenar hammer syndrome

Pathological alterations of the vessel wall

Embolic phenomena Structural deficiencies of the perivascular connective tissue Vasospasm

Repetitive vascular trauma

leukemia, Waldenström macroglobulinemia, or multiple myeloma. Types II and III cryoglobulinemia were discussed in detail earlier in the chapter. CLINICAL FEATURES Cutaneous lesions in patients with cryoglobulinemia may manifest as chronic palpable purpura, urticarialike lesions, livedo reticularis, Raynaud phenomenon, acrocyanosis, digital gangrene, and leg ulcers (see Table 9-27A). Systemic manifestations may include arthralgia, hepatosplenomegaly, lymphadenopathy, and glomerulonephritis.

Table 9-26B The Differential Diagnosis of Cutaneous Vascular Occlusive Conditions

204

Coagulopathy Cryoglobulinemia Cholesterol embolism Livedo reticularis Atrophie blanche Degos syndrome Calciphylaxis Oxalosis Secondary vasculopathy

HISTOPATHOLOGIC FEATURES In type I cryoglobulinemia, amorphous material (precipitated cryoglobulins) is deposited subjacent to endothelium, throughout the vessel wall, and within the vessel lumen, resulting in a thrombus-like appearance. These precipitates stain pink with hematoxylin and eosin and bright red with PAS stain, as opposed to less intense staining of fibrinoid material (see Fig. 9-8). Cracking of the precipitate may be a prominent feature. Some capillaries are filled with red blood cells, and extensive extravasation of erythrocytes may be present. An inflammatory infiltrate usually is lacking, in contrast to the vascular injury seen in mixed cryoglobulinemias, which typically show a vasculitis, as previously discussed. PAS-positive intramural and intravascular cryoprecipitate also may be found in mixed cryoglobulinemia (see Fig. 9-8), but less frequently than in type I cryoglobulinemia.15

Cutaneous Cholesterol Embolism Synonym: Atheroembolism. Cholesterol crystal embolization is usually a disease of the elderly with significant atherosclerosis102 (Table 9-28).

Table 9-27A Type I Cryoglobulinemia

Clinical Features Cutaneous: Palpable purpura Urticaria-like lesions Livedo reticularis Acrocyanosis Digital gangrene Leg ulcers Raynaud phenomenon Systemic: Arthralgia Hepatosplenomegaly Lymphadenopathy Glomerulonephritis Histopathologic Evaluation Amorphous, PAS-positive thrombi Cracking of thrombi Extensive extravasation of erythrocytes Differential Diagnosis Coagulopathies

Atheromatous plaque material may detach spontaneously or, more commonly, may follow an invasive procedure, such as arterial catheterization. Microemboli, composed of cholesterol crystals and/or other components of atheromatous plaque, often result in ischemic changes, most commonly involving the lower extremities. The cutaneous manifestations include livedo reticularis; purple discoloration; gangrene of toes; small, painful ulcerations; and on occasion, nodules or indurated plaques. The latter findings often closely mimic vasculitis, cryoglobulinemia, and chilblains. A helpful feature is the presence of intact arterial pulses on examination of the affected extremity, indicating that the ischemia is secondary to smallvessel involvement rather than major arteries. HISTOPATHOLOGIC FEATURES Cholesterol emboli may be found as needle-shaped clefts within the lumina of small vessels (Fig. 9-23). The intravascular clefts that are in effect dissolved crystals may be single or multiple and commonly are associated with amorphous eosinophilic material, macrophages, or a foreign body-giant cell reaction. Vascular walls exhibit intimal fibrosis and often obliteration of lumina in older lesions. In many instances only fibrin thrombi are observed. Often a deep biopsy is needed to reveal such emboli, which are distributed focally and therefore difficult to find.

Table 9-27B Clinical-Pathologic Associations of Cryoglobulinemias IMMUNOGLOBULIN

ASSOCIATIONS

SITE

CLINICAL FINDINGS HISTOPATHOLOGY

CHARACTERISTIC

Type I

Monoclonal IgG or IgM

Head, neck, oral, or nasal mucosa

Hemorrhagic crusts, skin ulcerations

Noninflammatory hyaline thrombosis Cutaneous infarction

Type II

Monoclonal and polyclonal immune complexes

Lymphoma, leukemia, Waldenström macroglobulinemia, or multiple myeloma Connective tissue disorders idiopathic (essential) Infection Autoimmune diseases

Legs

Erythematous to purpuric macules or papules

Leukocytoclastic vasculitis

Data from Cohen et al.19

CLINICAL FEATURES Livedo reticularis is red-blue mottling of the skin in a netlike pattern. This nonspecific physical sign indicates sluggish blood flow, which may result from a number of causes (Table 9-29). Physiologic livedo (cutis marmorata), commonly seen in young women, is mottling of the skin that subsides with warming. An idiopathic form, that is persistent and does not respond to warming, is limited to the lower extremities, may be associated with subtle coagulation abnormalities, and autoimmune phenomena.103 Druginduced livedo has been seen with interferon-alpha therapy for melanoma and amantadine therapy for Parkinson disease.104

HISTOPATHOLOGIC FEATURES Histopathologic changes may only be detected in punch biopsies sampling the dermis-subcutis boundry. Multiple areas from different areas of the livedo may need to be sampled, especially the seemingly uninvolved white skin at the center. Initially, blood vessels may show attachment of lymphohistiocytic cells and detachment of endothelial cells (endothelitis). Later, partial or complete occlusion of the lumen by a plug of lymphohistiocytic cells and fibrin may be seen, which is replaced by proliferating subendothelial cells accompanied by dilated capillaries in the adventitia of the occluded vessel. Late-stage vessels may show fibrosis and shrinkage. Intravascular aggregates of red blood cells suggest a low-flow state.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

Livedo Reticularis

 FIGURE 9-23 Cholesterol emboli. Needle-shaped clefts (arrow) are present within the lumen of a small vessel.

205

Livedo racemosa is also a violaceous mottling of the skin similar to livedo reticularis, but more generalized and widespread, and showing irregularities and breaks in the network patterning. Persistent livedo reticularis and livedo racemosa may be associated with vasoocclusive disorders, vasculitides, or connective tissue diseases including the antiphospholidid antibody syndrome. Lupus patients with livedo reticularis are more likely to suffer cerebral vascular accidents.105 Generalized livedo reticularis and livedo racemosa are also part of a potentially severe arterio-occlusive syndrome (Sneddon syndrome) that often is complicated by cerebrovascular disease.106,107

Table 9-28 Cutaneous Cholesterol Embolism

Clinical Features Elderly patient with significant atherosclerosis Often status post-arterial catheterization Often lower extremities effected Extremity with adequate pulsation Livedo reticularis, purple discoloration, gangrene of toes, and small, painful ulcerations on the legs, nodules, or indurated plaques Histopathologic Features Emboli with needle-shaped clefts in the lumina of small vessels associated with amorphous eosinophilic material Macrophages Foreign body giant cell reaction Intimal fibrosis Obliteration of lumina Fibrin thrombi

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Table 9-29 Livedo Reticularis

Table 9-30 Atrophie Blanche

Clinical Features Persistent red-blue mottling of the skin in a netlike pattern Histopathologic Features Erythematous areas: no distinct findings White areas: thick vessel walls, thrombi, arterioles obliteration, red blood cell slugging Associations Vasculitis or a vasculopathies due to infection Atrophie blanche Cholesterol emboli Connective tissue disease Calciphylaxis and oxalosis Idiopathic Sneddon syndrome

Clinical Features Seasonal Middle-aged or elderly females Lower portions of the legs ankles and the dorsa of the feet Purpuric macules and papules developing into small, painful ulcers then irregularly outlined with peripheral hyperpigmentation and telangiectasia Histopathologic Features Early: Fibrinoid material in vessel walls or lumina Infarction with hemorrhage and an inflammatory infiltrate Late: Thinning of epithelium Dermal sclerosis with little cellular thickening and intimal hyalinization of dermal vessel walls Occlusion of vessel lumina by intimal proliferation and/or fibrinoid recanalized vessels Differential Diagnosis Stasis Coagulopathy Lymphocytic vasculitis, not otherwise specified

Atrophie Blanche Synonyms: Livedoid vasculitis, segmental hyalinizing vasculitis, livedo reticularis with seasonal ulceration. CLINICAL FEATURES Atrophie blanche is a common condition that may be seasonal, with greatest disease activity in the summer and winter months. Usually middleaged or elderly females are affected.108 Initially, purpuric macules and papules develop into small, painful ulcers with a tendency to recur. Healing of the ulcers results in the white atrophic areas that have given the disease its name. Typically lesions are located on the lower portions of the legs, particularly on the ankles and the dorsa of the feet. In the fully developed state, there are irregularly outlined, whitish atrophic areas with peripheral hyperpigmentation and telangiectasia. Many of the patients have associated livedo reticularis. The etiology of atrophie blanche is unknown. Immune-complex deposits that have been observed in late lesions are likely secondary changes. A primary disturbance of fibrinolysis in the endothelium of affected microvessels has been postulated. HISTOPATHOLOGIC FEATURES The histologic findings are nonspecific and vary with the stage of the lesion (Table 9-30). However, in all stages, vascular changes are present. In early lesions, fibrinoid material may be noted in vessel walls or vessel lumina (Fig. 9-24A). Infarction with hemorrhage and an inflammatory infiltrate may be present as well. In late atrophic lesions, the epithelium is

thinned, and the dermis is sclerotic with little, if any, cellular infiltrate. The walls of the dermal vessels may show thickening and intimal hyalinization. Occlusion of vessel lumina by intimal proliferation and/or fibrinoid material and sometimes recanalized thrombotic vessels may be seen (Fig. 9-24B). In some cases the vessels in the superficial dermis are predominantly affected; in others, the vessels in the middle and even deep dermis are mostly affected. Cutaneous polyarteritis nodosum can show atrophie blanche-like histology in superficial biopsies and can look similar to atrophie blanche clinically. A deep biopsy may aid in distinguishing these two conditions.109

Degos Syndrome Synonyms: Malignant atrophic papulosis (MAP), Degos disease. Degos initially described a cutaneointestinal syndrome in which distinct skin findings (“drops of porcelain”) were associated with recurrent attacks of abdominal pain that often ended in death from intestinal perforations.110 He chose the name malignant atrophic papulosis to emphasize the serious clinical course of

the disease. Originally, the cutaneous lesions were thought to be specific and pathognomonic for a unique disease entity (Degos disease). Currently, MAP is considered to be a clinicopathologic reaction pattern that can be associated with a number of conditions other than the cutaneointestinal syndrome described by Degos and others.110 Lesions similar, if not identical, to MAP have been noted in particular in connective tissue diseases such as lupus erythematosus, dermatomyositis, and progressive systemic sclerosis; in atrophie blanche; and in CreutzfeldtJakob disease. A “benign” form, involving only the skin, has been reported.112,113 The etiology of Degos syndrome is unclear. The findings have been ascribed to a coagulopathy, vasculitis, or mucinosis. However, convincing evidence to support any single causal factor is lacking. CLINICAL FEATURES The cutaneous manifestations of Degos syndrome include crops of asymptomatic, slightly raised, yellowish red or pale rose papules (Table 9-31). Gradually the papules become umbilicated and develop an atrophic porcelain white center with a livid red, telangiectatic margin. These papules tend to affect the trunk and proximal extremities. Symptoms of an acute abdomen or, less commonly, of a cerebral infarction may supervene. HISTOPATHOLOGIC FEATURES The histopathology observed varies with the evolution of the lesions.113 Early papular lesions may show a superficial and deep perivascular, periadnexal, and perineural chronic inflammatory cell infiltrate associated with interstitial mucin deposition and an overlying mild vacuolar interface reaction mimicking tumid lupus. More evolved lesions with the porcelain white scale show a wedge-shaped area of altered dermis covered by atrophic epidermis with slight hyperkeratosis. Dermal alterations may include frank necrosis. However, more commonly, edema, extensive mucin deposition (which may mimic tumid lupus), and slight sclerosis or a lichen sclerosis-like appearance is seen (Fig. 9-25A). Typically, vascular damage is noted in the vessels at the base of the “cone of necrobiosis.” Vascular alterations may be subtle and manifest as endothelial swelling only. However, more characteristically, intravascular fibrin thrombi may be noted (see Fig. 9-25B). Their presence suggests that the dermal and epidermal changes result from ischemia. Altered vessels usually lack an inflammatory infiltrate.

B

 FIGURE 9-24 Atrophie blanche. (A) The microvessels show deposition of fibrinoid material in their walls (arrow) and an associated lymphoid infiltrate. (B) Fibrin thrombi (arrow) may be found in other vessels. (Courtesy of Dr. Charles Palmer.)

Calciphylaxis Synonyms: Widespread calcification with vascular thrombosis, calcific uremic arteriolopathy (CUA), calcifying panniculitis, vascular calcification-cutaneous necrosis syndrome. CLINICAL FEATURES Calciphylaxis is an uncommon complication of renal failure

Table 9-31 Degos Syndrome

Clinical Features Crops of asymptomatic, slightly raised, yellowish-red or pale rose papules which umbilicate and develop an atrophic porcelain-white center with a livid red, telangiectatic surrounding Trunk and proximal extremities commonly affected Acute abdominal crisis Cerebral infarction Histopathologic Features Atrophic epidermis with hyperkeratosis Wedge-shaped area of altered dermis Necrosis or edema Mucin deposition and slight sclerosis Vascular damage at the base of the wedge Fibrin thrombi common Differential Diagnosis Coagulopathies Cryoglobulinemia Atrophie blanche Pityriasis lichenoides

(Table 9-32). Usually secondary or tertiary hyperparathyroidism is found in these patients. Obesity, female gender, alcoholic cirrhosis, and poor nutritional status are some putative risk factors.114 Retiform purpura in plaques, palpable purpura in a livedoid, reticulate, or arciform pattern develop on the trunk and extremities (Fig. 9-26A). These dramatic painful lesions reflect occlusion of dermal and subcutaneous vasculature and can progress rapidly to form bullae, ulcers, eschars, and gangrene. The clinical differential diagnosis includes calciphylaxis, antiphospholipid antibody syndrome, warfarin-induced skin necrosis, and heparin-induced skin necrosis.101 The prognosis for calcifylaxis is extremely poor, especially for proximal disease, even with aggressive treatment by parathyroidectomy.115 Fulminant sepsis may develop from infection of necrotic or gangrenous tissue. The relationships amongst the calcification, thrombosis, and ischemic necrosis in calciphylaxis are unclear. Although vascular calcification is common in uremic patients, calciphylaxis is rare. Elevation of the calcium and phosphorous products, along with a poorly defined precipitating or challenging event or agent, is hypothesized to be necessary for calcium deposition in cutaneous tissues. However, the list of putative sensitizing agents is long, and the calcium and phosphorus products may be within normal limits. The development of a hypercoagulable state may be an additional important element in the pathogenesis of this entity but is not present in all cases.116

HISTOPATHOLOGIC FEATURES The principal histologic findings include (1) calcification of soft tissue and small vessels2 (Fig. 9-26), (2) nonspecific intimal proliferation of small vessels, often resulting in luminal narrowing, (3) variable fibrin thrombi, and (4) frequent ischemic necrosis of skin and subcutis (see Chap. 11). The small vessels involved by this process cannot be identified as either arterial or venous. Often one observes foreign body-giant cell reaction to calcium and mixed inflammatory cell infiltrates that are neutrophil-rich. Pseudoxanthoma elasticum-like changes and the changes of nephrogenic fibrosing dermopathy, also associated with chronic renal failure, can rarely be seen in association with calciphylaxis.117,118 DIFFERENTIAL DIAGNOSIS Cutaneous calcium deposits may be seen in a number of other conditions, especially cutaneous calcinosis and metastatic calcifications. In contrast to calciphylaxis (see Chap. 16), calcinosis usually lacks prominent vascular involvement. Occasionally, incidental medial calcification of blood vessels is seen as part of a mild atherosclerosis called Monckeberg medial calcific sclerosis. This change may be seen in patients without renal disease who have been biopsied for an unrelated condition. Other crystal-induced inflammatory diseases such as gout, pseudogout, or oxalosis that are associated with a giant cell reaction to crystal deposits and surrounding fibrosis may resemble calciphylaxis. Histopathologically, pancreatic

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A

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A

 FIGURE 9-25 Degos lesion. Atrophic epidermis overlies a wedge-shaped area of dermis with mucin deposition (A) and a thrombosed vessel at the base (B). This Degos lesion was seen in a patient with dermatomyositis.

panniculitis may suggest calciphylaxis. However, the polymorphous infiltrate and ghostlike cells are absent in calciphylaxis, in contrast to pancreatic panniculitis.119 If the sampling lacks significant

Table 9-32 Calciphylaxis

208

B

Clinical Features Renal failure with secondary hyperparathyroidism Primary hyperparathyroidism Hypercalcemia of malignancy Livedo reticularis Firm, indurated, painful, violaceous lesions Progression to bullae, ulcers, eschars, and gangrene Trunk and extremities involved Histopathologic Features Calcium deposition in soft tissue and small blood vessels Intimal proliferation and luminal occlusion Thrombi in uncalcified, noninflamed small vessels of the subcutis Full-thickness ischemic necrosis of skin Differential Diagnosis Coagulopathies Calcinosis cutis Panniculitis with calcification

calcium deposits, the biopsy may mimic ischemic damage or a coagulopathy.

Oxalosis CLINICAL FINDINGS Oxalosis is characterized by the deposition of calcium oxalate crystals in multiple organs, most frequently the kidneys and myocardium. The disease may be primary, owing to inborn errors of metabolism, or secondary. The most common cause of secondary oxalosis is hyperabsorption of dietary oxalate secondary to intestinal disease or ileal resection or excessive intake of oxalates or oxalate precursors, such as ethylene glycol. Deposition of calcium oxalate in small vessels of the dermis and subcutis may result in livedo reticularis, whereas involvement of larger peripheral blood vessels may lead to peripheral gangrene.120,121 HISTOPATHOLOGIC FEATURES Calcium oxalate is a light yellow-brown birefringent crystal exhibiting a number of shapes, including rosettes, ellipses, prisms, and radial patterns. The latter crystals may be deposited in the walls or occlude the lumina of small vessels with or without fibrin thrombi or localize to the media of larger vessels. There may

be infiltration of vessel walls by neutrophils. Varying degrees of ischemic necrosis of skin may result. DIFFERENTIAL DIAGNOSIS The histopathologic findings may resemble calciphylaxis. However, the calcium oxalate crystal morphology and birefringence allow discrimination from calcium phosphate. Although both oxalosis and calciphylaxis patients exhibit renal failure, the cutaneous clinical findings are distinct. Other crystal deposition syndromes, such as gout, may resemble oxalosis. However, urate crystals are dissolved during routine processing, unlike oxalate crystals, and are not deposited in vascular walls with associated thrombi. Oxalate thrombi may be confused with a cholesterol embolus; however, cholesterol is removed by routine processing and is not birefringent. Calcium oxalate can be identified histochemically by the method of Johnson and Pani.122

Conditions Leading to Alteration of the Vessel Wall Metabolic disorders may lead to the deposition of endogenously produced material within the walls of the small vessels supplying the skin. These metabolic

B

 FIGURE 9-26 Calciphylaxis. (A) Hyperpigmented and purpuric plaques with vaguely livedoid, reticulate, and arciform patterns showing coalescence on the lower extremity. (B) Vascular calcification of a small blood vessel in the panniculus. (Figure 9-26B is Courtesy of Dr Charles Palmer.)

vasculopathies may result in ischemic damage. Examples of such disorders include diabetes mellitus, amyloidosis, or porphyria, which are discussed in more detail in Chaps. 8 and 16. The salient histologic vascular alteration in the abovementioned disorders is the deposition of amorphous material in the walls of dermal capillaries. Atherosclerosis is by far the most common type of metabolic vasculopathy. However, atherosclerosis is primarily a disease of large vessels supplying visceral organs and is not a usual finding in skin biopsies. Cutaneous changes, usually secondary manifestations of peripheral ischemia, are more common in the amputation specimens seen in general surgical pathology. Luminal occlusion may result from intimal thickening and lipid deposition, superimposed thrombosis, or less frequently, cholesterol emboli (discussed earlier).

HISTOPATHOLOGIC FEATURES In senile purpura, extravasation of red blood cells occurs in atrophic skin with severe solar elastosis and normal-appearing capillaries (Fig. 9-27). Such lesions may simulate melanoma or angiosarcoma clinically.

Scurvy is characterized by dermal hemorrhage predominantly in the vicinity of hair follicles without evidence of vascular damage. Hemosiderin-laden macrophages, follicular keratotic plugs, and coiled hair are also seen.123

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

A

Vasculopathies Owing to Deficiencies of Connective Tissue Last, structural deficiencies of the perivascular connective tissue may contribute to vascular fragility and the attendant extravasation of erythrocytes. Such alterations underlie the hemorrhage in senile purpura and scurvy. This group of conditions can be described as noninflammatory purpura.

 FIGURE 9-27 Senile purpura. Extravasated red cells within elastotic dermis.

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associated with polycystic kidney disease and chronic renal failure. J Am Acad Dermatol. 1990;22:743-747. Greer KE, Cooper PH, Campbell R, Westervelt FB. Primary oxalosis with livedo reticularis. Arch Dermatol. 1980; 116:213-214. Arbus GS, Sniderman S. Oxalosis with peripheral gangrene. Arch Pathol. 1974;97:107-110. Johnson FB, Pani K. Histochemical identification of calcium oxalate. Arch Pathol Lab Med. 1962;74:347-351. Walker A. Chronic scurvy. Br J Dermatol. 1968;80:625-630.

CHAPTER 10 Disorders of Cutaneous Appendages David A. Whiting Douglas C. Parker Amy K. Reisenauer Alvin R. Solomon

tissue and therefore hair bulbs. For additional information, two 4-mm punch biopsies are taken from comparable sites. One biopsy is bisected vertically parallel to the direction of any hairs, and both halves are placed in a cassette for formalin fixation and standard staining with hematoxylin and eosin (H&E). If necessary, one-half of the vertical biopsy can be reserved for immunofluorescence or any other purpose that requires different processing. The other 4-mm punch is carefully bisected horizontally (transversely) parallel to the epidermis and 1 to 1.5 mm below it.4 Both segments are embedded in paraffin side by side with the cut surfaces face down in the block.5 Sectioning will progress down toward the subcutaneous tissue in one half and up toward the epidermis in the other. The pathologist who uses this technique and is familiar with the transverse anatomy of the hair follicle can then count the hair bulbs; terminal anagen, catagen, and telogen hairs; telogen germinal units; and stelae (fibrous tracts or streamers) in sections through reticular dermis6,7 (Tables 10-2 and 10-3). Terminal hairs, vellus hairs (which include true vellus hairs and miniaturized or velluslike hairs), and follicular units can be counted in sections of the papillary dermis (Tables 10-3 and 10-4). From these data, total follicular counts are derived with anagen-telogen ratios, terminal-vellus hair ratios, and follicular concentration per square millimeter. Comparative data for controls versus androgenetic alopecia, chronic telogen effluvium, alopecia areata, and trichotillomania are shown in Table 10-4.8-10 For pathologists who rely only on vertical sections, multiple sections may be required to estimate the total follicular counts and the terminalvellus and anagen-telogen ratios, which are helpful in the diagnosis of nonscarring alopecia. The presence or absence of inflammatory changes and fibrosis is also important in establishing the diagnosis.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

The interpretation of scalp biopsies from patients with hair loss can be difficult (Fig. 10-1). The pathologist depends on accurate clinical information when assessing scalp biopsies. The most common causes of hair loss or shedding are nonscarring and include androgenetic alopecia, diffuse alopecia, alopecia areata, trichotillomania, and other types of traumatic alopecia1 (Table 10-1). A basic understanding of the hair follicle and the hair cycle is needed to interpret scalp biopsies.1-3 The human hair follicle consists of a permanent upper segment, comprised of infundibulum and isthmus, and an impermanent lower segment, comprised of lower follicle and hair root. The infundibulum is lined with keratinized skin surface epithelium and ends at the entry of the sebaceous duct into the follicle. The isthmus extends down from the sebaceous duct and ends at the bulge where the arrector pili muscle inserts into the follicle. It is lined by trichilemma (external root sheath) and trichilemmal keratin. The lower segment surrounds a growing hair with internal and external root sheaths, hyaline membrane, and fibrous sheath. The bulb consists of the dermal papilla surrounded by hair matrix cells. It generates the growing hair. The dermal papilla and fibrous sheath are continuous. Human scalp hair follicles cycle continuously through periods of growth and rest. Asynchronous follicular growth produces an ever-changing mosaic pattern of growing follicles on the scalp. The growth or anagen phase lasts 2 to 7 years, 1000 days on average, and the resting or telogen phase lasts 2 to 4 months, an average of 100 days. The end of telogen is signaled by the appearance of a new anagen hair and the shedding of the telogen hair. Assuming an average of 100,000 hairs on the human scalp, with 5% to 10% in telogen at any one time, then up

to 10,000 hairs are shed every 100 days, an average loss of 100 hairs per day. Large hairs with a diameter exceeding 0.03 mm, growing more than 1 cm in length, often pigmented and medullated, are classified as terminal hairs. Small hairs with a diameter of less than 0.03 mm, growing less than 1 cm in length, and with no pigment or medullary cavity, are classified as vellus (downy) hairs. Depigmented hairs less than 0.03 mm in diameter that have been miniaturized by androgenetic alopecia, alopecia areata, or any other cause can be classified as vellus-like hairs. The designation vellus hairs used in this chapter includes true vellus hairs and vellus-like hairs. Terminal hairs are rooted in the subcutaneous tissue, but vellus hairs are rooted in the dermis. Terminal-to-vellus ratios therefore denote the proportions of large hairs to small hairs, and a normal scalp averages seven terminal hairs per vellus hair. Less than four terminal hairs to one vellus hair denotes a relative increase in vellus hairs, perhaps indicating a miniaturization process. The termination of anagen is signaled by the onset of catagen. Catagen is the short, 10- to 14-day intermediate phase between anagen and telogen that indicates the onset of telogen, since it irrevocably commits the growing follicle to a resting phase. In catagen, the hair shaft retracts upward, the hyaline basement membrane thickens and corrugates, and individual cell necrosis or apoptosis occurs in the outer root sheath or trichilemma. The hair displacement and volumetric reduction of root sheath lead to the progressive disappearance of the lower or impermanent part of the hair follicle so that in telogen the resting hair root is seen near the insertion of the arrector pili muscle, where the permanent follicle begins. A telogen bulb lacks pigment and internal and external root sheaths and is surrounded by trichilemmal keratin. An angiofibrotic strand extending down from the permanent follicle, known variously as a fibrous tract, streamer, or stela, indicates the former position of the retracted follicle. Histopathologic examination is helpful for diagnostic purposes and for evaluating the capacity for future hair regrowth. If possible, the biopsy should be taken from an area of active alopecia. For predictive purposes, an area of maximal hair loss can be sampled. Punch biopsies of the scalp are adequate substitutes for excisional biopsies. A sharp trephine of at least 4 mm diameter is used. The biopsy is angled in the direction of any emerging hairs and taken deep enough to include subcutaneous

TRANSVERSE VERSUS VERTICAL SECTION TECHNIQUES The advantages of transverse sections in evaluating alopecia are many (Table 10-5). Familiarity with follicular microanatomy is essential when evaluating transverse sections (see Tables 10-2 and 10-3), and several recent reviews describe this in detail.2-4,6-8 Transverse sections allow for rapid detection of pathologic alteration of this normal follicular microanatomy, especially follicular density.

213

Alopecia

Nonscarring alopecia

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

No follicular loss Normal terminal:vellus ratio Diffuse alopecia (telogen effluvium) Trichotillomania Traction alopecia

Slight decrease anagen:telogen ratio Diffuse alopecia Androgenetic alopecia

Mild follicular loss Decreased terminal: vellus ratio Androgenetic alopecia Alopecia areata

Moderate follicular loss Congenital hypotrichosis Congenital triangular alopecia

Peribulbar lymphocytic infiltrates absent Perifollicular lymphocytic infiltrates: 70% Androgenetic alopecia

Large decrease anagen:telogen ratio Trichotillomania

Trichomalacia often absent Traction alopecia

Scarring alopecia

Peribulbar lymphocytic infiltrates present Moderate decrease anagen: telogen ratio Alopecia areata

Trichomalacia often present Trichotillomania

Scarring alopecia

Primary scarring alopecia

Lymphocyte-associated scarring alopecia Discoid lupus erythematosus Lichen planopilaris Pseudopelade/follicular degeneration syndrome Alopecia mucinosa

Interface alteration Lupus erythematosus Lichen planopilaris

Vacuolar interface alteration Superficial and deep infiltrates Discoid lupus erythematosus

Lichenoid interface alteration Perifollicular infiltrates mainly Lichen planopilaris

Secondary scarring alopecia

Neutrophil-associated (pustulo-follicular) scarring alopecia Dissecting cellulitis Folliculitis decalvans Acne keloidalis Tinea kerion and favus

No interface alteration Pseudopelade Follicular mucinosis

No follicular mucin Perifollicular fibrosis Pseudopelade

Follicular mucin No perifollicular fibrosis Follicular mucinosis

Sclerosing disorders

Tumors

Physical/ chemical agents

Granulomatous infiltrates

Dermal infiltrative processes

Amyloidosis

 FIGURE 10-1 An algorithm for the histopathologic diagnosis of alopecia.

214

Transverse sectioning provides for either quantitative or semiquantitative evaluation of numerous follicles and follicular units in one section, thus allowing for a rapid, accurate assessment of whether the specimen represents a scarring or

nonscarring alopecia. By definition, scarring alopecias show diminished follicular density (complete follicular atrophy) and disruption of follicular unit morphology. Evaluation of follicular density is more difficult using traditional vertical sections

because multiple serial sections must be examined. Furthermore, follicular unit morphology cannot be assessed accurately with vertical sections. The dermalepidermal junction is evaluated more easily in vertical sections but also can be

Table 10-1 Common Causes of Alopecia NO

DISEASE Male androgenetic alopecia Diffuse alopecia Female pattern alopecia Alopecia areata Cicatricial alopecia Trichotillomania Other

NONSCARRING VERSUS SCARRING ALOPECIA Determining whether a patient clinically has scarring or nonscarring alopecia can be challenging, and in these cases, scalp biopsy is a very useful tool for specific diagnosis and prognosis for possible regrowth. The terms scarring and nonscarring are firmly entrenched in the dermatologic lexicon and are helpful for classification and prognosis in many cases of alopecia. However, some of the traditionally designated nonscarring alopecias may eventuate in permanent follicular atrophy and hair loss. Androgenetic alopecia, alopecia areata, traction alopecia, and trichotillomania are examples of nonscarring alopecia that may progress to complete, permanent hair loss. Thus the terms scarring

2447 1719 1848 1155 658 142 1123 9092

27.0 18.9 20.3 12.7 7.2 1.6 12.3 100

and nonscarring as they have been used historically do not always correlate with prognosis for hair regrowth. Some of the histopathologic differences in the common forms of nonscarring alopecia are set out in Table 10-6.

NONSCARRING ALOPECIA

Androgenetic Alopecia Androgenetic alopecia, or common baldness, affects at least 50% of the population by age 50 years in males11 and a decade later in females. The familiar pattern of frontoparietal hair loss is due to a genetically determined end-organ sensitivity of the hairs on the crown to androgens. The affected terminal hairs are replaced progressively by finer and shorter hairs.12 CLINICAL FEATURES Androgenetic alopecia predominantly affects the top of the scalp in both sexes, with relative sparing

HISTOPATHOLOGIC FEATURES The histopathologic changes in androgenetic alopecia are similar in males and females and reflect the pathogenesis of the condition17,18 (see Table 10-7). With shorter hair cycles, terminal hairs become vellus-like. The hair roots retreat upward toward the epidermis so that many of the miniaturized hair bulbs are found in mid- or papillary dermis. Residual follicular stelae (fibrous tracts or streamers) extending from the subcutaneous tissue up the old follicular tract to the miniaturized hair mark the former position of the original terminal follicle (Fig. 10-2). Thus the expected findings in androgenetic alopecia are decreased terminal hairs, increased follicular stelae, and increased vellus hairs17-24 (Fig. 10-3). A varying

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

viewed in transverse sections, although in tangential orientation.7

% OF PATIENTS

of the back and sides (Table 10-7). It is of dominant inheritance with variable penetrance.13 Hair thinning occurs in males at any time after puberty. It often begins with bitemporal hair recession followed by a circular patch of hair loss over the vertex and then thinning of the frontal hairline.11 In females, hair thinning also can begin after puberty, but an onset at between 25 and 35 years of age is more common, and many patients only present around menopause. Female-pattern alopecia causes diffuse thinning over the top of the scalp with an intact frontal hair margin14,15 and without total baldness. In females, severe bitemporal recession, vertex baldness, acne, hirsutism, and abnormal menses reflect significant hyperandrogenism, which needs investigation.16

Table 10-2 Description of Follicular Structures Terminal (big hair) Vellus (small)

Hair bulb Anagen hairs Telogen hairs

Follicular stelae

Follicular units

SOURCE: After Whiting32

Shaft diameter exceeds 0.03 mm and is thicker than its inner root sheath. A medullary cavity and/or pigment may be present. This definition includes “intermediate” hair shafts of diameter 0.03-0.06 mm. Shaft diameter equals 0.03 mm or less and is thinner than its inner root sheath. Shaft lacks pigment and medullary cavity, and arrector pili muscle is usually not found. All hairs of this size are counted as vellus hairs, whether true vellus hairs or vellus-like hairs secondary to miniaturization from any cause. The hair bulb consists of root sheath, hair matrix, and dermal papilla. Hair bulbs or hair shafts surrounded by inner and outer root sheaths. Only identifiable in lower follicle below bulge area. Catagen hairs with trichilemmal apoptosis and thickened, corrugated, vitreous membrane, telogen hairs containing trichilemmal keratin, and telogen germinal units (resting telogen follicles containing basaloid cells). Only identifiable in lower follicle below bulge area. Residual fibrous tracts or streamers representing the impermanent lower third of the hair follicle below the bulge area. Not counted as extra hair-forming structures because they are either downward prolongations of follicular structures that are counted in horizontal sections of the papillary dermis anyway or are permanently fibrosed follicles. Hexagonal areas seen in horizontal sections at sebaceous duct level, surrounded by collagen and containing terminal and vellus hairs, sebaceous glands and ducts, and arrector pili muscles. Not counted as follicular structures, but if fibrosed, represent severe cicatricial alopecia.

215

trichotillomania. Hair miniaturization does not occur in diffuse alopecia or in trichotillomania but is present in alopecia areata, often with a peribulbar lymphocytic infiltrate. Increased catagen hairs are present in trichotillomania and alopecia areata. Trichomalacia is characteristic of traction alopecia, notably trichotillomania, but can occur in alopecia areata.

Table 10-3 Normal Transverse Section Microanatomy: 4-mm Punch Biopsy Follicular unita composition

2-4 terminal follicles 2-4 vellus follicles Sebaceous lobules Arrector pili muscles 10-14 follicular units 20-40 terminal follicles 90%± 10%±

Follicular unit density Hair folliclea density Anagen follicles Telogen follicles

Diffuse Alopecia

a

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Follicular units include terminal and vellus hairs, sebaceous glands and ducts, and arrector pili muscles; hair follicle refers to terminal follicular units.

number of intermediate hairs, with a shaft diameter less than the average 0.06-mm terminal hair diameter but more than the 0.03-mm vellus hair diameter, may be present25; for simplicity, these intermediate hairs are classified as terminal hairs in follicular counts quoted in this chapter. The progressive reduction in duration of anagen, but not telogen, causes a relative increase in telogen hairs. The average follicular counts in horizontal sections of a 4-mm punch biopsy of male pattern alopecia are 20.9 terminal hairs + 14.7 vellus hairs + 35.6 total hairs, with a terminalvellus ratio of 1.4:1 and a ratio of 80% anagen to 20% telogen (see Table 10-4). The follicular counts in female pattern alopecia are 21.6 terminal hairs + 11.1 vellus hairs = 32.6 total hairs, with a terminal-vellus ratio of 1.9:1, and 86% anagen hairs and 14% telogen hairs. These counts contrast with those in normal controls, which are 35 terminal hairs + 5 vellus hairs + 40 total hairs, with a terminal-vellus ratio of 7:1 and a ratio of 93.5% anagen to 6.5% telogen17,18 (see Table 10-4). A terminal-vellus ratio of less than 4:1 indicates increased follicular miniaturization. A significant

reduction in the total follicular count is seen in 10% of cases of androgenetic alopecia, indicating a decreased capacity for follicular regrowth in these cases.17 A mild perifollicular lymphohistiocytic infiltrate, usually around upper follicles, is present in one-third of cases of androgenetic alopecia, as it is in one-third of normal controls. A moderate perifollicular lymphohistiocytic infiltrate, perhaps with concentric layers of collagen deposition, is present in 40% of cases of androgenetic alopecia but only in 10% of normal controls.17 Occasional mast cells and even eosinophils are seen. Despite the inflammatory changes, sebaceous glands remain intact in androgenetic alopecia. Routine stains are adequate to evaluate androgenetic alopecia, but periodic acid–Schiff (PAS) stains apoptotic cells and vitreous layer to highlight catagen, and elastic stains show up Arao-Perkins bodies (ie, elastin aggregates at the site of an antecedent follicular papilla) in follicular stelae. DIFFERENTIAL DIAGNOSIS Androgenetic alopecia must be distinguished from diffuse alopecia, alopecia areata, and

Diffuse alopecia implies generalized hair loss or shedding involving the back, sides, and top of the scalp. Common causes are listed in Table 10-8.26 The underlying mechanism is often a telogen effluvium.27 Headington has described five functional types of telogen effluvium based on changes occurring in different phases of the hair cycle.28 These consist of immediate anagen release (postfebrile), delayed anagen release (postpartum), short anagen cycle (inability to grow long hair), immediate telogen release (minoxidil), and delayed telogen release (molting). Basically, an abnormal number of hairs go into the telogen phase and only fall out 1 to 3 months later when new anagen hairs grow in.29 Classic acute telogen effluvium occurs after childbirth, severe illness, operations, stress, crash diets, or various drugs29 (Table 10-9). In chronic telogen effluvium, the trigger factor may be obscure, and any one of Headington’s functional types can be implicated, although short anagen cycle may be the most common. Anagen effluvium is a severe condition, often resulting from antimitotic drugs, in which large amounts of hair fall out within a few weeks of impaired DNA synthesis.30,31

Table 10-4 Horizontal Sections of 4-mm Scalp Biopsies Mean Follicular Counts in Differential Diagnosis of Alopecia: 1987-2007 DIAGNOSIS Controls Male pattern alopecia Female pattern alopecia Diffuse alopecia Alopecia areata Trichotillomania

216

NO. OF PATIENTS

AGE, YEARS

SEX (M:F)

TERMINAL (T) HAIRS

+

VELLUS (V) HAIRS

=

TOTAL HAIRS

T:V RATIO

ANAG: TELO %

22 305

43 34.4

1.4:1 M

35 20.9

+ +

5 14.7

= =

40 35.6

7:1 1.4:1

93.5:6.5 80:20

1338

46.2

F

21.6

+

11.1

=

32.6

1.9:1

86:14

1061 834 85

48.4 31.9 20.2

1:36 1:2 1:5.5

32.8 16.4 27.5

+ + +

4.4 12.9 6.6

= = =

37.2 29.3 34.1

7.4:1 1.3:1 4.2:1

89:11 56:44 65:35

Table 10-5 Advantages and Disadvantages of Transverse Sections

SOURCE: Adapted with permission from Templeton SF, Santa Cruz DJ, Solomon AR. Alopecia: histologic diagnosis by transverse section. Semin Diagn Pathol. 1996;13:2-18.

women, and usually does not cause severe baldness (see Fig. 10-3 and Table 10-10).

CLINICAL FEATURES In an acute phase of diffuse alopecia, hair pull tests are positive from all over the scalp (Table 10-10). In telogen effluvium, the extracted hairs show depigmented club roots and no root sheaths.29 In anagen effluvium, extracted hairs show a proximal taper with a fracture30; when the antimitotic influence is removed, hairs grow back promptly with a distal taper due to reversal of the pencilpointing process. Classic acute telogen effluvium affecting any age group has an abrupt onset and a short course of 3 to 6 months.29 Chronic telogen effluvium can last from 6 months to 7 years or more, with an abrupt or gradual onset and a cyclic course.32,33 It is often idiopathic,34 usually affects middle-aged

HISTOPATHOLOGIC FEATURES The histopathology of telogen effluvium is often similar to that seen in a normal scalp, except for the definite increase in telogen hairs seen during an active phase of hair loss35,36 (see Table 10-10). In vertical sections, many terminal hairs are present, few vellus hairs are seen, and follicular stelae are uncommon (Fig. 10-4). Follicular counts in horizontal sections of a 4-mm punch biopsy of the crown in chronic telogen effluvium average 32.8 terminal hairs + 4.4 vellus hairs = 37.2 total hairs, with a terminal-vellus ratio of 7:1 and a ratio of 89% anagen to 11%

DIFFERENTIAL DIAGNOSIS Diffuse alopecia usually can be diagnosed on clinical grounds but sometimes is confused with female androgenetic alopecia, diffuse alopecia areata,38 or congenital hypotrichosis, and biopsies may be necessary. There is no reduction in terminal hair numbers in diffuse alopecia, but there is a definite reduction in terminal hairs, with increased vellus hairs, in androgenetic alopecia, diffuse alopecia areata, and congenital hypotrichosis.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Advantages More follicles per section Rapid, accurate assessment of follicle density, the number of terminal follicles, and the preservation or loss of normal follicular unit morphology Easy assessment of follicle and shaft diameters Most accurate anagen-telogen ratios Disadvantages Must be familiar with scalp microanatomy in a different plane of sectioning Gross tissue specimen processing requires a different protocol The epidermis and dermal-epidermal interface is more easily evaluated in vertical sections Limitations of Both Methods The 4- to 6-mm scalp biopsy is a small sample compared with the total scalp area Biopsy site selection is critical The specificity of the histopathologic diagnosis decreases with the duration and extent of follicular destruction

telogen37 (see Table 10-4). These findings are the same as in normal controls, except that the 11% telogen hairs exceeds the 6.5% telogen hairs found in normal individuals (Figs. 10-5 and 10-6). The telogen count can increase to 20% to 30% or higher in active phases of telogen effluvium. Inflammatory changes are similar to controls in that mild perifollicular lymphohistiocytic infiltration occurs in one-third and moderate infiltration in 10% of cases of telogen effluvium. Normal numbers of follicular stelae are found.32 The diffuse alopecia caused by hypothyroidism, other systemic diseases, and many drugs and chemicals results from a telogen effluvium and shows a similar histology. Anagen effluvium involves 90% of scalp hairs in anagen.37 The diagnosis is usually simple, since there is a clear history of the drug or influence that interferes with DNA synthesis. Examination of plucked hairs is diagnostic, so biopsies are usually not indicated, except in cases of persistent hairloss following chemotherapy. The proximal tapering of a plucked hair in anagen effluvium is shown in Fig. 10-7.

Table 10-6 Histopathologic Features of Nonscarring Alopecias

Congenital hypotrichosis Congenital triangular alopecia Androgenetic alopecia Alopecia areata Diffuse alopecia (telogen effluvium) Trichotillomania Traction alopecia

FOLLICULAR LOSS

TERMINALVELLUS RATIO

ANAGEN-TELOGEN RATIO

PERIFOLLICULAR LYMPHOID INFILTRATES

PERIBULBAR LYMPHOID INFILTRATES

TRICHOMALACIA

Moderate

NA

Large decrease

Usually absent

Absent

Absent

Moderate

Decreased

Large decrease

Usually absent

Absent

Absent

Mild

Decreased

Slight decrease

70%a

Absent

Absent

Mild None

Decreased Normal

Moderate decrease Slight decrease

Usually absent 40%a

Present Absent

Absent Absent

None None

Normal Normal

Large decrease Large decrease

Usually absent Usually absent

Absent Absent

Often present Often absent

NA = Not applicable. a Percentage of patients with mild to moderate infiltrates; 40% of normal controls have mild to moderate infiltrates.

217

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 10-7 Androgenetic Alopecia

218

Clinical Features Progressive miniaturization of hairs on crown, with relative sparing of hair on back and sides of scalp Male: onset from puberty to 50 years; marked bitemporal recession with balding of vertex Female: onset often one decade later than males; intact frontal hairline with diffuse thinning over crown Histopathologic Features Increased miniaturized, vellus hairs Increased follicular stelae Decreased terminal hairs Increased telogen hairs Mild to moderate perifollicular lymphohistiocytic inflammation in 70% of cases Intact sebaceous glands Differential Diagnosis Diffuse alopecia, especially telogen effluvium Diffuse alopecia areata Diffuse trichotillomania

Peribulbar lymphocytes often are present in alopecia areata.

Alopecia Areata Alopecia areata presents with patchy hair loss.39,40 It is not uncommon and may affect 1.7% of Americans by age 50. The etiology of alopecia areata is unknown, and many believe it to be an autoimmune disease. Helper T cells are consistently found in the predominately lymphocytic infiltrate around affected hair bulbs. A family history is present in 20% of cases. Recent studies have shown the importance of the HLA class II antigen DQ3, DR4, and DR11 genes in susceptibility to alopecia areata and of DRW52A in resistance to the condition.41 Longstanding alopecia totalis or universalis patients have unique associations with HLA antigens DR4, DR11, and DQ7.42 Trigger factors include seasonal variation, emotional stress, and infections. CLINICAL FEATURES The initial patch of alopecia areata on the scalp is often barely noticeable,43 but it may enlarge, and further patches may appear (Fig. 10-8A) (Table 10-11). Disease activity is indicated by “exclamation point” hairs at the spreading margin of lesions. Specific forms of alopecia areata include ophiasis, a persistent bandlike loss of hair; diffuse alopecia areata including an acute form

 FIGURE 10-2 Female androgenetic alopecia. Vertical section: Two terminal hairs and five follicular stelae (streamers or fibrous tracts) project down into the subcutaneous tissue; four vellus (vellus-like or miniaturized) hairs are seen in the upper dermis, two of which are connected to follicular stelae extending down to subcutaneous tissue. There is no inflammation and no fibrosis.

labeled alopecia areata incognito; and reticular alopecia areata with multiple patches of hair loss.39 In some cases the alopecia primarily involves beard, eyebrow, eyelash, and rarely, body hair. In the most severe cases all scalp (alopecia totalis) and body (alopecia universalis) hair is lost. Alopecia areata is more common in females, except in children. Its course is unpredictable. HISTOPATHOLOGIC FEATURES In the active stage of alopecia areata there is a characteristic cluster of mononuclear cells around follicular bulbs that has been likened to a swarm of bees39 (see Table 10-11 and Figs. 10-9 and 10-10). The infiltrate in alopecia areata consists primarily of CD4 lymphocytes and Langerhans cells, but some eosinophils and plasma cells may be seen.44,45 This lymphocytic infiltrate can invade the hair bulb and cause pigment incontinence.46 The infiltrate also can surround the adjacent suprabulbar portion of the hair shaft. Inflammatory cells invading bulbar epithelium can cause inter- and intracellular edema; nuclear pyknosis; apoptosis of matrix and outer sheath keratinocytes,

melanocytes, Langerhans cells, and dermal dendrocytes; and necrosis and microvesicle formation in the upper bulb above the dermal papilla.47 In the initial stages the disease usually involves terminal hairs, but later on miniaturized, velluslike hairs also are involved.48 As the disease progresses, follicular stelae infiltrated with lymphocytes (see Fig. 10-8) and containing melanin pigment are common. The inflammatory process involves anagen hairs that either become tapered and dystrophic, sometimes progressing to trichomalacia,25 or more commonly are projected through catagen into premature telogen (Fig. 10-10). The increased number of catagen hairs that results (Figs. 10-11 and 10-12) is equaled or exceeded only by the number of catagen hairs found in trichotillomania. Persistent disease results in miniaturization of hairs with decreased terminal hairs and increased vellus hairs and follicular stelae. The average follicular count found in horizontal sections of a 4-mm punch biopsy consists of 16.4 terminal hairs + 12.9 vellus hairs = 29.3 total hairs, a terminal-vellus ratio of 1.3:1, and 56% of terminal hairs in anagen and 44% in telogen (see Table 10-4). The reduction

and loose anagen syndrome and in familial focal alopecia, in which a marked increase of telogen germinal units with no scarring indicates telogen arrest; terminal hairs are reduced in congenital triangular alopecia but not in loose anagen syndrome. Plasma cells may be sparse or plentiful in the diffuse inflammation of secondary syphilis. Cicatricial alopecia is characterized by permanent destruction of hair follicles with replacement by fibrosis. Follicles are undamaged in tick-bite alopecia, which is a localized telogen effluvium caused by an anticoagulant in tick saliva.

 FIGURE 10-3 Male androgenetic alopecia. Horizontal section, papillary dermis: Relatively few terminal hairs and many vellus hairs are visible. A mild lymphohistiocytic infiltrate is present around a few follicular infundibula, and no fibrosis is seen.

in total hairs and the increase in vellus and telogen hairs contrast with normal controls.49 Contrary to general belief, there is a definite follicular dropout with fibrosis in about 10% of patients with a long history of attacks of alopecia areata.9 Peribulbar lymphocytic infiltration may not be prominent between acute attacks. In such cases, the reduced anagen-telogen and terminal-vellus ratios and the possible presence of catagen hairs may be useful indicators of alopecia areata.9 Melanin incontinence, trichomalacia, and foreign-body tissue reaction may be further diagnostic pointers.39 It is surprising, however, that in some chronic and apparently inactive cases of alopecia areata, perifollicular mononuclear cell infiltrates are still found, often around miniaturized hairs.25

DIFFERENTIAL DIAGNOSIS Causes of patchy alopecia that may be confused with alopecia areata include tinea capitis, trichotillomania, traction alopecia, pressure alopecia, congenital triangular alopecia, loose anagen syndrome, familial focal alopecia,50 secondary syphilis,25 tick-bite alopecia, and scarring alopecia such as aplasia cutis and pseudopelade. These usually can be distinguished by the history and clinical appearance, but biopsies may be necessary. Tinea capitis shows chronic folliculitis, often granulomatous, with intrafollicular neutrophils; fungal spores and hyphae may still be present. Inflammation and miniaturized hairs are lacking in trichotillomania and other forms of traumatic alopecia, but catagen hairs occur. Inflammation is absent in congenital triangular alopecia

Table 10-8 Causes of Diffuse Alopecia Classic acute telogen effluvium Chronic telogen effluvium Anagen effluvium Drugs Other chemicals Thyroid disorders Iron deficiency

Nutritional causes Malabsorption Renal failure Hepatic failure Systemic disease Miscellaneous causes Idiopathic

SOURCE: Data from Simpson NB: Diffuse alopecia: endocrine, metabolic, and chemical influences on the follicular cycle. In: Rook A, Dawber R, eds: Diseases of the Hair and Scalp. 2nd ed. Oxford: Blackwell Scientific; 1991: Chap 5, 136-166.

Trichotillomania is an abnormal compulsion to pull out hair. It affects more children than adults and after age 6 years is more common in females. Two polar forms of trichotillomania occur: The juvenile type peaks between 2 and 6 years of age, and the adult type peaks between 11 and 17 years of age.51 In children, the habit may develop subconsciously and replace thumb sucking or represent an effort to gain attention. Mental retardation or severe psychological disturbances are more common in adults. CLINICAL FEATURES Trichotillomania presents with one or more patches of hair thinning52 (Table 10-12). The patches are characterized by an irregular stubble due to hair breakage at different times.53 In severe patches, only newly growing anagen hairs remain.54 The underlying scalp is usually normal. Trichotillomania can involve eyebrows and lashes. The onset is often sudden, and the course is fluctuating and prolonged. HISTOPATHOLOGIC FEATURES Normal numbers of hair follicles are present (Fig. 10-13), although some may be distorted by hair shaft avulsion and show perifollicular shearing and hemorrhages (see Table 10-12). Follicular plugging and pigment casts are common, but true trichomalacia, or softened, twisted hair, is less frequent. Hair plucking induces telogen via catagen, accounting for the high catagen and telogen counts seen in trichotillomania55 (Figs. 10-14 and 10-15). Miniaturized hairs are not typically seen, although true vellus hairs persist, because they are too small to grasp, thereby reducing the terminalvellus ratio.56 Inflammatory changes are not a feature of trichotillomania, unless excoriations are complicated by secondary bacterial infection with infiltration of neutrophils, lymphocytes, and

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Trichotillomania

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Table 10-9 Drugs Causing Diffuse Alopecia Allopurinol Amoxapine ACE inhibitorsa,TE AnticonvulsantsTE AspirinTE Beta blockersTE Boric acidAE Carbamazepine Clomiphene DanazolTE Ethionamide GoldAE LevodopaTE Methyldopa NitrofurantoinTE Para amino salicylic acid Probenecid RetinolTE Terfenadine

Alpha receptor blockers AmphetamineTE Anticancer drugsAE Antithyroid drugsTE Azathioprine Birth control drugsTE BromocriptineTE Cholesterol reducersTE Clonidine Estrogen Fluoxetine Haloperidol LithiumTE MethysergideTE NSAIDsb,TE Penicillamine Pyridostigimine bromidetTE SalicylatesTE Thallium saltsAE

a

Angiotensin-converting enzyme inhibitors. Nonsteroidal anti-inflammatory drugs. AE Cause of anagen effluvium. TE Cause of telogen effluvium. b

histiocytes.25 The average follicular count in horizontal sections of a 4-mm punch biopsy of trichotillomania consists of 27.5 terminal hairs + 6.6 vellus hairs = 34.1 total hairs, with a terminal-vellus ratio of 4.2:1, just within normal limits; however, a ratio of 65% anagen to 35%

Table 10-10 Diffuse Alopecia

Clinical Features Diffuse shedding, all over scalp, often abrupt Classic acute telogen effluvium: moderate hair thinning, within months of childbirth, severe illness, accident or operation, crash diets, drugs, etc. Chronic telogen effluvium: mild-tomoderate hair thinning, often idiopathic Anagen effluvium: severe hair thinning within weeks of cytostatic drugs, etc. Histopathologic Features Normal numbers of terminal hairs Normal numbers of vellus hairs Normal numbers of follicular stelae Increased numbers of telogen hairs in active phases of telogen effluvium Differential Diagnosis Female pattern androgenetic alopecia Diffuse alopecia areata Congenital hypotrichosis

220

Amiodarone Androgens AnticoagulantsTE ArsenicalsTE Azulfidine BismuthAE Calcium channel blockersTE CimetidineTE ColchicineAE Ethambutol Gentamycin Histamine 2 blockers Mercury MethyraponeTE Omerprazole Prazosin RetinoidsTE Sulfasalazine Tricyclic antidepressants

telogen and an average of 5 catagen hairs are strikingly abnormal9 (see Table 10-4). Catagen hairs are rare in normal controls. DIFFERENTIAL DIAGNOSIS Other causes of patchy alopecia must be excluded. Trichotillomania is often misdiagnosed as tinea capitis, alopecia areata, or even loose anagen syndrome. Other conditions to be excluded include other forms of traction alopecia, pressure alopecia, secondary syphilis, congenital triangular alopecia, tick-bite alopecia, and subtle forms of scarring alopecia such as pseudopelade and congenital aplasia cutis. The history and appearance are often diagnostic, but in some cases scalp biopsies are necessary. The lack of inflammation, fungal elements, and scarring and the presence of terminal hairs, catagen hairs, and trichomalacia exclude most other conditions (see discussion of differential diagnosis of alopecia areata). Differentiation from other forms of traction alopecia may depend on clinical history.

results from hair weaves, other hair additions glued or clipped in place,57,58 excessive brushing, backcombing, braiding, or tight ponytails (see Figs. 10-4 and 10-5). Prolonged pressure on the scalp from prolonged immobility can cause alopecia. CLINICAL FEATURES Bandlike traction alopecia involving frontal, temporal, and occipital scalp hair margins is usually due to ponytails with the maximum pull on peripheral hairs (Table 10-13). Traction alopecia from hair weaves and other hair additions occurs at the point of attachment.59 Traction alopecia can occur between tight braids and in areas where hair is wound too tightly on rollers.60 Sustained traction usually induces telogen in affected hairs, which eventually fall out. Pressure alopecia can occur in the newborn and in patients of any age who are severely injured, very ill, or anesthetized or who have sustained blunt trauma to the scalp. It usually results from prolonged immobilization of the patient on a hard operating table, bed, or floor.61 The soft-tissue compression over underlying skull causes ischemia.62 A patch of alopecia develops over the compressed scalp within 2 to 4 weeks but regrows within a few months, unless permanent scarring has resulted from necrosis and ulceration.60

Traction and Pressure Alopecia

HISTOPATHOLOGIC FEATURES The histopathology of traction alopecia is similar to trichotillomania. Due to the sustained traction, many catagen and telogen hairs are seen, which reduces the anagen-telogen ratio (see Table 10-13 and Figs. 10-16 and 10-17). There is usually a lack of inflammation. Total follicular counts on horizontal section are identical to normal controls. Pigment casts and trichomalacia are rare25 (Fig. 10-18). In chronic traction alopecia affecting hair margins, dense fibrosis may be present around upper and lower follicles. In the early stages of pressure alopecia, vascular thrombosis and tissue necrosis, with a mild lymphohistiocytic infiltrate, may be present. Most of the terminal hairs are then projected into a catagen or telogen phase. Fat necrosis with foamy macrophages and varied degrees of dermal fibrosis may eventuate.18

There are many other causes of traction alopecia besides trichotillomania.55 Acute traction alopecia results from sudden, painful avulsion in accidental or intentional hair pulling or domestic or industrial accidents. Chronic traction alopecia is more common and insidious and

DIFFERENTIAL DIAGNOSIS The diagnosis of an acute traction or avulsion alopecia is usually easy from the history and physical appearance. Marginal alopecia must be distinguished from ophiasis and tinea capitis and frontal fibrosing alopecia (FFA). Other forms of patchy hair loss

Miscellaneous Causes of Nonscarring Alopecia

 FIGURE 10-4 Diffuse alopecia, chronic telogen effluvium. Vertical section: Five terminal hairs and no follicular stelae are seen projecting into the subcutaneous tissue. A mild lymphohistiocytic infiltrate is present around a few upper follicles. The epidermis is normal.

 FIGURE 10-5 Diffuse alopecia, chronic telogen effluvium. Horizontal section, reticular dermis: Many terminal hairs are seen with relatively few vellus hairs; one telogen hair and four telogen germinal units are present. There is no inflammation of note.

Rarer causes of nonscarring alopecia include alopecia due to infections and infestations, alopecia due to hair shaft abnormalities, alopecia due to hereditary and congenital conditions such as ectodermal dysplasias, and alopecia due to various dermatoses involving the scalp that are sometimes accompanied by hair loss. Some of these conditions are discussed elsewhere, and others are beyond the scope of this chapter. CLINICAL FEATURES A common cause of patchy alopecia in small children is tinea capitis.63 This produces circumscribed areas of hair loss with inflammation, scaling, crusting, and broken-off hairs. Black dots from hairs broken off flush with the skin indicate endothrix ringworm due to Trichophyton tonsurans in the United States. Whitish gray hairs broken off a few millimeters away from the scalp and fluorescent to Wood light are caused by an ectothrix infection such as Microsporum canis or M audouini. Most cases of tinea capitis occur in children, peaking at 5 to 6 years of age, but endothrix ringworm caused by T tonsurans and favus caused by T schoenleinii can occur in adults. The diagnosis usually can be confirmed by a potassium hydroxide preparation or by culture, and a biopsy is rarely necessary. Bacterial infections such as syphilis and viral infections such as herpes zoster, which are capable of causing alopecia, will not be discussed here.63,64 Broken-off hairs can result from hair shaft abnormalities. Only the histopathology of loose anagen syndrome will be discussed in this chapter. The reader is referred to other source material for a discussion of hair shaft anomalies.65-68

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

such as loose anagen syndrome, secondary syphilis, alopecia from chemical trauma, congenital triangular alopecia, tick-bite alopecia, and subtle forms of scarring such as pseudopelade and congenital aplasia cutis also may have to be excluded (see Table 10-13 and Figs. 10-16, 10-17, and 10-18). This usually can be done on clinical grounds, but in some cases scalp biopsies are helpful. The frequent presence of scarring with increased catagen and telogen hairs in chronic cases and the lack of inflammation and fungal elements should exclude alopecia areata and tinea capitis. For discussion of other causes of patchy hair loss, see discussion of the differential diagnosis of alopecia areata.

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 FIGURE 10-6 Diffuse alopecia, chronic telogen effluvium. Horizontal section, reticular dermis: Two terminal hairs, one telogen germinal unit (left lower margin), and one telogen hair (right lower margin) are visible.

 FIGURE 10-7 Anagen effluvium. The broken-off hair shaft shows proximal tapering adjacent to the fracture.

A

222

There are many different forms of congenital or inherited hair loss.69,70 These include congenital hypotrichosis with or without associated defects, congenital triangular alopecia,71 and a large variety of ectodermal dysplasias affecting the hair, teeth, nails, and sweat glands. There are also major congenital hypotrichoses that occur in hereditary syndromes such as the hereditary hypotrichosis of Marie Unna,72 Hallerman-Streiff syndrome, and atrichia with papular lesions. Major congenital hypotrichosis also occurs in premature aging syndromes and with skeletal abnormalities. Minor hypotrichosis can occur in other hereditary syndromes and in chromosomal abnormalities. In general, the diseases causing congenital or inherited hypotrichosis are associated with hair loss due to a reduction in hair follicles that may be patchy or patterned or generalized. Various dermatoses that do not directly cause alopecia may lead to pruritus, erythema, scaling, crusting, and excoriations. A secondary alopecia may result that usually is reversed by treating the underlying cause. Such dermatoses include seborrheic dermatitis, psoriasis, tinea amiantacea, and prurigo and lichen simplex.63,25 HISTOPATHOLOGIC FEATURES If the alopecia is produced by an infection, the histopathology should reflect the pathology of that particular infection. Sometimes unsuspected fungal infections are seen on histopathologic examination and confirmed with a PAS stain. Secondary syphilis can be difficult to diagnose.64,25 Hair shaft abnormalities usually are diagnosed by microscopic examination

B

 FIGURE 10-8 Alopecia areata. (A) Confluent well-demarcated patch of alopecia. (B) Vertical section: Four hair bulbs are seen surrounded by lymphocytes, with follicular stelae beneath them, also infiltrated by lymphocytes. A lymphocytic infiltration is also present around lower hair follicles.

Table 10-11 Alopecia Areata

of the hair shaft. In loose anagen syndrome, the hair shafts may show absent inner and outer root sheaths, a ruffled cuticle, and longitudinal grooving73-75; in biopsies, loss of adhesion

 FIGURE 10-10 Alopecia areata. Horizontal section, reticular dermis: One catagen hair (left lateral margin), one follicular stela infiltrated by lymphocytes (right lateral margin), and two telogen germinal units are visible.

between follicular sheaths may be seen only with transmission electron microscopy. However, splits between follicular sheaths sometimes are seen with light microscopy and may represent real changes due to loose anagen syndrome rather than to fixation and sectioning artifacts (Fig. 10-19); inflammation is absent, but premature keratinization of the inner root sheath may be seen.76

Congenital triangular alopecia is distinguished by a normal follicular count with a reduction in the total number of terminal anagen hairs, although many vellus hairs are seen.25 However, a frequent feature of these cases is the presence of many telogen hairs. This arrested state of hair cycling also appears to be common in various types of congenital hypotrichoses (Figs. 10-20 and 10-21) and ectodermal dysplasia (Fig. 10-22). Associated dermatoses, such as seborrheic dermatitis, psoriasis, or lichen simplex, may be diagnosed by their specific pathologic appearance.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Clinical Features Periodic attacks of circumscribed patches of hair loss Unpredictable course: patches may regrow or progress to confluent patches, alopecia totalis or alopecia universalis Histopathologic Features Peribulbar and intrabulbar mononuclear cell infiltrate Degenerative changes in hair matrix Decreased numbers of terminal anagen hairs Increased numbers of terminal catagen and telogen hairs Increased numbers of follicular stelae Increased numbers of miniaturized vellus hairs Pigment incontinence of hair bulbs and follicular stelae Differential Diagnosis Other causes of patchy alopecia include tinea capitis, trichotillomania, traction and pressure alopecia, loose anagen syndrome, secondary syphilis, congenital triangular alopecia, familial focal alopecia, aplasia cutis, pseudopelade, tick bite alopecia, etc.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of infections, congenital and inherited causes of alopecia, hair shaft abnormalities, and miscellaneous dermatoses includes most of the conditions discussed in this chapter. The diagnosis usually can be made on clinical grounds or by examination of hair shafts, but scalp biopsies may be necessary to clarify diagnoses.

SCARRING (CICATRICIAL) ALOPECIA

 FIGURE 10-9 Alopecia areata. Horizontal section, reticular dermis: Two hair bulbs surrounded by lymphocytes and three follicular stelae infiltrated by lymphocytes are visible.

Clinically, scarring, or cicatricial, alopecia is characterized by loss of follicular orifices. Distinguishing characteristics that aid in diagnosis include the pattern of alopecia, pigmentary alteration, follicular prominence, keratinous plugs, follicular pustules, and any other associated

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Table 10-12 Trichotillomania

Clinical Features Recurrent attacks of patchy hair loss— chronic course Affected hairs broken off at different lengths Underlying scalp usually normal Histopathologic Features Normal follicular counts with normal terminal:vellus ratio Marked increase in catagen and telogen hairs Follicular damage may be present Follicles may contain pigmented casts Trichomalacia can occur Inflammatory changes usually absent Differential Diagnosis Other causes of patchy alopecia include alopecia areata, tinea capitis, loose anagen syndrome, traction and pressure alopecia, secondary syphilis, tick bite alopecia, aplasia cutis, congenital triangular alopecia, familial focal alopecia, pseudopelade, etc.  FIGURE 10-11 Alopecia areata. Vertical section: Two catagen hairs are present showing a thickened vitreous membrane and central apoptotic cells.

nonscalp cutaneous findings. 6,77-83 Histologic evaluation of progressive, “active” alopecia is often very helpful for diagnosis of specific scarring alopecias. However, biopsies from patients with

inactive, “burned out” scarring alopecia infrequently yield a specific diagnosis, but these specimens still may be useful in assessment of the extent of follicular destruction and regrowth potential.

As noted earlier, the traditional separation of alopecia into either scarring or nonscarring is not very helpful from a patient’s perspective because he or she is concerned with only one issue—whether or not the hair loss is potentially reversible or permanent.84,85 If a patch of alopecia areata never regrows, the patient will not be comforted by the fact that he or she has a nonscarring alopecia. Nevertheless, histopathologic differentiation of scarring from nonscarring alopecia remains of value because the former usually will progress to permanent hair loss unless therapeutic intervention is successful, whereas the latter is less predictable.

Scarring Alopecia Is Either Primary or Secondary

224

 FIGURE 10-12 Alopecia areata. Horizontal section, reticular dermis: Several hair bulbs surrounded by lymphocytes, a large number of catagen hairs surrounded by thickened vitreous membranes and lymphocytes, several telogen germinal units, and some follicular stelae infiltrated by lymphocytes are visible.

Many classification systems of scarring alopecia have been proposed according to clinical, histologic, and pathogenic factors. We endorse the concept of primary and secondary scarring alopecia based on the pattern of follicular destruction.6,80,81 Primary scarring alopecia occurs as the result of preferential destruction of follicular epithelium and/or its associated adventitial dermis, with relative sparing of the intervening reticular dermis. In primary scarring alopecia, the hair follicle is the primary target of destruction. The interfollicular epidermis may be affected as in lupus erythematosus and lichen planopilaris

impinge on and eventually destroy the follicle. Follicular destruction and subsequent permanent scarring alopecia are not the primary pathologic process, but they occur secondarily due to the close anatomic location of follicles to the primary pathologic event, eg, dermal sclerosis in coup de sabre linear morphea.

LYMPHOCYTE-ASSOCIATED PRIMARY SCARRING ALOPECIA

 FIGURE 10-13 Trichotillomania. Vertical section: One terminal hair, one telogen hair, and two follicular stelae are seen projecting into the subcutaneous tissue. Another telogen hair is seen in the middle dermis; one follicular infundibulum shows trichomalacia.

(LPP), but the epidermal changes in and of themselves do not result in follicular destruction. Primary scarring alopecias are a diverse group of diseases with differing or uncertain etiologies. The unifying feature of these varied disorders is destruction of sufficient follicles to yield permanent alopecia. Microscopically, primary

scarring alopecia can be further categorized into two groups according to the predominant inflammatory cell type: (1) lymphocyte-associated scarring alopecia and (2) neutrophil-associated (pustulofollicular) scarring alopecia.6,80,82 Secondary scarring alopecia occurs as the result of nonfollicular events that

 FIGURE 10-14 Trichotillomania. Horizontal section, reticular dermis: One hair bulb, some terminal hairs, many catagen hairs, a telogen hair, and a telogen germinal unit are visible.

Discoid Lupus Erythematosus CLINICAL FEATURES Scalp involvement in DLE is common, and 30% to 50% of patients develop scarring alopecia. DLE typically occurs in young to middle-aged females (2:1 female predominance), and lesions occur on sun-exposed sites, especially the face, scalp, and conchal bowl of the ear. Early lesions are scaly erythematous papules, whereas late lesions are sclerotic plaques with follicular plugging, telangiectasia, and pigmentary alteration.86 Patients with DLE uncommonly progress to systemic lupus erythematosus.87 Diffuse, nonscarring alopecia may occur in patients with systemic lupus erythematosus but is best categorized as inflammatory telogen effluvium. HISTOPATHOLOGIC FEATURES Vacuolar interface alteration at the level of the epidermis and hair follicle is the primary feature of DLE88,89 (see Table 10-14). Epidermal and follicular dyskeratosis are also present but less so than in LPP. The epidermis is often atrophic with overlying orthokeratotic hyperkeratosis, but the hypertrophic variant of DLE is characterized by marked acanthosis and hyperkeratosis. Focal parakeratosis may be seen in some lesions. Laminated keratin fills dilated follicular ostia corresponding to the clinical follicular plugs. The basement membrane zone of the epidermis and/or follicle may be thickened with a corrugated appearance. This finding is best seen with the PAS stain and ultrastructurally represents a multilayered basal lamina. Superficial and deep, perivascular and periadnexal lymphocytic infiltrates of

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Discoid lupus erythematosus (DLE), lichen planopilaris, central centrifugal scarring alopecia/follicular degeneration syndrome (CCSA/FDS), and alopecia mucinosa (AM) are lymphocyte-associated scarring alopecias that may be distinguished by the presence and type of interface alteration, pattern and density of lymphocytic infiltrates, and intrafollicular mucin deposits (Table 10-14).

225

as in LPP.88 The superficial and deep infiltrates are both perivascular and periadnexal in DLE as opposed to tightly perifollicular in LPP. FDS lacks interface alteration around follicles. The presence of increased dermal mucin is an important finding that points toward DLE rather than LPP or FDS.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Lichen Planopilaris Including Frontal Fibrosing Alopecia

226

 FIGURE 10-15 Trichotillomania. Horizontal section, papillary dermis: Terminal hairs, telogen hairs, telogen germinal units, and vellus hairs are visible. Several follicular infundibula show pigment casts or trichomalacia. There is no inflammation.

Table 10-13 Traction and Pressure Alopecia

Clinical Features Acute traction alopecia from avulsion: easily diagnosable from history and clinical findings Obvious linear alopecia at scalp hair margins, caused by chronic traction from ponytails Chronic traction alopecia under points of attachment of hair weaves or other hair additions more subtle Pressure alopecia: localized to the area of pressure and usually transient Histopathologic Features Normal follicular counts with normal terminal:vellus ratio Marked increase in catagen and telogen hairs Occasional pigmented casts; trichomalacia uncommon Inflammatory changes usually absent In late cases of marginal alopecia, terminal hairs decreased due to follicular fibrosis Catagen and telogen hairs increased from pressure alopecia Differential Diagnosis Common causes of patchy alopecia to be differentiated from traumatic alopecia include trichotillomania, alopecia areata—especially ophiasis, tinea capitis, loose anagen syndrome, and other causes of localized alopecia

variable density are present (Figs. 10-23 and 10-24). Occasional admixed plasma cells can be found. Lymphocyte exocytosis into the epidermis and follicular epithelium may be present but usually is not prominent. Pigment incontinence with melanophagocytosis is seen commonly in the papillary dermis. Increased dermal mucin (hyaluronic acid) is present both superficially and deep and is best detected in colloidal iron—or alcian blue—stained sections. Dermal sclerosis and complete follicular dropout occurs in advanced lesions and is similar to end-stage microscopic findings of other primary scarring alopecias (see section on CCSA below). Biopsies of well-established clinical lesions for immunofluorescence usually show granular immunoglobulin and complement at the dermal-epidermal junction. IgM deposits are more common but less specific for DLE than IgG deposits.90,91 The incidence of lesional immunoglobulin deposition in DLE is about 75%, with older, sun-exposed lesions more likely to be positive. DIFFERENTIAL DIAGNOSIS LPP and FDS are the primary differential diagnostic considerations, as described below (see Table 10-14). Both are also lymphocyteassociated scarring alopecias, and endstage biopsies from all these entities can be identical. However, in “active” clinical lesions, interface alteration in DLE is primarily vacuolar rather than lichenoid,

CLINICAL FEATURES LPP is an uncommon scarring alopecia. First described in 1895 by Pringle, LPP presents as acuminate, spinous, and hyperkeratotic follicular papules with perifollicular erythema (see Table 10-14). LPP is more common in women, and onset ranges from young adulthood to elderly age. As follicles are destroyed, smooth, atrophic, polygonalshaped patches of complete alopecia result. Typical lichen planus papules and plaques are present elsewhere on the body in 50% to 70% of patients. The clinical triad of typical lichen planus, spinous or accuminate lesions, and alopecia of the scalp or other nonglabrous skin is known as the Graham-Little syndrome. In 1994, Kossard described a distinctive form of cicatricial alopecia that he termed postmenopausal frontal fibrosing alopecia.92,93 The patients presented with a bandlike progressive zone of alopecia that ultimately spanned the entire frontal hairline from temple to temple. The frontal alopecia is usually accompanied by alopecia of the eyebrows and perifollicular erythema.94 FFA has subsequently been reported to also occur in premenopausal women and men.95,96 FFA may develop in association with other findings of the Graham-Little syndrome (follicular papules and alopecia in sites remote from the scalp).97 HISTOPATHOLOGIC FEATURES Lichenoid interface alteration of follicular epithelium is the primary microscopic feature of LPP (see Table 10-14).98 Although not always completely distinct from vacuolar interface alteration, lichenoid interface alteration of the follicle is characterized by disruption of the epithelial-adventitial dermal junction with angular, glassy, basal keratinocytes and a tight perifollicular lymphocytic infiltrate that is largely confined to the follicular adventitial dermis (Figs. 10-25 and 10-26). Exocytosis into the follicular epithelium and dyskeratosis are more prominent in LPP than DLE. Artifactual clefting similar to that seen at the dermal-epidermal junction in lichen planus (Max Joseph space) also can occur around hair follicles in LPP.88,89 In a

 FIGURE 10-16 Traction alopecia. Vertical section: One terminal catagen hair and one terminal telogen hair are seen. A mild lymphohistiocytic infiltrate is present around one follicular infundibulum.

minority of cases, lichenoid interface alteration typical of lichen planus may affect the intervening epidermis. Superficial and deep perivascular lymphocytic infiltrates and dermal mucin typical of DLE are lacking in LPP.

Complete follicular dropout with scattered unsheathed hair shafts surrounded by sparse histiocytic and granulomatous infiltrates occurs in late lesions. These end-stage features are not specific for LPP but may occur in all

 FIGURE 10-17 Traction alopecia. Horizontal section, reticular dermis: Three terminal hairs, three vellus hairs, and seven telogen germinal units are visible. There is no inflammation.

Central Centrifugal Scarring Alopecia/Follicular Degeneration Syndrome

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

scarring alopecias (see section on CCSA below). Lesional biopsy for direct immunofluorescence reveals globular IgM deposits on cytoid bodies and fibrin at the dermalepidermal junction and infundibularadventitial dermal junction.90 However these immunofluorescent findings are not specific for LPP and may be seen in other dermatoses with interface dermatitis. The histopathologic findings in FFA are reported to be similar if not identical to those of LPP.92,93 Abbas and coauthors reported a greater number of apoptotic (dyskeratotic) cells and less dense lymphocytic infiltrates in FFA along with complete sparring of the interfollicular epidermis, although these findings may be difficult to apply to individual cases.97

A century after it was coined, controversy still surrounds the term pseudopelade.6,79,80,82,83,88,99-104 Brocq first described this form of alopecia in 1885 as a clinically noninflammatory, progressive, idiopathic scarring alopecia.105 Since then, conflicting opinions have arisen as to whether pseudopelade of Brocq (PPOB) is a disease sui generis or the end-stage lesion of various types of scarring alopecia. Support for the concept of pseudopelade as a unique clinicopathologic entity appears to be continually dwindling, given the substantial overlap in the clinical and histopathologic features with other forms of scarring alopecia.80,99 The main argument for elimination of the term pseudopelade is that it has never been defined as a unique clinicopathologic entity. In other words, if defined clinically, there is no specific histopathology. If defined microscopically, there is no specific clinical presentation. To address the pseudopelade issue and the problem of overlap in the clinical and histopathologic findings of

227

DIFFERENTIAL DIAGNOSIS DLE and FDS are the primary entities considered in the differential diagnosis (see Table 10-14). Please see the discussions of these topics for details. In practice, it can be very difficult to distinguish between vacuolar and lichenoid interface change at the level of infundibulum, so that the presence or absence of other findings is extremely helpful, for example, increased dermal mucin in DLE. Another common cause of confusion is artifactual clefting that simulates true interface change between remnants of the infundibulum and the encompassing lymphocytes in advanced lesions of FDS.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 228

 FIGURE 10-18 Traction alopecia. Horizontal section, papillary dermis: Terminal and vellus hairs are seen. Several follicular infundibula are empty. No trichomalacia is present. There is a mild lymphohistiocytic infiltrate around a few follicular infundibula.

several types of scarring alopecia, Sperling and coauthors80 introduced the concept of central centrifugal scarring alopecia. As described, this term is meant to be a unifying concept with the goal of more rational clinical and microscopic diagnosis and eventually better therapeutic approaches.80 Central centrifugal scarring alopecia denotes alopecia with the following common

clinical features: (1) primary involvement of the crown and vertex, (2) relentless progression to broad areas of scalp devoid of follicular orifices, and (3) symmetric expansion with an active, inflammatory border. These clinical features are common to several subtypes of scarring alopecia, such as the follicular degeneration syndrome, follicullitis decalvans, and

 FIGURE 10-19 Loose anagen syndrome. Horizontal section, reticular dermis: In many follicles, clefts are present between the hair shaft and the internal root sheath, within the layers of the internal root sheath, between the internal root sheath and the external root sheath, or between the external root sheath and the surrounding connective tissue layer. One hair bulb shows a cleft between the matrix of the bulb and the surrounding connective tissue sheath.

tufted folliculitis. Other well-defined types of scarring alopecia, including LPP and DLE, also may present as CCSA. These subtypes of scarring alopecia usually can be defined by the clinical presentation and histopathologic features, but there may be significant overlap in both, especially in chronic lesions with extensive follicular destruction. The concept of CCSA is most useful in addressing the late-stage lesions because attempts to make a specific clinicopathologic diagnosis are frequently futile.106 It should be noted that pseudopelade was included in the construct for conceptual reasons, but the authors conclude that it could be abolished “if we had the courage to eliminate the redundant nomenclature of the past century.” We agree. In this section FDS will be discussed as a discrete entity within CCSA in order to highlight the earlier important diagnostic findings. CLINICAL FEATURES The FDS, described by Sperling and Sau, usually can be recognized both clinically and microscopically in early-stage lesions.107,108 The central scalp (crown) is by far the most frequent location. The alopecia progressively expands centrifugally to involve the entire crown and vertex, leaving a smooth skin surface devoid of follicular orifices. Variable perifollicular erythema and scale are present. Only isolated hair fibers remain in the alopecic regions. Polytrichia may be present. It is the most common form of scarring alopecia in African American women. It occurs occasionally in Caucasian women and African American men as well. HISTOPATHOLOGIC FEATURES The earliest findings are perifollicular lymphocytic infiltrates and perifollicular fibroplasia without interface alteration (see Table 10-14). The infiltrate is more dense in these early lesions and present from the level of the follicular infundibulum to the midsegment of the follicle.107,108 Sparse adjacent perivascular lymphocytic infiltrates also may be present. Follicular density is diminished, and follicular unit morphology is disrupted. Scattered residual fibrous tracks indicating the site of destroyed follicles are present (Fig. 10-27). In more advanced areas, the predominant finding is concentric lamellar fibroplasia and follicular epithelial atrophy (Fig. 10-28). Frequently, the follicular canal is eccentrically located, and premature disintegration of the inner root sheath is emphasized in FDS.107,108 Finally, the residual follicular epithelium

decalvans are indistinguishable from each other, forming the basis for the concept of CCSA.

Alopecia Mucinosa

ruptures, and a foreign-body giant cell reaction ensues. In end-stage FDS, only rare, viable though somewhat miniaturized follicles and numerous residual fibrous tracts are present (Fig. 10-29). Direct immunofluorescence usually is negative, but occasional, minimal, nonspecific IgM deposits may be seen around the follicular infundibulum.

DIFFERENTIAL DIAGNOSIS DLE, LPP, and end-stage folliculitis decalvans (FD) may be considered (see Table 10-14). The lack of interface dermatitis in FDS is the primary distinguishing microscopic feature from DLE and LPP. The neutrophil is the predominant inflammatory cell in active folliculitis decalvans. End-stage lesions of FDS, DLE, LPP, and folliculitis

 FIGURE 10-21 Congenital hypotrichosis. Horizontal section, middle dermis: One terminal hair, two telogen hairs, two telogen germinal units, and one vellus are visible.

HISTOPATHOLOGIC FEATURES Mucin (hyaluronic acid) deposition in hair follicle epithelium is the cardinal microscopic feature of AM and is termed follicular mucinosis (see Table 10-14). Follicular keratinocytes are stellate shaped and splayed apart by extracellular mucin.110,111 The mucin is deposited initially in the infundibulum but involves the entire follicle in advanced lesions with intrafollicular mucin-filled cystic spaces (Fig. 10-30). The mucin can be identified in H&E–stained sections but is best appreciated with colloidal iron or alcian blue stains. Variably dense perifollicular lymphocytic infiltrates with admixed eosinophils are present. Folliculotropism of lymphocytes can be seen in both lymphoma-associated and benign AM. Although it is difficult to distinguish the banal form from the lymphoma-associated form, lymphocytes surrounded by clear spaces, pronounced epidermotropism, cellular atypia, lymphocytes that line up along the basal layer, and confluent papillary dermal infiltrates are suspicious for coexisting cutaneous T-cell lymphoma.112 DIFFERENTIAL DIAGNOSIS Follicular mucinosis is considered by some to be a synonym of AM, but this term is best used as a microscopic description of intrafollicular mucin deposits and not the clinical pathologic entity AM.113 Focal, limited follicular mucinosis outside the setting of AM occurs and likely represents a reactive follicular process. Follicular spongiosis in follicular eczema and seborrheic dermatitis may mimic early AM, and mucin stains help to differentiate follicular mucin from follicular

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-20 Congenital hypotrichosis. Vertical section: Two terminal hairs and four follicular stelae are seen in the subcutaneous tissue; one telogen hair is seen in the dermis. There is no inflammation.

CLINICAL FEATURES Alopecia mucinosa most commonly involves the head and neck, but involvement of the trunk and extremities may occur (see Table 10-14). Lesions are erythematous, infiltrated plaques devoid of hair. When AM affects children and young adults, it is usually self-limited without permanent alopecia; however, follicular destruction by extensive mucin deposits occasionally can lead to permanent alopecia in some patients.109 An associated lymphoproliferative disorder, most commonly cutaneous T-cell lymphoma (CTCL), occurs in approximately 30% of cases, especially older patients with numerous lesions on the trunk and extremities.110,111

229

surrounds the sinus tracts, and the follicles are destroyed by the fibroinflammatory process. The infiltrate in older, more scarred lesions is primarily lymphoplasmacytic and histiocytic with few neutrophils. DIFFERENTIAL DIAGNOSIS Other pustulofollicular scarring alopecias need to be considered (see Table 10-15). The microscopic features of DCS are very similar to those in hidradenitis suppurativa. PAS and Gram stains should be done to rule out fungal and bacterial infection.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Folliculitis Decalvans

 FIGURE 10-22 Anhidrotic ectodermal dysplasia. Vertical section: Only one terminal hair is present and no mature eccrine glands are seen. Primordial eccrine glands are present at the inferior margin of the specimen.

spongiosis. If an epidermotropic lymphocytic infiltrate is also present, CTCL must be considered, especially in lesions not located on the scalp.

PUSTULOFOLLICULAR, NEUTROPHIL-ASSOCIATED PRIMARY SCARRING ALOPECIA The pustulofollicular, neutrophil-associated primary scarring alopecias are dissecting cellulitis of the scalp (DCS), folliculitis decalvans, acne keloidalis (AK), erosive pustular dermatosis of the scalp (EPDS), and tinea capitis (TC) (Table 10-15). Common features include early follicular dilatation and predominately neutrophilic infiltrates within and around the affected follicles. Early lesions have overlapping clinical and microscopic features, but welldeveloped cases usually are distinct both clinically and microscopically.

Dissecting Cellulitis of the Scalp (Perifolliculitis Capitis Abscedens et Suffodiens) 230

CLINICAL FEATURES In 1908, Hoffman described perifolliculitis capitis abscedens

et suffodiens.114 It was later renamed dissecting cellulitis of the scalp, and synonyms include dissecting perifolliculitis and dissecting folliculitis of the scalp. It is most common in young black men and begins as fluctuant scalp nodules that coalesce progressively to form complex, interconnected, crusted abscesses and sinus tracts that drain spontaneously or with slight pressure. Well-developed lesions are painful and result in extensive scarring of the scalp. Some patients with DCS also have acne conglobata and hidradenitis suppurativa and are said to have the follicular occlusion triad. HISTOPATHOLOGIC FEATURES The initial finding is acneiform dilatation with neutrophilic infiltrates (see Table 10-15). Biopsies from fluctuant nodules and sinuses reveal large dermal and subcutaneous abscesses.6,82,115 Well-developed lesions are abscesses and sinus tracts partially lined with squamous epithelium derived from the overlying epidermis or follicular epithelium (Fig. 10-31). Bacteria may be seen superficially in follicular infundibula but not in abscesses, and the pathogenic significance is unclear. Dense dermal and subcutaneous fibrosis eventually

CLINICAL FEATURES FD is a rare pustulofollicular alopecia that presents as round to irregular-shaped patches of alopecia with follicular pustules at the peripheral, advancing edge116 (see Table 10-15). Tufts of hair shafts may occur.117 FD occurs in both sexes and primarily affects the scalp, but involvement of the beard, axillae, pubic area, arms, and legs also may occur.118 End-stage FD without pustules is included within CCSA by some, but not all, authors.80,119 HISTOPATHOLOGIC FEATURES The initial finding is comedonal dilatation with intra- and perifollicular neutrophilic infiltrates (see Table 10-15 and Fig. 10-32). Follicular rupture ensues with resulting perifollicular fibrosis and eventual permanent follicular destruction.6,82 Localized perifollicular dermal abscesses are often present but are not as extensive or deep as seen in DCS. Sinus tracts are not seen in FD. In later stages, the infiltrate is mixed with lymphocytes, plasma cells, and neutrophils. Unsheathed hair shafts surrounded by foreign-body giant cells are present after the follicular epithelium has been destroyed, and as in all primary scarring alopecias, numerous residual fibrous tracts mark sites of destroyed follicles. DIFFERENTIAL DIAGNOSIS Special stains are necessary to rule out fungal and bacterial folliculitis (see Table 10-15).

Acne Keloidalis CLINICAL FEATURES AK is a destructive pustulofollicular process that primarily affects the occipital scalp and neck of young black men (see Table 10-15). Lesions begin as discrete follicular papules or pustules and may progress to large exophytic keloidal plaques devoid of hair.120,121 Similar lesions may occur in the beard region in patients with pseudofolliculitis barbae. HISTOPATHOLOGIC FEATURES Early lesions display comedonal dilatation and pustular

Table 10-14 Lymphocyte-Associated Primary Scarring Alopecia DISCOID LUPUS ERYTHEMATOSUS

LICHEN PLANOPILARIS

CENTRAL CENTRIFUGAL SCARRING ALOPECIA/FOLLICULAR DEGENERATION SYNDROME

FOLLICULAR MUCINOSIS

Clinical Features Young to middle-aged Women > men Erythematous papules to sclerotic plaques Follicular plugging, telangiectasia, dyspigmentation

Perifollicular infiltrates Perieccrine infiltrates Intrafollicular mucin Dermal mucin Concentric lamellar fibrosis Pigment incontinence

Primarily vacuolar Primarily vacuolar Minimal to moderate Lymphocytic Superficial and deep

Present, prominent Present Minimal Moderate to prominent End-stage finding Yes

Primarily lichenoid if present Primarily lichenoid Moderate to prominent Lymphocytic Minimal superficial perivascular, primarily perifollicular Present, prominent Absent Absent Absent Yes in advanced lesions Yes

Young to middle-aged African American Women >> men Slowly progressive, irregularly shaped alopecic patches (“footprints in the snow”) Confluence of patches Noninflammatory

All ages Head and neck > trunk, extremities Erythematous infiltrate Sometimes boggy plaques with scaling, expression of mucin Adults have lymphoproliferative disorder in about 30% of cases

Absent Absent Absent Lymphocytic Mostly superficial

Absent Absent Absent Lymphocytic May be superficial and deep in lymphoma

Present, sparse Absent Absent Absent Prominent

Present, variable Absent Prominent Minimal No

Minimal

No

*Source: Data from Templeton SF, Solomon AR. Scarring alopecia: a classification based on microscopic criteria. J Cutan Pathol 1994:21:97–109.81

folliculitis as in other pustulofollicular alopecias (see Table 10-15). Follicular rupture with subsequent mixed neutrophilic infiltrates occurs. Well-developed lesions are characterized by dense dermal scar with many entrapped unsheathed hair shafts surrounded by lymphohistiocytic infiltrates with admixed neutrophils and abundant plasma cells (Fig. 10-33). Variable numbers of broad eosinophilic hyalinized keloidal collagen bundles may be present but are not essential for diagnosis.6,82,120-123 DIFFERENTIAL DIAGNOSIS Special stains are necessary to rule out bacterial and fungal infections (see Table 10-15). The extensive dermal fibrosis typical of keloidal scar is the most distinctive microscopic feature of AK.

Tinea Capitis/Kerion/Favus CLINICAL FEATURES Kerion and favus subtypes of tinea capitis (TC) can result in

permanent alopecia and are seen most commonly in children. Kerion is inflammatory TC caused by a zoophilic or geophilic follicular dermatophyte infection and presents as boggy, erythematous, scaling, crusted, partially alopecic plaques with regional adenopathy. Favus is an uncommon follicular dermatophyte infection of the scalp seen in rural regions and associated with poor nutrition and poor hygiene. Yellow, cup-shaped crusts termed scutula are present on the scalp and often result in permanent alopecia. The causative organism is T schoenleinii. In adults, noninflammatory endothrix dermatophyte infections, usually T tonsurans, occasionally can cause a more diffuse alopecia mimicking female-pattern androgenetic alopecia or FDS. HISTOPATHOLOGIC FEATURES The follicular infundibula generally are dilated and often hyperkeratotic. Pustular folliculitis with incipient or complete rupture is seen

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Histopathological Features Interface alteration at DEJ at follicle Dyskeratosis Inflammation type Perivascular pattern

Adults Women > men Acuminate, spinous hyperkeratotic follicular papules Perifollicular erythema Smooth atrophic polygonal patches of alopecia

commonly in kerion. Dense, mixed inflammatory infiltrates including many neutrophils surround the affected follicles. Endothrix (hyphae within hair shafts) and ectothrix (hyphae around hair shafts) patterns of follicular dermatophytosis may be seen and are best appreciated in PAS-stained or silver-impregnated sections (Fig. 10-34). Hyphae usually are not seen in the overlying epidermis. Some endothrix infections do not illicit a brisk inflammatory response but result in a relatively noninflammatory diffuse alopecia with broken shafts and perifollicular fibroplasia. Thick parakeratotic and orthokeratotic hyperkeratosis overlying an atrophic dermis with lymphoplasmacytic and granulomatous dermal infiltrates and follicular dermatophytosis are seen in favus.8.82,124 DIFFERENTIAL DIAGNOSIS Definitive diagnosis requires demonstration of the fungal organisms in either routine or special stains.

231

morphea, lichen sclerosus et atrophicus, and external trauma (Table 10-16).

FORMS OF ALOPECIA THAT ARE DIFFICULT TO CLASSIFY

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Erosive Pustular Dermatosis of the Scalp CLINICAL FEATURES Erosive pustular dermatosis of the scalp is an uncommon erosive and pustular process that may lead to permanent alopecia.125,126 It generally begins on the crown as a localized area of crusted erosion with occasional pustules, and it occurs most commonly in elderly Caucasian women. HISTOPATHOLOGIC FEATURES The histology is not specific and consists of neutrophilfilled pustules, ulcers, and erosions with subjacent-mixed inflammatory infiltrates and abscesses.127,128

Lipedematous Alopecia  FIGURE 10-23 Discoid lupus erythematosus. Vertical sections: Superficial and deep perifollicular and perivascular lymphocytic infiltrates with vacuolar interface alteration of follicular epithelium.

 FIGURE 10-24 Discoid lupus erythematosus. Horizontal sections: Perifollicular lymphocytic infiltrate with vacuolar inerface alteration of the follicular epithelium.

Secondary Scarring Alopecia

232

Hair loss in secondary scarring alopecias is the result of nonfolliculocentric skin disease.74-76,116-120 The pilosebaceous apparatus is not the focus of disease but is only involved secondarily. The clinical

and microscopic features of secondary scarring alopecia are characteristic for the specific disease involved. Some examples include hair loss produced by neoplasms, sarcoidal granulomas, sclerodermoid porphyria cutanea tarda, necrobiosis lipoidica, and dermal sclerosis from

CLINICAL FEATURES Lipedematous alopecia (LA) is the term used to describe alopecia associated with boggy thickening of the subcutaneous adipose tissue of the scalp.129 This rare form of alopecia has been described primarily in African American females, but has also been reported in Caucasian women and a Japanese man.130.131 The defining clinical feature is the compressible bogginess of the thickened scalp. The latter may occur without associated alopecia (lipedematous scalp). When present, the associated alopecia ranges from extensive and diffuse to limited and patchy. Some patients with this condition state their hair will not grow beyond a short length. HISTOPATHOLOGIC FEATURES Histopathologic studies have found the primary abnormality to be an increase in the thickness of the subcutaneous adipose tissue of the scalp.132,133 In some cases the latter structure is nearly 1 cm thick, as opposed to the reported 3 mm in normal scalp.131 In addition, the thickened adipose tissue shows other abnormalities including edema and dilated lymphatics, but neither inflammation nor mucin is increased.131,134 Peculiarly, characteristic and reproducible follicular changes in alopecic scalp have not yet been documented.

Follicular Hyperkeratosis Synonyms: Keratosis pilaris (KP), lichen spinulosus, phyronoderma, scarring follicular keratosis.

CLINICAL FEATURES Keratosis pilaris is a common follicular dermatosis often associated with ichthyosis and atopic dermatitis.135 Onset occurs in the first and second decades of life with persistence into

adulthood. Lesions consist of patches of follicular hyperkeratosis with variable perifollicular erythema commonly affecting the upper outer arm, thighs, and buttocks. Lichen spinulosus (LS) is a closely related

HISTOPATHOLOGIC FEATURES Follicular dilatation with compact follicular hyperkeratosis, at times tightly adherent to the hair shaft, is present in KP and LS (Fig. 10-35). Follicular infundibular atrophy with slight perifollicular lymphocytic infiltrates is also present. Follicular rupture with subsequent inflammatory folliculitis may occur.135,136,137 Similar findings are seen in the scarring follicular keratosis. Early lesions display typical KP features but may have more prominent infundibular hypergranulosis. Inflammatory and pustular lesions show follicular rupture and folliculitis. Late lesions are no different from other end-stage scarring alopecias, with complete follicular dropout, numerous residual fibrous tracts, and scattered “naked” hair shafts.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-25 Lichen planopilaris. Vertical sections: Infundibular keratinocytes are glassy with lichenoid interface alteration and perifollicular lymphocytic infiltrate. The epidermis is largely spared.

follicular hyperkeratotic condition presenting in children as patches of minute horny follicular spines. Patients with vitamin A deficiency develop numerous follicular hyperkeratotic lesions termed phrynoderma that begin on the thighs and posterolateral arms with subsequent involvement of extensor surfaces. Night blindness, xerophthalmia, keratomalacia, diarrhea, weakness, and generalized wasting may occur in hypovitaminosis A. Several genetically determined syndromes characterized by KP, follicular destruction, and typical clinical findings have been described.136,137 This group of disorders is often termed scarring follicular keratosis. Three major variants include keratosis pilaris spinulosa decalvans (KPSD), keratosis pilaris atrophicans (KPA; also known as ulerythema oophryogenes), and atrophoderma vermiculata (AV, also known as acne vermiculata and folliculitis ulerythematosa reticulata). Scarring alopecia with KP-like lesions occurs in KPSD with onset during the teenage years. Loss of eyebrow hair with atrophy and follicular hyperkeratosis is characteristic of KPA. AV is characterized by reticulate, ice-pick scarring of the cheeks with follicular hyperkeratosis. Overlapping clinical findings may be seen in these three clinical subtypes of scarring follicular keratosis.

FOLLICULITIS

 FIGURE 10-26 Lichen planopilaris. Horizontal sections: Dense perifollicular lichenoid infiltrates with artifactual clefting.

Folliculitis is characterized by inflammation within and adjacent to hair follicles. The folliculitides comprise a group of diseases that share the histopathologic findings of folliculitis and/or perifolliculitis and can be broadly characterized as infectious, acneiform, eosinophilic, and miscellaneous (Table 10-17).

233

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Gram-negative folliculitis may occur as a complication of long-term oral antibiotic treatment for acne and presents clinically as worsening acneiform papules and pustules around the nose, mouth, and cheeks. Culture of these lesions usually grows a species of Enterobacter, Klebsiella, or Escherichia coli.138 Hot-tub folliculitis is a less common gram-negative folliculitis usually caused by Pseudomonas aeruginosa and acquired through exposure to inadequately chlorinated water in swimming pools and hot tubs.139 Lesions generally are distributed over areas covered by the bathing suit. Mud-wrestling folliculitis caused by soil bacteria, Enterobacteriaceae, also occurs on covered skin in individuals participating in this activity.140  FIGURE 10-27 Follicular degeneration syndrome. Vertical sections: Diminished follicular density with vertically oriented residual fibrous tracts and sparse lymphocytic infiltrates.

INFECTIOUS FOLLICULITIS Bacterial, fungal, parasitic, viral, and mycobacterial follicular infections comprise the infectious folliculitides (see Table 10-17).

Bacterial Folliculitis CLINICAL FEATURES Bacterial folliculitis may affect the superficial portion of the hair follicle and present clinically as a pustule or the deep portion of the hair follicle and present as indurated,

erythematous nodules or plaques. Superficial bacterial folliculitis, also known as Bockhart impetigo, is usually caused by Staphylococcus aureus. Furuncles, or deep folliculitis, are larger, tender, warm, erythematous nodules and plaques with central pustules, generally caused by S aureus. Furuncles may occur on any nonglabrous skin but are more common on the legs, buttocks, posterior neck, and axillae. Carbuncles, composed of two or more coalescing furuncles, are more common in diabetics.

Fungal Folliculitis CLINICAL FEATURES Fungal folliculitis is typically caused by Malassezia furfur, formerly termed Pityrosporum ovale (Pityrosporum folliculitis) or dermatophytes (Majocchi granuloma and tinea capitis). Pityrosporum folliculitis occurs on the trunk as pruritic acneiform papules and pustules most commonly in young adults.141 Majocchi granuloma is a form of follicular dermatophytosis that occurs on nonglabrous skin, most commonly on extremities.142 The lesions present as grouped, somewhat annular inflammatory papulopustules or as deep furuncle-like nodules. Topical corticosteroid usage prior to a correct diagnosis is common in Majocchi granuloma and may allow for more extensive infection of hair shafts. HISTOPATHOLOGIC FEATURES Bacterial and fungal folliculitis share similar microscopic features and show intra- and perifollicular, predominantly neutrophilic inflammatory infiltrates. Follicular rupture with adjacent dense, mixed inflammatory infiltrates, abscess formation, and granulation tissue is common. Bacterial organisms may be present in the infundibular region in bacterial folliculitis and at a deeper follicular level in furuncles and carbuncles (Fig. 10-36). Acneiform dilatation with budding yeast and follicular hyperkeratosis is seen in Pityrosporum folliculitis (Fig. 10-37). The histology of Majocchi granuloma is similar to tinea capitis/kerion with follicular rupture, abscess, and dermatophyteinfected hair shafts (Fig. 10-38).

Demodex Folliculitis 234

 FIGURE 10-28 Follicular degeneration syndrome. Horizontal sections: Concentric lamellar fibroplasia surrounds a follicle with eccentric thinning of follicular epithelium. Only sparse lymphocytes are seen.

CLINICAL FEATURES The ectoparasites Demodex folliculorum and D brevis are hair

HISTOPATHOLOGIC FEATURES Demodex mites are elongate eosinophilic ectoparasites and are more numerous on the head and neck.145 One or more mites may be found in normal follicular infundibula. Mites also may be seen within the sebaceous duct. Follicular spongiosis with perifollicular lymphohistiocytic infiltrates can occur in rosacea-like lesions, especially on the face (Fig. 10-39).

Viral Folliculitis

follicle mites found frequently in normal adult skin. The pathogenicity of the mites in folliculitis, especially acne rosacea, is controversial.143 However, in some cases, facial rosacea-like papules and pustules respond to topical acaricidal therapy,

suggesting that Demodex mites may play a role in some instances. In addition, the mean mite count in a facial biopsy was significantly higher in patients with rosacea than in matched control patients in one study.144

HISTOPATHOLOGIC FEATURES In herpes folliculitis, viral cytopathic changes of herpesvirus infection may be seen initially in the follicular infundibulum. These changes include keratinocyte pallor with chromatin margination, nuclear molding, acantholysis, dyskeratosis, and multinucleation. In papular chronic herpesvirus infections, typical viral cytopathic changes are seen in the epidermis and hair follicles with prominent overlying hyperkeratosis.147 Early herpes folliculitis lesions may show a lymphocytic folliculitis without diagnostic cytopathic changes.146 Extensive necrosis occurs in some cases. The adjacent dermis shows moderate to dense, perivascular and occasionally perineural lymphocytic inflammatory infiltrates. In addition, dense, atypical, but reactive lymphocytic infiltrates-simulating lymphoma can occur in herpesvirus folliculitis.150 Molluscum contagiosum folliculitis is characterized by multiple molluscum bodies within the epithelium of the hair follicle.148,149

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-29 End-stage scarring alopecia. Horizontal sections: Complete follicular dropout with numerous residual fibrous tracts. These end-stage features occur in many primary scarring alopecias and are not diagnostic of a specific entity.

CLINICAL FEATURES Although not typically a follicular process, herpesvirus infections (herpes simplex and herpes zoster) can involve hair follicles, especially in early lesions. A recent study showed herpes zoster more commonly affects hair follicles than herpes simplex virus.146 In addition, chronic cutaneous herpesvirus infections can involve follicles and present as persistent hyperkeratotic papules in an acneiform distribution on the trunk in immunocompromised patients.147-149 Cases of herpetic sycosis, with widespread vesiculopustular eruptions in the beard area, have been reported in immunocompetent men.148 A case of molluscum contagiosum folliculitis in an HIV-positive man presented with asymptomatic, numerous, nonumbilicated, flesh-colored papules in the beard area.148

Atypical Mycobacterial Folliculitis  FIGURE 10-30 Alopecia mucinosa. Vertical sections: Extensive mucin deposits are present, including mucin-filled cystic spaces.

CLINICAL FEATURES Cutaneous nontuberculous mycobacterial infections are rare and can present clinically as papules, pustules, nodules, abscesses, plaques, ulcers, or cellulitis. A linear (sporotrichoid) spread of

235

Table 10-15 Pustulofollicular, Neutrophil-Associated Primary Scarring Alopecia DISSECTING CELLULITIS

FOLLICULITIS DECALVANS

ACNE KELOIDALIS

TINEA KERION AND FAVUS

African American men Fluctuant scalp nodules Progression to extensive interconnected abscesses, sinus tracts Spontaneous drainage Painful, prominent scarring Associated follicular occlusion triad

Adults of either sex Round or irregularly shaped patches of alopecia with follicular pustules Other sites may be affected

African American men Occipital scalp, neck Follicular papules, pustules progress to large, exophytic, keloidal alopecic plaques

Children, adolescents Boggy, erythematous, crusted, scaling nodules and plaques with variable alopecia Zoophilic and geophilic forms of dermatophyte Yellow, cup-shaped crusts (scutula) with favus

Early finding, persists

Early finding, persists

Early finding, persists

Present Present in dermis

Present Less prominent in dermis

Present Variable, may be prominent

Absent

Largely absent

Absent

Less dense perifollicular fibrosis in dermis

Dense dermal hypertrophic scar and/or keloid

Perifollicular dermal scar, may be extensive in favus

Occasional staph within follicular infundibulum Neutrophilic initially, later mixed

Occasional propionibacteria acnes Neutrophilic initially, later mixed with lymphocytes and prominent plasma cells Primarily peri-infundibular, may extend to involve entire follicle

Endothrix and ectothrix

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Clinical Features

Histopathologic Features Acneiform follicular Early finding, persists dilatation Follicular rupture Present Abscess formation Extensive dermal and subcutaneous Sinus tract formation Yes, partially squamous-lined Location of fibrosis Dense fibrotic scar around sinus tracts in dermis and subcutis Infectious agents Occasional staph within follicular infundibulum Inflammation type Neutrophilic initially, later mixed granulomatous with plasma cells Location Initially peri-infundibular, progresses to involve entire follicle and subcutis

Primarily peri-infundibular, may extend to involve entire follicle

*SOURCE: Data from Templeton SF, Solomon AR. Scarring alopecia: a classification based on microscopic criteria. J Cutan Pathol 1994:21:97–109.81

lesions along lymphatic drainage lines may be observed, especially in Mycobacterium marinum infections.151 HISTOPATHOLOGIC FEATURES Acute suppurative folliculitis has been demonstrated in M chelonae infections.151 The histopathologic features of nontuberculous mycobacterial infection range from diffuse granulomatous dermatitis with tuberculoid, sarcoidal, or palisading patterns of inflammation to cutaneous abscesses, suppurative granulomas, and necrotizing folliculitis. Therefore, folliculitis generally is not an isolated histopathologic finding in the biopsy specimen.

ACNEIFORM FOLLICULITIS

236

Primarily peri-infundibular, may extend to involve entire follicle

Neutrophilic initially, later mixed granulomatous

Acne vulgaris (Table 10-18), other acne subtypes, pseudofolliculitis barbae, hidradenitis suppurativa (Table 10-19), and pustulofollicular scarring alopecias are all acneiform folliculitides. Some forms

of rosacea are also included in this group of diseases (Table 10-20).

Acne Variants CLINICAL FEATURES Acne can be comedonal, papular, pustular, nodular, or cystic. The face, chest, and back are involved, and this disorder primarily affects adolescents and young adults152,153 (see Table 10-18). Comedonal, papular, and pustular acnes are the most common variants and are termed acne vulgaris. Comedones are either open (blackheads) or closed (whiteheads). Acne conglobata is a severe form of nodulocystic acne that usually involves the back, chest, and posterior neck and consists of numerous coalescing large comedones, acne cysts, and nodules. Extensive irregularly shaped scars and epidermoid cysts occur in the later stages, and association with the follicular occlusion triad is common. Chloracne is a rare acne variant occurring after exposure to halogenated aromatic

compounds, especially dioxin.154 Patients using systemic and topical corticosteroids may develop a monomorphic acneiform follicular eruption termed steroid acne.155 A number of other drugs, including anticonvulsants, anabolic steroids, lithium, isoniazid, azathioprine, cyclosporine A, etretinate, and epidermal growth factor inhibitors also may cause acneiform eruptions.138,156,157 Acne cosmetica (pomade acne) is more common in women and occurs on the face as the result of persistent follicular occlusion by cosmetics and applied hair oils.152 Noninflammatory comedones and cysts associated with nodular solar elastosis is termed the Favre-Racouchot syndrome and generally occurs on the upper to lateral cheeks and temples near the eyes.158 HISTOPATHOLOGIC FEATURES The follicular infundibulum is thinned, dilated, and filled with compact hyperkeratosis in acne comedones (see Table 10-18 and

may occur in old, scarred acne lesions. Extensive solar elastosis, open comedones, and small epidermoid cysts are seen in the Favre-Racouchot syndrome.

Pseudofolliculitis Barbae CLINICAL FEATURES Pseudofolliculitis barbae is an acneiform eruption of the bearded area most common in men with thick, tightly curled hair. Concomitant acne keloidalis often occurs in these patients.159-162

 FIGURE 10-31 Dissecting cellulitis of the scalp. Vertical sections: Partially squamous-lined abscess with unsheathed hair shaft. Follicles are destroyed by the fibroinflammatory process.

Fig. 10-40). Inflammatory comedones, papules, and pustules show mixed infiltrates of increasing density within and around dilated follicles.138 Follicular rupture with dermal abscess is seen in nodu-

locystic acne lesions, and subsequent scarring is common. Extensive abscesses and partially squamous-lined sinuses with prominent scarring are seen in acne conglobata. Focal dystrophic calcification

Hidradenitis Suppurativa CLINICAL FEATURES Hidradenitis suppurativa is a painful, deep, scarring folliculitis of the axillae and groin often associated with nodulocystic acne and dissecting cellulitis of the scalp (see Table 10-19). HISTOPATHOLOGIC FEATURES The histopathology of hidradenitis is very similar to that of dissecting cellulitis of the scalp and consists of extensive scarring of the dermis and subcutis with deep dermal and subcutaneous abscesses and sinuses partially lined with squamous epithelium163 (see Table 10-19 and Fig. 10-41). Follicular occlusion occurs initially with subsequent superficial and deep folliculitis and abscess formation. A persistent fibro-inflammatory response occurs as the result of continuous keratin production by ruptured squamous-lined sinuses. Abundant granulation tissue is seen in some patients. Suppurative inflammation of apocrine glands occurs secondarily and only in a minority of patients.164,165 In one study, secondary apocrine gland involvement was found in 12% of specimens, and secondary involvement of eccrine glands was found in 25%.163

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

HISTOPATHOLOGIC FEATURES Pseudofolliculitis barbae results from close shaving in individuals with thick, tightly curled hair. The hair shafts either penetrate their own follicular infundibulum or curl back and penetrate the adjacent epidermis after exiting the acrotrichium. The histopathologic features show a follicular and perifollicular mixed inflammatory infiltrate with an associated foreign-body histiocytic giant cell response and variable fibrosis.159-162

Rosacea and Perioral Dermatitis

 FIGURE 10-32 Folliculitis decalvans. Horizontal sections: Pustular folliculitis with incipient rupture and adjacent mixed dermal infiltrates.

CLINICAL FEATURES Rosacea is an acneiform disorder that most commonly affects the middle-aged and elderly (see Table 10-20). Telangiectatic, papulopustular, granulomatous, and rhinophyma variants occur.166

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 10-16 Secondary Scarring Alopecia

238

 FIGURE 10-33 Acne keloidalis. Vertical sections: Chronic lesion with dense dermal scar, recent follicular rupture, unsheathed hair shafts, and mixed infiltrates including neutrophils and numerous plasma cells.

The nose, cheeks, and chin typically are affected, but extrafacial involvement can occur rarely. Transient and persistent flushing of the face is common and may be aggravated by external and psycho-

logical factors. Inflammatory papular and granulomatous lesions can mimic basal cell carcinoma clinically and therefore often are biopsied. Although once considered a tuberculid, lupus miliaris

 FIGURE 10-34 Tinea capitis. Horizontal sections: Dermatophyte hyphae extensively permeate (endothrix) and surround (ectothrix) hair shafts in this patient treated with topical steroids. Numerous neutrophils are seen.

Sclerosing disorders Morphea Sclerodermoid porphyria cutanea tarda Lichen sclerosus et atrophicus Parry-Romberg syndrome Physical/chemical agents Mechanical trauma, laceration Thermal burns Chemical burns Radiation dermatitis Dermal infiltrative processes Tumors Basal cell carcinoma Squamous cell carcinoma Metastatic carcinoma Lymphoma Adnexal tumors Dermatofibrosarcoma protuberans Others Granulomatous conditions Sarcoidosis Necrobiosis lipoidica Miecher granuloma Actinic granuloma Infections Syphilis (tertiary) Tuberculosis Viral infections Protozoal infections Other Amyloidosis SOURCE: Data from Templeton SF, Solomon AR. Scarring alopecia: a classification based on microscopic criteria. J Cutan Pathol 1994:21: 97–109.81

disseminata facei is now considered a variant of granulomatous rosacea and consists of discrete red-brown papules distributed over the face and eyelids.167,168 Rhinophyma is an end-stage variant of rosacea that results in enlargement of the nose, especially the nasal tip, due to sebaceous gland hypertrophy.169 On occasion, other areas of the face or ears may be involved by rhinophyma. The pathogenesis is poorly understood, but the vascular flushing reaction is one of the earliest stages in the development of rosacea and recent evidence suggests angiogenesis is an important factor in the pathogenesis of rosacea.170 Aggravating factors include hot, spicy foods and liquids, alcohol, certain vasodilatory drugs, and sunlight.166 Ocular rosacea is relatively common, with symptoms of stinging, burning, tearing, photophobia, scratchiness, and feelings of foreign material in the eye.167

Perioral dermatitis is a relatively common facial eruption consisting of acneiform papules and pustules distributed around the mouth of young women.171 Use of topical fluorinated corticosteroids on the face is often the inciting cause, but idiopathic cases occur. Clinically, perioral dermatitis has features of acne rosacea

and seborrheic dermatitis. Granulomatous variants of perioral dermatitis occur, especially in children, and in these cases involvement of the eyelids and neck is common.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-35 Keratosis pilaris. Follicular hyperkeratosis with slight perifollicular fibroplasia and sparse lymphocytic infiltrates are seen.

HISTOPATHOLOGIC FEATURES Histopathologic features vary according to clinical subtype172-174 (see Table 10-20). In telangiectatic rosacea, increased numbers of ectatic venules with sparse perivascular lymphocytic infiltrates are seen. Solar elastosis is common. Papular rosacea lesions have perivascular and perifollicular lymphohistiocytic infiltrates involving the superficial to middle dermis (Fig. 10-42). Admixed multinucleate histiocytes and loose granulomas are seen in papular and granulomatous rosacea (Fig. 10-43). Nonfollicular epithelioid granulomas that occasionally exhibit caseation necrosis occur less frequently. The inflammatory infiltrate in papular rosacea may have a perivascular to nodular pattern rather than a strictly perifollicular distribution. Suppurative folliculitis with admixed lymphohistiocytic infiltrates, including foreign-body giant cells, is characteristic of pustular rosacea. Extensive hypertrophy of mature sebaceous glands, follicular dilatation, and hyperkeratosis with variable inflammation are seen in rhinophyma. In contrast to discrete lesions of sebaceous hyperplasia, in which sebaceous lobules radiate around a central dilated sebaceous duct, rhinophyma exhibits more extensive and diffuse sebaceous gland hypertrophy, fibroplasia, fibrovascular hypertrophy (fibroplasia with prominent vascular ectasia), and nodular accumulation of solar elastotic material. The histopathology of perioral dermatitis is similar to that of papular,

Table 10-17 Folliculitis Subtypes Infectious folliculitis Bacterial—Staphylococcus, Pseudomonas, other Fungal folliculitis—Majocchi granuloma, Pityrosporum folliculitis Demodex folliculitis Herpesvirus folliculitis Acneiform folliculitis Acne variants Hidradenitis suppurativa Pseudofolliculitis barbae Pustulofollicular scarring alopecias Rosacea Perioral dermatitis Eosinophilic folliculitis Neonatal and adult HIV associated

 FIGURE 10-36 Bacterial folliculitis. Numerous intrafollicular gram-positive bacteria are seen as well as early follicular rupture.

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 FIGURE 10-37 Pityrosporum folliculitis. Numerous oval to round M furfur organisms are present within an inflamed follicle.

pustular, and granulomatous variants of rosacea.171

Perforating Folliculitis CLINICAL FEATURES Perforating folliculitis was defined as a clinicopathologic entity

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in 1968 by Mehregan and Coskey.175 The primary lesion was described as a follicular centered erythematous papule perforated by a central hair shaft. The papules typically are located on the thighs and buttocks of young adults, anatomic sites where chronic friction,

 FIGURE 10-38 Majocchi granuloma. A disintegrating hair shaft with numerous endothrix dermatophyte hyphae is present in a dermal abscess.

presumably secondary to tight-fitting clothing on hair-bearing surfaces, could induce the lesion. The perforating hair shaft may be encompassed by a keratotic plug. Other than the postulated role of chronic rubbing and friction, no pathogenesis is known. In addition to the discrete clinicopathologic entity described above, the microscopic finding of infundibular perforation is common to several types of folliculitis, including bacterial and fungal folliculitis, acne vulgaris, keratosis pilaris, and pustulofollicular forms of alopecia such as folliculitis decalvans and acne keloidalis.176-178 Perforating folliculitis also may occur in patients with chronic renal failure on hemodialysis, and in this clinical setting, the disease can be considered part of the spectrum of acquired perforating dermatoses previously termed Kyrle disease.179-181 Perforating folliculitis is also associated with TNF-alpha inhibitor therapy.182 Therefore, infundibular perforation appears to be a nonspecific event occurring in the course of inflammatory follicular destruction. The microscopic finding of perforating folliculitis should not be considered indicative of the specific entity bearing the same name without appropriate clinicopathologic correlation. HISTOPATHOLOGIC FEATURES The diagnostic microscopic change of the specific clinicopathologic entity known as perforating folliculitis is an eccentric infundibular perforation.176,177,179 A plug of hyperkeratotic stratum corneum usually is present within the acrotrichium. The infundibular epithelium is variably hyperplastic, but attenuation of the epithelium usually is evident adjacent to the site of rupture. The dilated infundibulum is filled with necrotic basophilic debris, sebaceous material, keratin, and inflammatory cells. Intact and karyorrhectic neutrophils predominate. A hair shaft may be present within the follicular canal at or near the site of perforation, but it is not invariably present. A mixed inflammatory infiltrate composed of neutrophils, lymphocytes, and plasma cells is found in the dermis adjacent to the ruptured infundibular epithelium. Granulomatous inflammation may be present in older lesions. The reticular dermal collagen near the site of perforation frequently is basophilic and granular. DIFFERENTIAL DIAGNOSIS Perforating folliculitis must be distinguished from elastosis perforans serpiginosa (EPS) and reactive perforating collagenosis (RPC). EPS contains altered perifollicular elastic fibers not seen in perforating folliculitis.

Table 10-20 Rosacea and Rhinophyma

Table 10-18 Acne Vulgaris

Table 10-19 Hidradenitis Suppurativa

Clinical Features Adolescence, early adulthood Men ≥ women Face >> back, chest, shoulder Comedones Erythematous papules, pustules, nodules, cysts Occasional scarring Association with hidradenitis suppurativa and dissecting cellulitis Histopathologic Features Comedone: dilated follicular infundibulum with keratinous plug, open to surface or closed Follicular pustule with or without rupture into surrounding dermis Neutrophilic and foreign-body granulomatous reaction to keratin and follicular contents in dermis Epithelial cyst and sinus tract formation Dermal scarring Differential Diagnosis Keratosis, pilaris, and related conditions Other forms of folliculitis, eg, bacterial, fungal, viral

Clinical Features Onset after puberty Axillae, inguinal, and perineal areas, other sites Erythematous nodules followed by draining abscesses, sinus tracts, prominent scarring Association with severe acne, dissecting cellulitis of scalp Histopathologic Features Early lesions Follicular plugging, folliculitis Chronic lesions Features of chronic folliculitis Abscesses within apocrine glands and in the dermis and subcutis Prominent foreign body granulomatous reaction Dermal scarring often extensive Sinus tract and cyst formation Differential Diagnosis Other chronic active deep folliculitides, infectious and noninfectious Pyoderma gangrenosum Crohn disease

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-39 Demodex folliculitis. Elongated D folliculorum mites are present in the follicular infundibulum with perifollicular infiltrates.

Clinical Features Age 20-50 years common Women > men Fair-skinned individuals Central face: nose, cheek, chin, glabella, forehead; rarely neck, upper trunk Blushing, flushing Erythema, telangiectasia, edema Papules, pustules Rhinophyma, other phymas involving forehead, chin Histopathologic Features Variable degrees of the following: Vascular ectasia Perivascular and perifollicular lymphoid infiltrates Folliculitis Solar elastosis Edema Granulomatous inflammation Epithelioid granulomas, especially perifollicular Sebaceous hyperplasia Rhinophyma and other phymas show variable degrees of the following: Florid sebaceous gland hyperplasia Diffuse fibroplasia Ectatic venular vessels Nodular solar elastosis Differential Diagnosis Lupus erythematosus Perioral dermatitis Acne vulgaris Sarcoidosis Other granulomatous dermatitides

In RPC, the epidermis is the site of perforation rather than the follicular infundibulum.

Eosinophilic Folliculitis (Eosinophilic Pustular Folliculitis) CLINICAL FEATURES Eosinophilic folliculitis (EF) is a histopathologically distinct group of diseases that occur in several patient populations: (1) adult males, usually Japanese (classic form), (2) neonates and young children, (3) HIV-infected and other immunocompromised patients, and (4) a miscellaneous group of patients, including those with atopic dermatitis. The etiology of EF has not been determined. Classic EF was first described in Japanese men by Ofuji and colleagues in 1970 but has been reported in non-Japanese patients.183-186 Clinically, patients present with erythematous follicular papules and pustules that coalesce to form polycyclic plaques with

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 FIGURE 10-40 Comedone. A large comedone displays a keratin-filled dilated follicle with atrophy of infundibular epithelium. Inflammation is variable.

centrifugal extension and central clearing. Postinflammatory hyperpigmentation occurs frequently. The lesions typically affect the face, trunk, and proximal extremities and can be pruritic. Peripheral leukocytosis and eosinophilia are often present.183,184

The pediatric variant occurs predominately in males younger than 1 year of age and generally affects the scalp and forehead as pruritic indurated erythematous plaques with pustules.187-189 Lesions also can occur on the face, trunk, and extremities.190,191 The lesions typically

 FIGURE 10-41 Hidradenitis suppurativa: Extensive dermal scarring is present with a partially squamous-lined sinus tract and associated suppurative infiltrates.

lack the polycyclic morphology and centifugal extension seen in the adult form. Peripheral leukocytosis and eosinophilia are often present. HIV-associated EF was described initially by Soeprono and authors in 1986.192 In contrast to classic EF, HIV-associated EF is associated with severe pruritus, rare pustules, and the absence of polycyclic plaques. Discrete follicular urticarial papules, which are often excoriated, occur on the head, neck, and trunk with sparing of the lower extremities.193,194 Females may show predominantly facial involvement.195 CD4 counts typically are below 200 cells/mm3, and the presence of EF suggests more advanced disease. Serum IgE levels frequently are elevated. Follicular mucinosis has been coexistent in two reported cases.196 EF has also been reported in patients immunosuppressed secondary to bone marrow transplantation.197 A necrotizing variant of EF has been described in nine patients with an atopic diathesis.198 The cases in atopic patients differed from the presentation of classic EF clinically by ulceration and nodule formation and microscopically by follicular necrosis and eosinophilic vasculitis. HISTOPATHOLOGIC FEATURES The various subtypes of EF share similar microscopic features. Intra- and perifollicular mixed inflammatory infiltrates with numerous eosinophils and associated follicular spongiosis are characteristic of EF199 (Table 10-21 and Fig. 10-44). Spongiosis of the sebaceous lobules is commonly present. Subcorneal eosinophilic pustules also may be seen. In many cases, variably dense, perivascular and interstitial lymphocytic infiltrates are present in both the superficial and deep reticular dermis. Flame figures are rare. In the variant reported in atopic patients, follicular necrosis and eosinophilic vasculitis are present in addition to follicular inflammation. DIFFERENTIAL DIAGNOSIS Lesions that may present with a similar eosinophilic infiltrate include papular urticaria, arthropod bite reactions, papular eruption of HIV, scabies infestation, dermatophyte infection, drug reactions, and erythema toxicum neonatorum. A PAS and/or silver stain should be performed to exclude an infectious etiology. The inflammatory infiltrate in papular urticaria, arthropod bite reactions, and drug reactions generally lacks the folliculocentric distribution of EF. The neonatal presentation and rapid resolution of erythema toxicum neonatorum should allow clinical distinction from EF.

Table 10-21 Eosinophilic Folliculitis

MISCELLANEOUS DISORDERS OF CUTANEOUS APPENDAGES

Fox-Fordyce Disease (Apocrine Miliaria) CLINICAL FEATURES Fox-Fordyce disease is a rare, chronic, pruritic, follicular-based

papular eruption that affects skin containing apocrine glands.200,201 It occurs almost exclusively in adolescent and adult females, although rare cases in males and prepubertal females have been reported.202,203 It typically affects the axilla, but lesions can be present in other

 FIGURE 10-43 Granulomatous rosacea. Loose to well-formed granulomas comprised of histiocytes and multinucleate giant cells are seen. Granulomas may or may not be perifollicular.

apocrine gland–bearing sites, including the pubis, labia, perineum, areola, intramammary region, umbilicus, and proximal thigh. Severe paroxysmal pruritus initiated by emotional stimuli, physical activity, and sexual activity is common.204 The pathogenesis remains unknown, although keratotic plugging of the apocrine duct is a consistent finding. HISTOPATHOLOGIC FEATURES The microscopic presentation usually is not specific and can show significant variation, requiring examination of multiple serial sections.205 Transverse sections have been reported to be more effective in demonstrating the histopathologic features.206 The most reproducible findings are hyperkeratosis and spongiosis of the follicular infundibulum. Hyperkeratotic plugging of the follicle at the level of apocrine duct entry is often present but may be difficult to demonstrate in conventional sections. Spongiosis and apocrine sweat retention are observed occasionally in the distal apocrine duct.207 A sparse, predominantly lymphocytic inflammatory infiltrate often is present in a perivascular, perifollicular, and periductal distribution. Xanthoma cells may also be present.205,208 The overlying epidermis may exhibit acanthosis and spongiosis.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-42 Rosacea. Papular lesion: Perifollicular and perivascular lymphohistiocytic infiltrates are characteristic of papular rosacea.

Clinical Features Adult young to middle-aged men, mainly Japanese Neonates and young children HIV-infected patients Face, trunk, upper extremities Erythematous follicular pustules Polycyclic plaques often with centripetal extension, central clearing Urticarial follicular papules often in HIV patients Low CD4 counts (usually < 200 cells/mm3) Histopathologic Features Peri and intrafollicular eosinophilic infiltration Occasional subcorneal eosinophilic pustules Follicular spongiosis often Perivascular and interstitial lymphocytic infiltrates Flame figures rare Differential Diagnosis Other folliculitides, especially infectious Arthropod bite reaction Papular urticaria Papular eruption of HIV

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leukemia.214 It has since been reported in association with other chemotherapeutic agents, particularly bleomycin, nonmyeloid malignancies, and granulocyte colony-stimulating factor.215-219 It also has occurred in HIV-infected patients and in patients with myeloid leukemia prior to induction chemotherapy.220,221 NEH is a polymorphous cutaneous eruption affecting the neck, trunk, and extremities. Lesions consist of tender erythematous macules, papules, and plaques. Spontaneous resolution of the lesions may occur.

 FIGURE 10-44 Eosinophilic folliculitis. Both intrafollicular and perifollicular eosinophils are seen in this case of eosinophilic folliculitis.

DIFFERENTIAL DIAGNOSIS Keratosis pilaris, lichen spinulosis, pityriasis rubra pilaris, ichthyosis, and some eczematous lesions have prominent follicular hyperkeratosis and may mimic Fox-Fordyce disease microscopically. The clinical distribution of lesions should allow distinction of these entities from Fox-Fordyce disease. Infundibulofolliculitis (disseminate and recurrent infundibulofolliculitis) is a microscopic consideration but generally has less prominent follicular hyperkeratosis and occurs predominantly in black males.

Chromhidrosis (Apocrine Chromhidrosis) CLINICAL FEATURES Chromhidrosis is a rare disorder that is characterized by the production of colored perspiration by apocrine or eccrine glands.209-211 The face and axilla are the most common sites, although involvement of the areola has been reported.212 Secretion of brown or black perspiration occurs in response to emotional or mechanical stimulation. Less commonly, the secretions may be colored blue, green, yellow, or red. The common coloring of perspiration by exogenous

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HISTOPATHOLOGIC FEATURES The predominant microscopic finding in classic NEH is a sparse to dense neutrophilic infiltrate surrounding eccrine units214,217 (Table 10-22 and Fig. 10-45). Secretory coils in the superficial subcutis generally show more extensive involvement by the neutrophilic infiltrate, and eccrine epithelial vacuolization and necrosis are commonly present. Focal degenerative mucinous changes often are evident in the adjacent subcutis. Squamous metaplasia and variable dyskeratosis can affect part or all of the eccrine unit in chemotherapy and has been termed eccrine squamous syringometaplasia. In association with chemotherapy, it is considered in the histopathologic spectrum of NEH.218

pigments or chromogenic microorganisms is known as pseudochromhidrosis.213 HISTOPATHOLOGIC FEATURES Apocrine secretory cells exhibit increased basophilia and contain variably sized yellow-brown granules. The granules show a positive Schmorl reaction and are autofluorescent with fluorescent microscopy. The difference in the clinical color of perspiration has been suggested to reflect varying amounts of lipofuscin in different states of oxidation. DIFFERENTIAL DIAGNOSIS Given the distinctive clinical presentation, the diagnosis should be straightforward. Since exogenous pigments and chromogenic microorganisms can show similar changes in the color of perspiration, those entities should be excluded by clinical history and special stains.

Neutrophilic Eccrine Hidradenitis CLINICAL FEATURES Neutrophilic eccrine hidradenitis (NEH) was described initially by Harrist and colleagues in 1982 as a complication of cytarabine chemotherapy in patients with acute myelogenous

Table 10-22 Neutrophilic Eccrine Hidradenitis

Clinical Features Onset a few days after administration of chemotherapeutic agents such as cytarabine, bleomycin Neck, trunk, extremities Tenderness Erythematous macules, papules, plaques Spontaneous resolution Histopathologic Features Neutrophilic infiltrates associated with eccrine sweat coil Eccrine epithelial cells show vacuolar degeneration and necrosis Mucin deposition in peri-eccrine adipose tissue Dermal edema Sparse dermal infiltrates composed of lymphocytes and neutrophils Differential Diagnosis Infectious hidradenitis and pyoderma Other neutrophilic dermatitides

an abrupt onset of tender, erythematous papules and nodules on the plantar and less commonly palmar surfaces.222-224 The lesions resolve spontaneously in most cases. The disease affects children and young adults of both sexes. There is no disease or chemotherapy association, and no specific etiology has been identified.222-224

 FIGURE 10-45 Neutrophilic eccrine hidradenitis. An eccrine sweat coil is infiltrated by neutrophils. The epithelial tubular structures show slight degenerative changes.

DIFFERENTIAL DIAGNOSIS The differential diagnosis is identical to that of NEH. The clinical distribution and presentation in healthy patients should allow distinction from NEH.

Sweat Gland Necrosis DIFFERENTIAL DIAGNOSIS The microscopic differential diagnosis includes infectious hidradenitis, neutrophilic dermatoses, leukocytoclastic vasculitis, and coma or pressure-induced eccrine necrosis. Special stains and/or tissue culture should be used to exclude an infectious hidradenitis. NEH has been hypothesized to be in the spectrum of neutrophilic dermatoses; however, in contrast to Sweet syndrome, the neutrophilic infiltrate is confined to the

eccrine unit. Although the pattern of the infiltrate in NEH may mimic vasculitis at low magnification, vessels typically are not affected.

Palmoplantar Eccrine Hidradenitis (Idiopathic Palmoplantar Hidradenitis) CLINICAL FEATURES Palmoplantar eccrine hidradenitis shares clinical and microscopic features with NEH. It presents as

 FIGURE 10-46 Sweat gland necrosis. Extensive noninflammatory necrosis of eccrine units is seen in coma-associated sweat gland necrosis.

CLINICAL FEATURES Patients in a comatose state due to carbon monoxide poisoning, drug overdose (especially barbiturates), severe illness, or trauma may develop bullae with sweat gland necrosis at pressure sites.225-227 The cause of these blisters is thought to be related to pressureinduced ischemia and possible toxic effect of offending drugs. HISTOPATHOLOGIC FEATURES Intra- and subepidermal vesiculation with variable dyskeratosis and necrosis is present in the epidermis. Eosinophilic coagulative necrosis of the eccrine secretory coils with minimal inflammation is the most characteristic finding in this entity (Fig. 10-46). Similar necrotic changes can be observed in adjacent hair follicles and sebaceous lobules. The dermis may be acellular or contain degenerating fibroblasts. Generally, the inflammatory infiltrate is minimal, but sparse neutrophils can be present around necrotic adnexal structures. DIFFERENTIAL DIAGNOSIS Other causes of cutaneous necrosis, such as coumarin necrosis, purpura fulminans, and vascular insufficiency–induced necrosis should be considered, but occlusion of vessels by fibrin, thrombi, or embolic material is identified in these cases. Chemotherapy-associated squamous metaplasia and necrosis also can be considered but lack the homogenized eosinophilic necrosis is seen in comaassociated sweat gland necrosis.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

HISTOPATHOLOGIC FEATURES The microscopic findings are similar to NEH. There is a moderate to dense neutrophilic infiltrate involving the eccrine unit. Superficial and deep perivascular neutrophilic inflammatory infiltrates may be present.224

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41. Colombe B, Price V, Khoury E. HLA class II antigen associations help to define two types of alopecia areata. J Am Acad Dermatol. 1995;33:757. 42. Duvik M, Hordinsky M, Fiedler V. HLAD locus associations in alopecia areata. Arch Dermatol. 1991;127:64-68. 43. Mitchell A, Krull E. Alopecia areata: pathogenesis and treatment. J Am Acad Dermatol. 1984;11:763-765. 44. Elston D, McCollough M, Bergfeld W. Eosinophils in fibrous tracts and near hair bulbs: a helpful diagnostic feature of alopecia areata. J Am Acad Dermatol. 1997;37:101-106. 45. Hull S, Nutbrown M, Pepall L. Immunohistologic and ultrastructural comparison of the dermal papilla and hair follicle bulb from “active” and normal areas of alopecia areata. J Invest Dermatol. 1991;96:673-681. 46. Tobin D, Fenton D, Kendall M. Ultrastructural observations on the hair bulb melanocytes and melanosomes in acute alopecia areata. J Invest Dermatol. 1990;94:803-807. 47. Tobin D, Fenton D, Kendall M. Cell degeneration in alopecia areata. Am J Dermatopathol. 1991;13:248-261. 48. Whiting D. The histopathology of alopecia areata in vertical and horizontal sections. Dermatol Ther. 2001;14: 297-305. 49. Whiting D. Histopathologic features of alopecia areata. Arch Dermatol. 2003;139:1555-1559. 50. Headington J, Astle N. Familial focal alopecia: a new disorder of hair growth clinically resembling pseudopelade. Arch Dermatol. 1987;123:234-237. 51. Dawber R. Self-induced hair loss. Semin Dermatol. 1985;4:53-57. 52. Sanderson K, Hall-Smith P. Tonsure trichotillomania. Br J Dermatol. 1970;82: 343-350. 53. Muller S. Trichotillomania. Dermatol Clin. 1987;5:595-601. 54. Steck W. The clinical evaluation of pathologic hair loss with a diagnostic sign in trichotillomania. Cutis. 1979; 24:298-301. 55. Whiting DA. Traumatic alopecia. Int J Dermatol. 1999;38:34-44. 56. Muller S. Trichotillomania: a histopathologic study of sixty-six patients. J Am Acad Dermatol. 1990;23:50-62. 57. Hwang S, Lee W, Choi E. Nurse’s cap alopecia. Int J Dermatol. 1999;38:187-191. 58. Trueb R. Chignon alopecia: a distinctive type of non-marginal traction alopecia. Cutis. 1995;55:178-179. 59. Perlstein H. Traction alopecia due to hair weaving. Cutis. 1969;5:440. 60. Lopresti P, Papa C, Kligman A. Hot comb alopecia. Arch Dermatol. 1968;98: 234-238. 61. Hanly A. Post operative pressure induced alopecia: a report of a case and discussion of the rate of apoptosis in nonscarring alopecia. J Cutan Pathol. 1999;26: 357-361. 62. Wiles J, Hansen R. Postoperative (pressure) alopecia. J Am Acad Dermatol. 1985;12:195-198. 63. Roberts J, DeVillez R. Infectious, physical and inflammatory causes of hair and scalp abnormalities. In: Olsen E, ed. Disorders of Hair Growth: Diagnosis and Treatment. 2nd ed. New York, NY: McGraw-Hill; 2003.

86. Callen J. Chronic cutaneous lupus erythematosus. Clinical, laboratory, therapeutic, and prognostic examination of 62 patients. Arch Dermatol. 1982;118: 412-416. 87. Callen J. Systemic lupus erythematosus in patients with chronic cutaneous (discoid) lupus erythematosus. Clinical and laboratory findings in seventeen patients. J Am Acad Dermatol. 1985;12: 278-288. 88. Annessi G, Lombardo G, Gobello T, et al. A clinicopathologic study of scarring alopecia due to lichen planus: comparison with scarring alopecia in discoid lupus erythematosus and pseudopelade. Am J Dermatopathol. 1999;21:324-331. 89. Wilson CL, Burge SM, Dean D, et al. Scarring alopecia in discoid lupus erythematosus. Br J Dermatol. 1992;126: 307-314. 90. Abell E. Immunofluorescent staining technics in the diagnosis of alopecia. South Med J. 1977;70:1407-1410. 91. Dahl M, Gilliam J. Direct immunofluorescence in lupus erythematosus. In: Beutner E, Chorzelski T, Kumar V, eds. Immunopathology of the Skin. 3rd ed. New York, NY: John Wiley & Sons; 1987. 92. Kossard S, Lee MS, Wilkinson B. Postmenopausal frontal fibrosing alopecia: a frontal variant of lichen planopilaris. J Am Acad Dermatol. 1997;36:59-66. 93. Kossard S. Postmenopausal frontal fibrosing alopecia. Scarring alopecia in a pattern distribution. Arch Dermatol. 1994;130:770-774. 94. Tosti A, Piraccini BM, Iorizzo M, et al. Frontal fibrosing alopecia in postmenopausal women. J Am Acad Dermatol. 2005;52:55-60. 95. Faulkner C, Wilson N, Jones S. Frontal fibrosing alopecia associated with cutaneous lichen planus in a premenopausal woman. Aust J Dermatol. 2002;43:65-67. 96. Jumez N, Bessis D, Guillot B. Frontal fibrosing alopecia is not always postmenopausal.[comment]. Annales de Dermatologie et de Venereologie. 2005; 132:263. 97. Abbas O, Chedraoui A, Ghosn S. Frontal fibrosing alopecia presenting with components of Piccardi-LassueurGraham-Little syndrome. J Am Acad Dermatol. 2007;57:S15-S18. 98. Mehregan D, Van Hale H, Muller S. Lichen planopilaris: clinical and pathologic study of forty-five patients. J Am Acad Dermatol. 1992;27:935-942. 99. Amato L, Massi D, Berti S, et al. A multiparametric approach is essential to define different clinicopathological entities within pseudopelade of Brocq. Br J Dermatol. 2002;146:532-533. 100. Amato L, Mei S, Massi D, et al. Cicatricial alopecia: a dermatopathologic and immunopathologic study of 33 patients (pseudopelade of Brocq is not a specific clinico-pathologic entity). Int J Dermatol. 2002;41:8-15. 101. Anderton R, Cullen S. Pseudopelade of Brocq secondary to lichen planus. Cutis. 1976;17:916-918. 102. Braun-Falco O, Imai S, Schmoeckel C, et al. Pseudopelade of Brocq. Dermatologica. 1986;172:18-23. 103. Prieto JG. Pseudopelade of Brocq: its relationship to some forms of cicatricial alopecias and to lichen planus. J Invest Dermatol. 1955;24:323-335.

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CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

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200. 201.

202. Effendy I, Ossowski B, Happle R. FoxFordyce disease in a male patient– response to oral retinoid treatment. Clin Exp Dermatol. 1994;19:67-69. 203. Ranalletta M, Rositto A, Drut R. FoxFordyce disease in two prepubertal girls: histopathologic demonstration of eccrine sweat gland involvement. Pediatr Dermatol. 1996;13:294-297. 204. Miller ML, Harford RR, Yeager JK. FoxFordyce disease treated with topical clindamycin solution. Arch Dermatol. 1995;131:1112-1113. 205. Boer A. Patterns histopathologic of FoxFordyce disease. Am J Dermatopathol. 2004;26:482-492. 206. Stashower M, Krivda S, Turiansky G. Fox-Fordyce disease: diagnosis with transverse histologic sections. J Am Acad Dermatol. 2000;42:89-91. 207. Shelley WB, Levy EJ. Apocrine sweat retention in man. Arch Dermatol. 1956; 73:38-49. 208. Kossard S, Dwyer P. Axillary perifollicular xanthomatosis resembling Fox-Fordyce disease.[see comment]. Aust J Dermatol. 2004;45:146-148. 209. Cilliers J, de Beer C. The case of the red lingerie—chromhidrosis revisited. Dermatol. 1999;199:149-152. 210. Mali-Gerrits M, van de Kerkhof P, Mier P, et al. Axillary apocrine chromhidrosis. Arch Dermatol. 1988;124:494-496. 211. Shelley WB, Hurley HJ. Localized chromhidrosis: a survey. Arch Dermatol Syphilol. 1954;69:449-471. 212. Saff D, Owens R, Kahn T. Apocrine chromhidrosis involving the areolae in a 15-year-old amateur figure skater. Pediatr Dermatol. 1995;12:48-50. 213. Thami GP, Kanwar AJ. Red facial pseudochromhidrosis. Br J Dermatol. 2000;142:1219-1220. 214. Harrist TJ, Fine JD, Berman RS, et al. Neutrophilic eccrine hidradenitis. A distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy. Arch Dermatol. 1982;118:263-266. 215. Bachmeyer C, Aractingi S. Neutrophilic eccrine hidradenitis. Clin Dermatol. 2000; 18:319-330.

216. Bachmeyer C, Chaibi P, Aractingi S. Neutrophilic eccrine hidradenitis induced by granulocyte colony-stimulating factor. Br J Dermatol. 1998; 139: 354-355. 217. Fitzpatrick JE, Bennion SD, Reed OM, et al. Neutrophilic eccrine hidradenitis associated with induction chemotherapy. J Cutan Pathol. 1987;14:272-278. 218. Hurt MA, Halvorson RD, Petr FC, Jr., et al. Eccrine squamous syringometaplasia. A cutaneous sweat gland reaction in the histologic spectrum of ‘chemotherapy-associated eccrine hidradenitis’ and ‘neutrophilic eccrine hidradenitis’. Arch Dermatol. 1990;126:73-77. 219. Templeton SF, Solomon AR, Swerlick RA. Intradermal bleomycin injections into normal human skin. A histopathologic and immunopathologic study. Arch Dermatol. 1994;130:577-583. 220. Bachmeyer C, Reygagne P, Aractingi S. Recurrent neutrophilic eccrine hidradenitis in an HIV-1-infected patient. Dermatol. 2000;200:328-330. 221. Roustan G, Salas C, Cabrera R, et al. Neutrophilic eccrine hidradenitis unassociated with chemotherapy in a patient with acute myelogenous leukemia. Int J Dermatol. 2001;40:144-147. 222. Landau M, Metzker A, Gat A, et al. Palmoplantar eccrine hidradenitis: three new cases and review. Pediatr Dermatol. 1998;15:97-102. 223. Simon M, Jr., Cremer H, von den Driesch P. Idiopathic recurrent palmoplantar hidradenitis in children. Report of 22 cases. Arch Dermatol. 1998;134:76-79. 224. Stahr BJ, Cooper PH, Caputo RV. Idiopathic plantar hidradenitis: a neutrophilic eccrine hidradenitis occurring primarily in children. J Cutan Pathol. 1994;21:289-296. 225. Leavell UW. Sweat gland necrosis in barbituate poisoning. Arch Dermatol. 1969;100:218-221. 226. Leavell UW, Farley CH, McIntire JS. Cutaneous changes in a patient with carbon monoxide poisoning. Arch Dermatol. 1969;99:429-433. 227. Mandy S, Ackerman A. Characteristic traumatic skin lesions in drug-induced coma. JAMA. 1970;213:253-256.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

194.

childhood. J Am Acad Dermatol. 1992; 27:55-60. Dupond A, Aubin F, Bourezane Y, et al. Eosinophilic pustular folliculitis in infancy: report of two affected brothers. Br J Dermatol. 1995;132:296-299. Larralde M, Morales S, Santos Munoz A, et al. Eosinophilic pustular folliculitis in infancy: report of two new cases. Pediatr Dermatol. 1999;16:118-120. Soeprono F, Schinella R. Eosinophilic pustular folliculitis in patients with acquired immunodeficiency syndrome. Report of three cases. J Am Acad Dermatol. 1986;14:1020-1022. Blauvelt A, Plott R, Spooner K, et al. Eosinophilic folliculitis associated with the acquired immunodeficiency syndrome responds well to permethrin. Arch Dermatol. 1995;131:360-361. Rosenthal D, LeBoit PE, Klumpp L, et al. Human immunodeficiency virus-associated eosinophilic folliculitis. A unique dermatosis associated with advanced human immunodeficiency virus infection. Arch Dermatol. 1991;127:206-209. Parker SRS, Parker DC, McCall CO. Eosinophilic folliculitis in HIV-infected women: case series and review. Am J Clin Dermatol. 2006;7:193-200. Buezo G, Fraga J, Abajo P, et al. HIVassociated eosinophilic folliculitis and follicular mucinosis. Dermatol. 1998; 197:178-180. Goiriz R, Guhl-Millán G, Peñas P, et al. Eosinophilic folliculitis following allogeneic peripheral blood stem cell transplantation: case report and review. J Cutan Pathol. 2007;34:33-36. Magro C, Crowson A. Necrotizing eosinophilic folliculitis as a manifestation of the atopic diathesis. Int J Dermatol. 2000;39:672-677. McCalmont T, Altemus D, Maurer T, et al. Eosinophilic folliculitis. The histologic spectrum. Am J Dermatopathol. 1995; 17:439-446. Macmillan DC, Vickers HR. FoxFordyce disease. Br J Dermatol. 1971; 84:181. Winkelmann RK, Montgomery H. FoxFordyce disease: a histopathologic and histochemical investigation. Arch Dermatol. 1956;74:63.

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CHAPTER 11 Panniculitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Raymond L. Barnhill Birgitta Schimdt

One of the more difficult subjects in all of dermatopathology is the study and classification of inflammatory processes that involve the subcutaneous fat.1-6 Why does panniculitis pose such a challenge to dermatopathologists? On the whole, many of these conditions have not been studied at the molecular level in detail, and thus inadequate information is available to date concerning their pathogenesis. Some of the reasons for this lack of data include the following: (1) in general, panniculitis is relatively uncommon, (2) dermatologists and other physicians often are reluctant to biopsy subcutaneous nodules because poor wound healing is commonly expected, (3) biopsies often are too small and do not sample the affected area adequately (Table 11-1), (4) the clinical findings for

Table 11-1 Evaluation of Panniculitis 1. Excisional wedge biopsy is necessary for adequate sampling. 2. Punch biopsies are to be discouraged and may be misleading. 3. Biopsy an active rather than a late-stage lesion. 4. Special stains for infectious organisms include Gram, acid-fast, fungal,WarthinStarry, Fite-Faraco. 5. Examine specimen under polarized light for foreign material. 6. Laboratory investigation includes cultures and other techniques, such as immunostaining and polymerase chain reaction, for infection; serologic testing for syphilis, borreliosis, connective tissue disease, vasculitis, alpha-l-antitrypsin deficiency, calcium, phosphorus, oxalate, coagulopathy, lipase, amylase. 7. Directed clinical history for isolated lesion (eg, ruptured cyst), trauma, factitial causes, psychiatric illness, drug abuse, cold exposure, recent medications, systemic disease, eg, vasculitis, connective tissue disease, sarcoidosis, infections, malignancy.

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many panniculitides are fairly similar, (5) the response of adipose tissue to injury is limited, and (6) the histopathologic findings depend on when the biopsy is obtained during the time course of the disease process. Based on these points, skin pathologists often have tended to ascribe too much specificity to morphologic observations made on limited samplings taken from limited numbers of patients, often without considering when the specimen(s) were obtained in the natural history of the panniculitis. To gain a better understanding of the nature of pathologic processes in subcutaneous tissue, it is necessary to review briefly (1) the microanatomy of adipose tissue and (2) the reactions of subcutaneous fat to injury. In this chapter, we provide an overview and update of the findings of interest to the dermatopathogist in the diagnosis of panniculitis and fasciitis.

MICROANATOMY OF SUBCUTANEOUS FAT The subcutaneous tissue consists of depot fat sandwiched between the reticular dermis above and the superficial fascia beneath.1,2 Adipose tissue is organized into two compartments: (1) discrete round or ovoid lobules composed of confluent aggregates of the clearappearing fat cells and (2) fibrous trabeculae (or septa) that form a meshwork separating the individual fat lobules. The fibrous septa are continuous with collagen of the reticular dermis and the superficial fascia and contain all the blood vessels, lymphatics, and nerves of the subcutaneous fat. In one sense, the fibrous septa simply serve as scaffolding for vascular and nerve plexi traversing the subcutis from deeper tissue to supply the skin. Thus, inflammatory conditions affecting the fat often involve the reticular dermis and fascia, and vice versa. Arterial vessels in the fat are small to medium in size and are categorized as muscular arteries. Thus it is not possible to develop large-vessel arteritis in the subcutaneous fat but rather an arteritis affecting vessels of the caliber noted in polyarteritis nodosa. Each fat lobule is vascularized by a single arteriole and, in effect, is an end organ with no collateral blood supply.1,2 There are no lymphatics within the lobules. Any interruption to this arterial supply will eventuate in ischemia or infarction of the fat lobule depending on the speed with which vascular compromise develops. The individual fat cells

are supplied by arterial capillaries with drainage to venous capillaries and venules at the peripheries of the fat lobules. Based on these vascular patterns, in very general terms pathologic processes affecting arterial vessels may result in a “lobular” pattern of panniculitis versus a “septal” pattern associated with venular or venous inflammatory disorders.

REACTIONS OF SUBCUTANEOUS FAT TO INJURY Many of the morphologic changes observed in panniculitis are simply nonspecific reparative reactions of the fat tissues (ie, adipocytes ) and surrounding tissue to local injury, often irrespective of the particular etiologic agent1-5 (Table 11-2). For sometime it has been recognized that injury to the fat cells result in the release of lipid that becomes a foreign body or irritant. Also, recent results indicate that activation of adipocytes leads to the release of local mediators, such as eicosanoids and adipokines, that serve similar functions as chemokines and thus can elicit a local leukocytic infiltrates via chemotaxis.7 The ensuing host response is thus involved in removing this “foreign” substance or chemoattractants to restore the tissue to normal homeostasis. The initial reaction within seconds to minutes is the influx of neutrophils (acute inflammation) and then the local proliferation of blood vessels. The next phase of the tissue reaction is characterized by the arrival of mononuclear cells, that is, lymphocytes and monocytes/macrophages. The latter cells are concerned primarily with the phagocytosis

Table 11-2 Manifestations of Fat Necrosis Lipophages—macrophages containing phagocytosed lipid following necrosis of adipocytes Microcysts—coalesced tissue spaces in fat following fat necrosis Liquefactive alterations—granular cellular debris Hyalinizing (sclerosing) alterations— intact mummified lipocytes with a grainy and, at late stages, glassy amorphous appearance Membranous (lipomembranous) microcyst formation—microcysts lined by feathery, almost ciliated membranes Ischemic alterations—pallor of adipocytes with loss of nuclei and microvessels, hemorrhage, hemosiderin deposits, karyorrhexis

of the damaged adipocyte-released lipids and other debris which can often result in the formation of lipidized macrophages (foamy histiocytes) and multinucleate giant cells. The final histologic stage in this response to local injury of adipose tissue is fibroplasia and the eventual reconstitution of tissue integrity. The ultimate outcome in many instances is a scarring process. These three stages of the host reaction—acute inflammation, chronic inflammation, and fibrosis—are fairly constant but obviously may vary depending on the intensity and nature of the insult to the local fat tissues.

Major problems with traditional classification of panniculitis include the tendency to place too much emphasis on categorizing a process as either a septal or lobular panniculitis and the application of often arcane terminology, such as Weber-Christian disease or erythema induratum, to the condition rather than investigation for a specific cause. Indeed, many panniculitides may be either septal or lobular, and probably most are both septal and lobular; thus this pattern approach often adds little additional

SEPTAL PANNICULITIS As stated above, the goals of the histopathologist are to systematically evaluate a mainly septal process (see Fig. 11-3) for histopathologic findings or clues leading to a specific diagnosis if at all possible1-9 (see Tables 11-3 and 11-5). Such alterations include vasculitis; prominent sclerosis of septa as in morphea, scleroderma, and eosinophilic fasciitis; lymphoid infiltrates or nodules, as in connective tissue disease; lymphoid infiltrates and hyalinization, as in lupus panniculitis; infectious agents; foreign bodies; and palisading granulomas. If no characteristic features are observed, one is often left with a nonspecific panniculitis. Based on the cellular composition and degree of fibrosis, the septal panniculitis may be categorized as (1) an acute process, that is, neutrophils, eosinophils, edema, little or no septal thickening, (2) a subacute panniculitis (predominantly mononuclear cells), that is, presence of lymphocytes, monocytes/macrophages, some septal thickening, and fibrosis, or (3) a chronic or late-stage septal panniculitis with clear septal thickening and marked fibrosis. Many processes may produce a nonspecific predominantly septal panniculitis, particularly in the early stages (see Table 11-4).

CHAPTER 11 ■ PANNICULITIS

PANNICULITIS: APPROACH TO THE INTERPRETATION

information to the diagnostic evaluation when, in fact, it is not so important as looking for a cause of the panniculitis (Figs 11-1 and 11-2 and Table 11-3). The overall objective of this chapter is to emphasize the systematic evaluation of panniculitis for a specific etiology and to discourage the use of outdated terminology. The use of outdated terms can, if anything, obfuscate the rational investigation of disorders of adipose tissue. The objectives of the histopathologist when confronted with a disease process in subcutaneous fat are (1) to identify the predominant pattern as septal or lobular, or both septal and lobular, without placing too much emphasis on this exercise (Table 11-4), (2) to identify whether there is any alteration of the epidermis, dermis, or fascia; and (3) to look for particular histologic findings that would indicate or suggest a specific diagnosis (see Table 11-3). The histopathologic findings must then be correlated with clinical history and laboratory studies. The evaluation of panniculitis will be approached using the major categories of septal panniculitis and lobular panniculitis, realizing that this categorization is often of limited value because many processes may be septal or lobular or show varying degrees of both septal and lobular involvement.

Panniculitis

Fasciitis: eosinophilic fasciitis and related disorders; borreliosis; nonborrelial

Neutrophils, edema: infection; neutrophilic dermatosis

Epidermal and/or dermal alterations

Interface changes, dermal mucin: lupus panniculitis

Dermal sclerosis: morphea, scleroderma

Panniculitis only (see Fig. 11-2)

Vasculitis

Small-vessel vasculitis (see Chap. 9)

Medium-sized vessel (see Chap. 9)

Artertis Polyarteritis nodosa Arteritis, not otherwise specified

Superficial migratory  FIGURE 11-1 Algorithmic Approach to Diagnosis of Panniculitis.

Thrombophlebitis

Venous insufficiency

251

Panniculitis only

Septal

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Erythema nodosum reactions

Short duration reactions

Other, early

Septal, lobular

Lymphoplasma cellular infiltrates: connective tissue disease

Chronic reactions

Crystals

Cytophagocytosis: Cytophagocytosis: cytophagic cytophagichistiocytic histiocytic panniculitis; panniculitis; immunosuppression: infection; infection;malignancy malignancy

Inflammation; crystals in macrophages; lipocytes: subcutaneous fat; necrosis; poststeroid panniculitis

Septal sclerosis: morphea; scleroderma

Granulomatous inflammation: infection; physical panniculitis; metastatic Crohn disease; pyoderma gangrenosum

Neutrophilicinfiltrates: infiltrates: Neutrophilic EN EN reactions; reactions; infection; infection; neutrophilic neutrophilicdermatosis; dermatosis; pyoderma pyodermagangrenosum; gangrenosum; physicalpanniculitis panniculitis physical

Little or no inflammation; crystals in lipocytes: sclerema neonatorum

 FIGURE 11-2 Algorithmic Approach to Diagnosis of Panniculitis.

In many cases, based on thorough evaluation of the patient and clinical history and follow-up, it is possible to identify a cause or presumed cause.

Erythema Nodosum

252

Ghost cells saponification: pancreatic panniculitis

Lobular

Thought by many clinicians to be a rather distinctive clinicopathologic entity,2-4,6-11 erythema nodosum (EN) is in fact a relatively nonspecific hypersensitivity reaction associated with a wide variety of causes (see Table 11-5) eventuating in fairly short-lived tender red nodules and raised plaques most often located on the extensor aspects of the legs.8-17 Streptococcal infections are the most common etiology in children, whereas sarcoidosis, drugs, and inflammatory bowel disease are among the most common causes in adults.18 In a recent review of the literature, upper respiratory tract infection was the most frequent cause of EN in adults, and in many parts of the world tuberculosis is still a common underlying condition. EN has now been shown to be the most prevalent cutaneous manifestation of inflammatory bowel disease, and about

15% of Crohn disease patients exhibit EN reactions.19 Of interest, EN may be the first manifestation of inflammatory bowel disease.20 EN may be thought of as a nonspecific clinical finding, perhaps analogous to urticaria or a maculopapular erythematous eruption. A major problem is that the clinical lesions are thought to be distinctive, almost regardless of the histopathologic findings. Histologic examination of the red nodules most commonly discloses a (predominately) septal panniculitis, but in some instances lobular infiltrates are observed. Thus the histologic spectrum associated with EN has expanded and now includes neutrophilic,9 eosinophilic,21 and granulomatous lobular infiltrates.10 Furthermore, the clinical spectrum of EN has been extended to encompass long-standing or chronic forms of panniculitis, termed chronic EN, EN migrans, or subacute nodular migratory panniculitis of Villanova and Piñol.18,22-26 However, some authors believe that chronic EN and EN migrans are related but have clinical and histopathologic differences.26 The term EN probably should be reserved for panniculitides that have been

thoroughly investigated and monitored for a specific etiology and show the appropriate clinical and pathologic features. CLINICAL FEATURES Typical EN is strictly defined as a rapid onset of symmetric crops of tender, bright-red nodules lasting usually 3 to 6 weeks and often resolving with a bruiselike appearance (erythema contusiformis) but always without ulceration, scarring, or atrophy3,4,8-13,18 (Fig. 11-3A) (Table 11-6). Recurrence is not uncommon.18 The bruiselike progression and appearance is very characteristic of EN.18 The lesions may occur anywhere but characteristically involve the ankles, knees, and anterior shins. Women are afflicted three to six times more often than men.18 The age typically ranges between 20 and 50 years, with the peak incidence between 20 and 30 years of age.18 However, EN can occur at any age.18 Often the lesions are accompanied by abdominal pain, arthralgias, cough, diarrhea, fever, headache, malaise, and vomiting.11,18 Chronic EN and EN migrans appear to represent hypersensitivity reactions of longer duration, often 1 to 4 years or

Table 11-4 Predominant Patterns of the Panniculitides

Vasculitis Small-vessel vasculitis Thrombophlebitis Polyarteritis and other arteritides Calcification of vessels Calciphylaxis Thrombotic occlusion of vessels Coagulopathy Cryoprecipitate Septal sclerosis Morphea profunda Scleroderma Eosinophilic fasciitis Lymphoplasma cellular infiltrates Connective tissue disease Lupus panniculitis Dermatomyositis Connective tissue panniculitis Lipoatrophy Necrobiosis lipoidica Hyalinization and lymphoplasmacellular infiltrates Lupus panniculitis Infectious organisms Palisading granulomas Granuloma annulare Rheumatoid nodule Necrobiosis lipoidica Panniculitis with crystal formation Subcutaneous fat necrosis Sclerema neonatorum Poststeroid panniculitis Oxalosis Gout Ghost cells, saponification Pancreatic (enzymic) panniculitis Cytophagocytosis Cytophagic histiocytic panniculitis Infection Lymphoma Sclerosing lipogranuloma Injected or implanted lipids Foreign bodies Chemical and factitial panniculitis Atypical cellular infiltrates Lymphoma Leukemia

Hypersensitivity reactions Short duration (erythema nodosum reactions) Longer duration (chronic EN) Vasculitis Small-vessel vasculitis Medium- to large-vessel vasculitis Lipodermatosclerosis

more.22-26 Some authors maintain that chronic EN is characterized by fairly discrete, persistent nodules that are symmetric and not migratory, whereas EN migrans tends to show nodules that coalesce into spreading plaques that are commonly unilateral.26 HISTOPATHOLOGIC FEATURES Although erythema nodosum may be thought of

PATTERN OF PANNICULITIS

CONDITION

Septal → lobular Septal → lobular

Calciphylaxis Oxalosis Morphea profunda, scleroderma, eosinophilic fasciitis Palisading granulomas Alpha-l-antitrypsin deficiency Cytophagic histiocytic panniculitis Pancreatic panniculitis Subcutaneous fat necrosis Sclerema neonatorum Poststeroid panniculitis Infection-related panniculitis Physical panniculitis Cold panniculitis Trauma-related Chemical and factitial Connective tissue disease Lupus panniculitis Dermatomyositis Connective tissue panniculitis Eosinophilic panniculitis Noninfectious granulomatous panniculitis Sarcoidosis Metastatic Crohn disease Lymphoma and leukemia

as a nonspecific reaction resulting from a wide variety of agents, the histopathologic findings may be categorized as principally early, intermediate/established, or late stage8-13 (Figs. 11-3B and 11-4; see also Table 11-4). Early or acute lesions commonly show changes primarily confined to the fibrous trabeculae: edema, hemorrhage, and variable inflammatory cell infiltrates composed primarily of neutrophils, possibly with some admixture of lymphocytes and eosinophils (Table 11-6) (Fig. 11-3 and 11-4f). This infiltrate often extends into the peripheries of the fat lobules. Otherwise, the fat lobules are largely unaffected. Older lesions often exhibit some thickening of the septa and a predominance of mononuclear cells, lymphocytes in particular (see Fig. 11-4). There may be greater encroachment into the fat lobules by the inflammatory cell infiltrates. Often at this stage one

Septal → lobular Septal and lobular Septal and lobular Septal early Septal and lobular Septal and lobular Septal → lobular Septal early Septal → lobular Septal and lobular Lobular → septal Lobular → septal Lobular → septal Lobular → septal Lobular → septal Septal and lobular Septal and lobular Lobular → septal Lobular → septal

CHAPTER 11 ■ PANNICULITIS

Table 11-3 Histopathologic Findings Suggesting a Particular Category or Type of Panniculitis

Septal and lobular Septal and lobular Septal and lobular Septal and lobular

Septal and lobular Septal and lobular Lobular → septal

begins to encounter mononuclear cells arranged in a radial array and somewhat later multinucleate histiocytic giant cells in the thickened fibrotic septa, the so-called Miescher granulomas27 (see Figs. 11-4E). The latter feature is considered by some authors to be diagnostic or supportive of EN. It appears as a radially shaped granuloma with well-delineated, small collections of histiocytes surrounding a staror crescent-shaped fissure.18 However, this granulomatous reaction involving the fibrous trabeculae is likely to be a nonspecific reparative response associated with phagocytosis of collagen and other materials. With evolution of lesions, there is greater thickening and fibrosis of the septa. The infiltrate becomes more granulomatous, and there is a general tendency to greater involvement of the lobules.4,8,10 With time, there is gradual obliteration of fat lobules by the septal fibrosis.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

B

A

C  FIGURE 11-3 Erythema nodosum. (A) Erythematous plaques involving the lateral aspects of lower extremities below the knees and near the ankle. (B) Erythema nodosum reaction pattern. Acute erythema nodosum: Scanning magnification shows inflammation and extravasation of erythrocytes involving the fibrous trabeculae and peripheries of the fat lobules. The fat lobules are virtually uninvolved. (B and C) Acute erythema nodosum: Note that the fibrous septae are not significantly thickened at this stage.

Although some fat necrosis is observed occasionally, this is not a prominent feature in EN. To the extent that fat necrosis does occur, lipophages and granulomatous inflammation are present. Two additional reaction patterns observed in this setting of EN include (1) acute (neutrophilic) panniculitis9 (see Fig. 11-4F) and (2) eosinophilic panniculitis21 (see the heading later in the chapter). Both present as predominately lobular infiltrates of neutrophils and

254

eosinophils, respectively. The inclusion of panniculitides with the preceding histologic features speaks to the nonspecific nature of EN. By definition, vasculitis is not a major feature of EN. However, low-grade vascular injury and thrombophlebitis have been emphasized as findings commonly encountered in the EN reaction pattern.8 One must determine whether septal panniculitis or thrombophlebitis is the predominant finding and also consider

the clinical features in order to arrive at a final interpretation of their significance. Chronic EN and EN migrans have been reported to have histopathologic as well as clinical differences.26 Chronic EN has been described as showing discrete perivascular lymphocytic infiltrates and very little fibrosis and thickening of fibrous trabeculae. Characteristic findings of chronic EN also include extravasated erythrocytes and phlebitis.18 On the other hand, EN migrans may have septal thickening and

Table 11-5 Causes of Septal Panniculitis (Erythema Nodosum Reactions)

fibrosis, epithelioid granulomas with multinucleated giant cells, and vascular proliferation resembling granulation tissue.18 EN migrans does not have phlebitis or extravasated erythrocytes.18 These differences may represent a spectrum of the same pathologic process (EN) rather than two other distinct entities.18 DIFFERENTIAL DIAGNOSIS As already discussed, this reaction pattern is nonspecific,

Clinical Features Women > men Age 20-50 years Tender reddish nodules 3-6-week duration No ulceration or scarring—anterior shins most often Fever Malaise Arthralgias Bilateral hilar lymphadenopathy (Löfgren syndrome) Histopathologic Features Septal panniculitis Neutrophils, occasional eosinophils, followed by lymphocytes, mononuclear cells Edema, hemorrhage Thickening of septa Peripheral involvement of fat lobules Usually no fat necrosis Thrombophlebitis on occasion Lobular panniculitis Acute neutrophilic panniculitis Granulomatous panniculitis Usually minimal fat necrosis Differential Diagnosis Septal panniculitis Sclerosing panniculitis Connective tissue disease Many conditions early Lobular panniculitis Infection Neutrophilic dermatosis Sweet syndrome Pyoderma gangrenosum Vasculitis Calciphylaxis Physical and factitial panniculitis Alpha-l-antitrypsin deficiency Subcutaneous fat necrosis of newborn

since a number of processes may begin or present as a septal panniculitis. Thus one must consider connective tissue disease, infection, neutrophilic dermatoses (Sweet syndrome and pyoderma gangrenosum),16,28 physical insults, fibrosing panniculitides, and palisading granulomas in this differential diagnosis. Recently, a case of nephrogenic systemic fibrosis, seen in patient with end-stage renal disease, demonstrated histologic findings consistent with EN with several Miescher radial granulomas.29 Careful scrutiny of the specimen for histologic findings leading to one of the latter diagnoses, special stains for organisms,

evaluation with polarized light, serologic evaluation, and clinical history are needed to exclude specific causes of the panniculitis.

Vasculitis, Vasculopathy, and Ischemic Necrosis of Subcutaneous Fat As discussed previously, vascular injury is a common component and cause of panniculitis. Vessels ranging from capillaries to medium-sized arteries or veins may be involved.1-4,8 Thus the subcutis should be examined for leukocytoclastic venulitis, arteritis, as in polyarteritis nodosa, or thrombophlebitis. Vasculitis is discussed in detail in Chap. 9 and is beyond the scope of this chapter. In general, vasculitis should be assessed with respect to the caliber of the vessel involved; the type of vessel, that is, venule, arteriole, vein, or medium-sized artery; and the composition of the infiltrate, that is, the presence of neutrophils, eosinophils, lymphocytes, or granulomatous elements. The vasculitis must be correlated with the extent of systemic involvement, that is, other organs involved. The patient must be evaluated for infection, connective tissue disease, inflammatory bowel disease, or other systemic disease. Terms such as nodular vasculitis should be discouraged because they may impede thorough investigation of the patient for a specific etiology and may be confused with other entities (specifically, nodular vasculitis is also called erythema induratum of Bazin).30 A vasculitis or arteritis without obvious cause is best designated as such and the patient followed with the goal of eventually identifying a cause of the process. Ischemic fat necrosis is the end result of interruption of the vascular supply to fat lobules from any cause. Potentially any type of vasculitis or intravascular occlusive process can result in ischemic necrosis of fat. The latter entities, which include hypercoagulable states and other occlusive vasculopathies, are discussed in Chap. 9. However, three distinctive forms of ischemic fat necrosis will be discussed in this chapter: sclerosing panniculitis, calciphylaxis, and oxalosis.

CHAPTER 11 ■ PANNICULITIS

Sarcoidosis Streptococcal infection Mycobacteria Tuberculosis Leprosy Gastrointestinal infections and infestations Yersiniosis Salmonellosis Campylobacter colitis Shigellosis Deep fungal infections Coccidioidomycosis Histoplasmosis Blastomycosis (North American) Deep trichophytosis Other infections Ornithosis Cat-scratch disease Syphilis Gonorrhea Lymphogranuloma inguinale Other chlamydial infections Infectious mononucleosis Inflammatory bowel disease Crohn disease Ulcerative colitis Hormonal causes Pregnancy Contraceptive pills Malignancies Leukemias Carcinomas Sarcomas Hodgkin disease Drugs Iodine Bromine Sulphathiazole Penicillin Phenacetin Pyritinol Other causes Periarteritis nodosa Sweet syndrome Behçet disease

Table 11-6 Erythema Nodosum

Lipodermatosclerosis CLINICAL FEATURES Lipodermatosclerosis is a distinctive clinicopathologic entity associated with striking induration of the distal third of the lower extremity and ischemic fat necrosis.31-33 The condition is observed most commonly in

255

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

B

C

D

E

F

 FIGURE 11-4 Erythema nodosum reaction pattern. (A-C) Well-developed erythema nodosum. The fibrous trabeculae are thickened by fibroplasia. (D) Higher magnification showing thickened fibrous trabeculum. (E) Inflammatory cell infiltrates are present at the periphery of fat lobules. (F) A thickened fibrous septum contains Miescher granulomas. (G) Acute neutrophilic lobular panniculitis associated with clinical presentation of erythema nodosum.

256

 FIGURE 11-4 (Continued.)

adult women with a history of venous insufficiency and stasis of one or both of the lower extremities, often resulting from superficial or deep thromboses, thrombophlebitis, arterial ischemia, or varicosities 30-34 (Table 11-7). The stasis causes decreased flow in the capillaries of the lobules, leading to ischemia and centrolobular necrosis of the fat. 30 Characteristically, the distal

Table 11-7 Lipodermatosclerosis

Clinical Features Adult women > men Venous insufficiency Stasis Thromboses Erythematous, edematous indurated plaques with “inverted bottle” appearance, distal lower extremities above ankles Histopathologic Features Stasis dermatitis Septal and lobular involvement Perivascular lymphocytic infiltrates Ischemic fat necrosis Pallor of adipocytes, loss of nuclei Karyorrhexis, hemorrhage, hemosiderin deposition Progressive fibrosis, obliteration of fat lobules and vessels Lipomembranous fat necrosis Fat microcysts Differential Diagnosis Septal panniculitides (erythema nodosum) Other fibrosing panniculitides Lupus panniculitis Morphea profunda, fasciitis Physical panniculitis

third of the lower extremities is affected by circumferential, erythematous, edematous, telangiectatic woodlike plaques that give place to hyperpigmented, indurated, depressed lesions that have a characteristic “inverted bottle” appearance resulting from atrophy of the subcutaneum secondary to deep fibrosis.30 Vascular damage early in this process causes blood vessel fragility and hemorrhage into the dermis, which causes the skin to appear a red-brown color.35 Lipodermatosclerosis has been recognized clinically for many years under a variety of terms, including hypodermitis sclerodermiformis, membranous lipodystrophy, lipomembranous fat necrosis, lipomembranous change in chronic panniculitis, stasis-associated lipomembranous panniculitis (SALP), and stasis-related (or associated) sclerosing panniculitis.33-38 HISTOPATHOLOGIC FEATURES The epidermis and dermis commonly show stasis dermatitis with variable acanthosis, spongiosis, lobular vascular proliferation, fibroplasia, dermal atrophy, and hemosiderin deposition.30-32 The panniculitis is septal and lobular, and the histopathologic findings are related to the age of the lesion (see Table 11-7). At any age, however, the superficial dermis will show stasis dermatitis, and the papillary dermis will show increased numbers of capillaries and venules.30 Early lesions show perivascular lymphocytic infiltrates involving the fibrous trabeculae and the peripheries of fat lobules. At this stage, ischemic fat necrosis is typified by pallor of and loss of nuclei in adipocytes in the central part of the fat lobule; loss of lobular vessels; and variable karyorrhexis, extravasation and degeneration of erythrocytes, and hemosiderin

DIFFERENTIAL DIAGNOSIS Early lesions may be confused histologically with almost any septal panniculitis; however, the clinical features with evidence of venous insufficiency and stasis should provide evidence in favor of lipodermatosclerosis and the exclusion of other conditions. More developed lesions may be difficult to distinguish from lupus profundus and other fibrosing panniculitides. Lipodermatosclerosis shows ischemic fat necrosis, whereas lupus profundus is notable for prominent lymphoplasmacytic

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G

deposits within and outside of the macrophages.33,34 The endothelium of the vessel walls is thicker in the early stages.39 The presence of pericapillary fibrin cuffs has been shown not to act as a barrier to oxygen flow between capillaries and tissues, as was supposed originally.39 With time, there is progressive fibrosis and sclerosis of septa and gradual obliteration of fat lobules (Fig. 11-5A). The inflammatory infiltrates show an admixture of lymphocytes, macrophages, some lipidized, and plasma cells. Lipophagic granulomas are not uncommon around the fat lobules.30 Necrosis of fat with microcysts is also observed with evolution of the process. Later stages of these lesions show sclerosis of the septa as the main finding with little or no inflammation.30 A finding commonly observed in this context but not specific for this entity is membranous (pseudomembranous, lipomembranous, or membranocystic) fat necrosis33,36,37,40,41 (Fig. 11-5B). The latter change refers to cystic spaces in areas of fat necrosis that are lined by eosinophilic, feathery, crenulated membranous structures suggesting the cuticle of a parasite. These membranes stain with periodic acid–Schiff (PAS)-diastase and the lipid stains Sudan black and Luxol fast blue. Ultrastructurally, the membranes are composed of tubular structures containing neutral fat corresponding to the breakdown and collapse of lipocytes. Although membranous fat necrosis is perhaps observed most commonly in ischemia, it also has been reported in a variety of other settings, including traumatic injury and connective tissue disease.37,40 Elevated expression of urokinase-type plasminogen activator and its receptor CD87 has been reported as a possible early step in lipodermatosclerosis and other venous stasis disorders through activation of matrix metalloproteinase-2 (MMP2).42 MMP2 is an interstitial collagenase thought to contribute to the development of the ulcers found in advanced lipodermatosclerosis.42-44

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A

B

 FIGURE 11-5 Lipodermatosclerosis. (A) There is obliteration of fat lobules by hyalinized fibrous tissue. There is relatively little inflammation at this late stage. (B) There is prominent lipomembranous alteration resulting in a feathery membrane in this fat lobule. The latter changes are nonspecific.

infiltrates and hyalinizing fat necrosis. Morphea and related conditions should not show stasis changes, dermal atrophy, and ischemic necrosis to the degree observed in lipodermatosclerosis. The clinical manifestations should easily allow distinction of even late-stage sclerosing panniculitis from collagen-vascular disease.

Calciphylaxis A rare syndrome of vascular calcification and ischemic necrosis has been recognized for almost a hundred years, yet its pathophysiology remains poorly understood.46-55 Patients presenting with this dramatic condition often have a systemic disease commonly associated with perturbation of calcium and/or phosphorus metabolism, such as chronic renal failure and/or renal transplant, primary or secondary hyperparathyroidism, idiopathic hypercalcemia, or hypervitaminosis D.30,47-51,54,55 However, rare patients without any of the latter conditions or abnormal calcium or phosphorus levels have been reported.54 Although Selye described many features of the syndrome in an animal model, the mechanisms responsible for triggering ischemia and necrosis have yet to be fully elucidated.46,54 Possible etiologic factors include (1) endovascular fibrosis and calcification of small vessels, (2) a hypercoagulable state, and (3) luminal narrowing by calcification. Risk factors include AIDS, arterial hypertension, calcium/phosphate imbalance, Caucasian race, chronic dialysis, corticosteroid use, Crohn disease, diabetes mellitus type 1, female gender, hypotension, liver disease (including hypoalbuminemia),

malnutrition (including morbid obesity) and overload of iron, peripheral vascular disease, polycythemia, posthemodialysis metabolic alkalosis, protein C or protein S deficiency, recent weight loss, localized trauma, and/or warfarin use.30,52,,56-58 Controversy exists about the name calciphylaxis, but until a consensus can be reached on another name, it will continue to be used. It is also known as azotemic or uremic calcific arteriolopathy, calcifying panniculitis, uremic gangrene syndrome, and vascular calcification—cutaneous necrosis syndrome.56,58 CLINICAL FEATURES The clinical manifestations of calciphylaxis are distinctive.47-55 Patients usually develop painful erythematous to dusky lesions that undergo necrosis in a background of livedo reticularis (Table 11-8). Bullae have been reported occasionally.30 The lesions are often bilateral and may involve the trunk and extremities. Radiographic examination commonly reveals vascular calcification of large vessels, the so-called pipe-stem pattern of calcific medial stenosis, which is nonspecific. Small-vessel (<.5 mm) calcification is more specific.54,55 The mortality rate has been reported to be as high as 80%.29 HISTOPATHOLOGIC FEATURES Calcium phosphate deposits are found in the intimal and medial layers of small to medium-sized blood vessels of the subcutaneous fat and reticular dermis.57 The vascular calcification and endovascular fibrosis are thought to be the precipitating factors leading to ischemia.30 In established lesions, mural calcification of small vessels ranging in size from 30

to 600 (average about 100) μm is observed54,55 (see Table 11-8). The vessels also exhibit a distinctive yet nonspecific intimal proliferation, which has

Table 11-8 Calciphylaxis

Clinical Features Abnormalities of calcium and/or phosphorus metabolism Chronic renal failure Primary or secondary hyperparathyroidism Protein C deficiency Livedo reticularis Painful inflammatory nodules that ulcerate Vascular calcification Histopathologic Features Small vessels (30-600 μm) show: Mural calcification Intimal proliferation Soft-tissue calcification Fibrin thrombi, variable Ischemic fat necrosis Mixed inflammatory cell infiltrates involving panniculus with neutrophils and mononuclear cells Differential Diagnosis Other calcifying panniculitides (dystrophic and metastatic calcification) Connective tissue disease Peripheral vascular disease, sclerosing panniculitis Cholesterol emboli Marantic and septic emboli Oxalosis Intravascular thrombotic and occlusive vasculopathies Vasculitis Infection Pyoderma gangrenosum

may occur as a primary inherited autosomal recessive metabolic enzyme defect or as a secondary metabolic condition resulting from excessive ingestion of oxalate and other substances, such as glycolic acid and ethylene glyocol.30,63 Secondary oxalosis may follow longterm hemodialysis, deficiency of pyridoxine, methoxyflurane anesthesia, resection of the ileum or other disease of the intestines, or intravenous xylitol or glycerol.30,64 Secondary oxalosis is also associated more commonly with cutaneous involvement than primary oxalosis.30 The clinical manifestations include hyperoxaluria, nephrolithiasis, nephrocalcinosis, renal failure in many cases, and widespread tissue deposition of calcium oxalate. Death is not uncommon. CLINICAL FEATURES Patients often have late-stage renal failure. Those with primary oxalosis manifest livedo reticularis and acral cyanosis, which can lead to ulcerated lesions60-62 and a necrotizing cutaneous syndrome that may be fatal.34 In secondary oxalosis, calcium oxalate often deposits in a miliary pattern on the palmar surfaces of the fingers.20

Oxalosis

HISTOPATHOLOGIC FEATURES Histologically, the findings are similar to calciphylaxis; there is ischemic fat necrosis with birefringent oxalate crystals in the walls of small blood vessels situated in the deep dermis and subcutaneous fat. In primary oxalosis, biopsies show calcium deposits and crystals of oxalate in the vessel walls, similar to that seen with calciphylaxis.30 Involved blood vessels may contain thrombi.30 Granulomatous inflammation occurs in the middle and upper dermis around the large collections of calcium crystals in secondary oxalosis.30,34 The crystals are yellow-tan and have a rod- or diamond-shaped or radial appearance.34 The microscopic appearance of the crystals is characteristic; however, the nature of the crystals may be confirmed by a histochemical method (oxalate is incinerated to carbonate, and the resulting calcium carbonate is stained with alizarin red S),60,61 infrared spectroscopy, x-ray diffraction, or scanning electron microscopy. The crystals are resistant to formalin fixation and embedding in paraffin. They are seen as black deposits when stained with Pizzolato calcium oxalate stain.34

An extremely rare form of panniculitis associated with deposition of the crystalline material calcium oxalate in vessels may closely resemble calciphylaxis.60-62 Oxalosis, also known as hyperoxaluria,

DIFFERENTIAL DIAGNOSIS In general, the same group of disorders should be considered as mentioned under the differential diagnosis for calciphylaxis.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes peripheral vascular disease, atheroemboli, Monckeberg medial calcific sclerosis, cryofibrinogenemia, marantic and septic emboli, oxalosis, intravascular thrombotic and occlusive vasculopathies (protein C deficiency, warfarin necrosis, circulating lupus anticoagulant, cryoprecipitates, disseminated intravascular coagulation), vasculitis including livedoid vasculitis, pyoderma gangrenosum, lipodermatosclerosis, and infection-related panniculitis, as well as other variants of dystrophic and metastatic calcifying panniculitis.58 The clinical presentation and the presence of small-vessel calcification with endovascular proliferation and fat necrosis should allow distinction from the latter entities. Benign nodular calcification is also in the differential diagnosis, but lesions will disappear with resolution of the abnormal serum calcium and phosphate levels.29

Thrombophlebitis Two principal forms of thrombophlebitis are associated with panniculitis: (1) superficial migratory thrombophlebitis and (2) thrombophlebitis secondary to venous insufficiency.64,65 The first condition occurs more often in men than in women and is characterized by multiple discrete tender nodules most commonly involving the lower extremities but occurring anywhere. These lesions tend to develop in crops and last 1 to 3 weeks. The nodules tend to be smaller than those in conventional panniculitis, for example, as in EN, and have a linear pattern. The nodules may change location along the vein from day to day because several segments of the vein may be affected, leading to use of the term migratory.18 In general, patients have few complaints, and ulceration does not occur. There tends to be a ropelike thickening of the skin above the involved vein.18 This form of thrombophlebitis often develops in association with hypercoagulable states, Behçet syndrome, Buerger disease, malignancy (Trousseau sign), for example, gastric or pancreatic carcinoma, and especially venous insufficiency.18 Histologically, small to mediumsized veins show thrombosis, prominent infiltration of the vessel wall by mixed inflammatory cell infiltrates, and with time varying degrees of fibrosis of the wall. The infiltrate contains neutrophils in early lesions and lymphocytes and histiocytes in later lesions. The veins affected are usually larger than those involved by other forms of panniculitis. This form of thrombophlebitis is notable for little or no inflammatory reaction (panniculitis) in the surrounding fat. Thrombophlebitis associated with venous insufficiency is more common in women and usually characterized by much more extensive panniculitis involving fat lobules.4,65

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been identified in arteries, arterioles, and capillaries.58 A regular finding is the presence of fibrin thrombi in vessels. The adipose tissue generally shows foci of intralobular calcification and ischemic lobular fat necrosis, as well as variable mixed inflammatory cell infiltrates containing neutrophils and mononuclear cells.30 Recently, osteopontin (OPN), a noncollagenous protein, has been identified in affected calciphylactic blood vessels.59 Thrombospondins (TSPs), particularly TSP-1 (a group of proteins native to bone osteoid), have been found adjacent to calciphylactic vessels but not in the affected vessels themselves.59 A third protein, matrix glutamic acid protein (MGP), is normally related to vascular cell differentiation and has been found to be upregulated in calciphylactic blood vessels.59 These three proteins are not normally expressed in blood vessels, but in addition to being localized in calciphylactic vessels, they have also been found in atherosclerotic vessels, suggesting a possible common mechanism.59 Three-dimensional analysis has been performed recently on a postmortem calciphylactic plaque. This analysis revealed a circumferential ring of vascular calcification surrounding an intravascular thrombus, suggesting that the calcification preceded the thrombus formation.45

Morphea Profunda, Scleroderma, Eosinophilic Fasciitis (Shulman Syndrome) Morphea, scleroderma, and eosinophilic fasciitis may show prominent involvement of subcutaneous fat as well as the dermis and fascia.2,4,66-76 Although there are clinical and histopathologic features shared by morphea, scleroderma, and eosinophilic fasciitis, there are also substantial differences among these entities.67-70 There is still no consensus as to whether eosinophilic fasciitis is simply a deep variant of morphea/scleroderma or a distinct entity. Eosinophilic fasciitis has been associated with drugs, vigorous exercise,

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Borrelia infection, and malignancy, a rare paraneoplastic phenomenon most often associated with hematopoietic malignancies. Recently this phenomenon has been described in a patient with metastatic colorectal carcinoma and where the symptoms of eosinophilic fasciitis preceded the diagnosis of metastatic colorectal carcinoma. It was also noted in these cases that the symptoms of eosinophilic fasciitis were not responsive to corticosteroids.77 The term fasciitis-panniculitis syndrome has been proposed to describe this sclerosing reaction pattern that occurs in a number of conditions, including morphea profunda, eosinophilic fasciitis, toxic oil syndrome, tryptophan-related fasciitis or eosinophilia myalgia syndrome, sclerodermoid graft-versus-host reaction, and cancer-associated fasciitis panniculitis.76,78 The authors proposing the latter reaction pattern have suggested that this syndrome is distinct from scleroderma.76 Although this hypothesized reaction pattern has merit, further study is needed to validate the extent of this reaction pattern. Tryptophan-related fasciitis (the eosinophilia-myalgia syndrome) refers to a disorder with features of morphea, scleroderma, and eosinophilic fasciitis occurring after ingestion of l-tryptophan.79 Cancer-associated fasciitis panniculitis appears to be a rare paraneoplastic phenomenon occurring in adult patients with a predominance of hematopoietic malignancies.78 In addition, it is possible that morphea and eosinophilic fasciitis developing in some patients is related to borrelial infection.80,81 CLINICAL FEATURES These conditions usually present with pitting edema followed by cutaneous indurations and a typical “bound down” quality (Table 11-9). In the case of morphea, the lesions are generally well-circumscribed guttate (< 10 mm in diameter) or oval plaques most commonly found on the trunk or occasionally linear processes (coup de sabre) that commonly involve the lower limbs.82 The plaques often have an ivory appearance with an erythematous or purple border. Scleroderma is characterized by diffuse cutaneous induration principally involving the trunk and upper limbs that leaves atrophic, hyperpigmented areas when healed.18 Eosinophilic fasciitis is distinctive and usually typified by a sudden onset following stress or intense exercise. The extremities are involved most frequently and demonstrate an extensive sleeve like circumferential, symmetric induration with dimpling of the skin and have a peau d’orange appearance.18,82 A peripheral eosinophilia is present in

Table 11-9 Morphea Profunda, Scleroderma, Eosinophilic Fasciitis

Clinical Features Pitting edema early Cutaneous induration Plaques, linear lesions Sleeve-like circumferential pattern Diffuse Histopathologic Features Lymphoplasma cellular infiltrates, occasionally dense, involving fibrous trabeculae Sclerosis, thickening of fibrous trabeculae Progressive obliteration of fat lobules Variable sclerosis of dermis, fasciitis Occasional eosinophils, mucinosis Lymphocytic vasculopathy, vasculitis Differential Diagnosis Lupus panniculitis Borrelial infection Other fibrosing panniculitides, sclerosing panniculitis Necrobiosis lipoidica

up to 60% of patients.67-69,82 The face, fingers, and feet are usually spared.82 Patients usually improve gradually with or without treatment.18 Many recover completely over a period of a few years, yet others may develop hematologic or myelodysplastic disorders or other associated complications.18,81

HISTOPATHOLOGIC FEATURES The involvement of the panniculus by these disorders is characterized by two principal features67-81 (Figs. 11-4 and 11-5): (1) inflammatory infiltrates localized to the fibrous trabeculae composed principally of lymphocytes and plasma cells with a variable admixture of eosinophils, neutrophils, and mucinous edema and (2) a progressive sclerosis of the fibrous trabeculae (see Fig. 11-6) resulting in the obliteration of the fat lobules in the final stages (see Table 11-9). The septal sclerosis is often continuous, with sclerosis involving the reticular dermis, fascia, and perimysium. The septa and fascia show progressive hypertrophy and hyalinization of the collagen fibers as in the dermis. Collagen is also deposited in place of the normal fat surrounding the eccrine glands, which causes them to incorrectly appear as though they are in the dermis.18 Edema and inflammatory infiltrates generally are most prominent in the initial stages and have a perivascular and septal localization with involvement of the peripheries of the fat lobules. The lymphoplasma cellular infiltrates also vary in density from sparse infiltrates to large nodules with germinal centers. While the “center of gravity” for the disease activity of morphea and scleroderma is frequently the interface of the reticular dermis and subcutis, the focus of eosinophilic fasciitis and related processes is the fascia (Fig. 11-7) and immediately contiguous deep adipose

 FIGURE 11-6 Morphea. The fibrous septa are markedly thickened and sclerotic with inflammation at the periphery of the fat lobules.

complement in the walls of blood vessels in the area of the lesions and in addition, Glut-1 expression in the areas of the sclerotic collagen.84 Pandermal involvement by zonal necrosis (necrobiosis) with palisading infiltrates and the typical clinical features of necrobiosis lipoidica should facilitate this discrimination.

LOBULAR PANNICULITIS

tissue (see Fig. 11-6). Morphea and scleroderma often show progressive involvement of the entire panniculus (including blood vessels, nerves, and other adnexae except arrector pilae muscles) and occasionally the fascia (termed morphea profunda).18 Conversely, eosinophilic fasciitis commonly progresses to involve the upper subcutaneous fat and reticular dermis. It also may show lymphoid follicles in the septa on occasion and eosinophils in the fascia.18 Tissue eosinophilic infiltrates range from none to marked. There also is frequent edema, hemorrhage, and variable mucin deposition. Vascular damage is observed commonly as fibrinoid deposition, thrombosis, lymphocytic vasculitis, or uncommonly as a necrotizing vasculitis. On occasion, spirochetes consistent with borrelial organisms can be demonstrated with silver stains, such as the Warthin-Starry reaction.80,81 DIFFERENTIAL DIAGNOSIS Long-standing septal panniculitis of any cause may result in septal thickening and fibrosis that may suggest morphea or scleroderma. However, other septal panniculitides generally do not show the degree of septal thickening or sclerosis, the associated involvement of the dermis or fascia, and the frequency of lymphoplasma cellular infiltrates observed in morphea and related process. Lupus panniculitis may show

considerable similarity on occasion because of dermal and septal sclerosis, lymphoplasma cellular infiltrates, mucin deposition, and a vasculopathy.83 However, lupus panniculitis differs from morphea/scleroderma because of prominent hyalinization of connective tissue, adipocytes, and vessels and a lesser degree of septal sclerosis. Epidermal and dermal involvement by lupus and clinical information are also helpful in distinguishing lupus panniculitis from morphea.

Panniculitis Associated with Palisading Granulomas Granuloma annulare, necrobiosis lipoidica, rheumatoid nodules, and rheumatic nodules may localize to the panniculus with the fibrous trabeculae, the initial site of involvement.4 The disease process often extends into the periphery of fat lobules with possible obliteration of the lobules by the disease process. These entities are discussed in greater detail in Chap. 6. DIFFERENTIAL DIAGNOSIS Necrobiosis lipoidica in some instances may prove difficult to distinguish from morphea profunda/fasciitis and lupus panniculitis because of septal fibrosis and degenerative changes, lymphoplasma cellular infiltrates, and vascular injury. New findings have shown the presence of IgM and

CHAPTER 11 ■ PANNICULITIS

 FIGURE 11-7 Eosinophilic fasciitis. The fascia is thickened and shows infiltration by inflammatory cell infiltrates containing lymphocytes, plasma cells, and eosinophils.

Many disease processes may eventuate in a predominately lobular panniculitis.1-5,9,10,85-87 However, as already mentioned, many of these panniculitides also may be septal initially, remain septal, or display both septal and lobular patterns. In a large proportion of cases, the lobular panniculitis is entirely nonspecific. However, the particular features observed in any given biopsy, while nonspecific, may be influenced by when the biopsy was taken in the natural history of the panniculitis and the severity of the insult to the fat. As already mentioned, early lesions tend to show predominately neutrophilic infiltrates, and older lesions, mononuclear cell infiltrates with lymphocytes, lipid-laden macrophages, granulomatous elements, and finally, fibrosis. It is incumbent on the histopathologist to look for certain histopathologic features that are clues to diagnosis (see Table 11-3). The purpose of this section will be to outline the recognizable causes of predominately lobular panniculitis.

Weber-Christian Disease Historically, Weber-Christian disease (WCD) refers to recurrent crops of erythematous nodules on the lower limbs or trunk accompanied by fever, malaise, arthralgias, and fatigue.2,4,86-90 It has been called idiopathic lobular panniculitis, nodular panniculitis, idiopathic nodular panniculitis, and relapsing febrile nonsuppurative nodular panniculitis.30 These nodules occasionally discharge oily material and hence have been termed liquefying panniculitis.87 Women aged 30 to 60 years have been affected most commonly. Histopathologically, Weber-Christian disease has been reported to show a predominately lobular panniculitis, and the presence of numerous lipophages has been considered diagnostic. As mentioned previously, it is likely that WCD is entirely a nonspecific reaction pattern whose histologic picture varies according to the age of the lesion biopsied, for example, neutrophils early > mononuclear cells/lipophages > granulomas > fibrosis (Figs. 11-8). As will be outlined in the following sections, over

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A

B

C

D

E

F

 FIGURE 11-8 Lobular panniculitis. (A) Acute lobular panniculitis. The fat lobule shows prominent infiltration by neutrophils. These changes are nonspecific and may be associated with a wide variety of etiologies. (B) Acute lobular panniculitis. The adipocytes are separated by sheets of neutrophils. (C) Lobular panniculitis at a later stage of evolution and characterized by predominence of mononuclear cells infiltrating fat lobule. These changes represent the typical sequence of inflammation irrespective of etiology. (D) Lipidized macrophages diffusely infiltrate fat lobule. (E) Granulomatous inflammation involving fat lobules. (F) Later fibrosing stage of lobular panniculitis. Mononuclear and granulomatous infiltrates progressively subside and the fat lobule gradually undergoes fibrosis. (G) Endstage lobular panniculitis. The fat lobules are obliterated by fibrosis.

262

adipocytes. In some instances, particularly early in the disease, the clinical picture is similar to cellulitis.30 Patients may have other manifestations of the protease inhibitor deficiency such as emphysema, hepatitis, and acquired angioedema. Laboratory evaluation usually discloses a reduction in level of the serum alpha-1antitrypsin activity, although too few cases have been reported to make a definitive correlation.96 Resolution of the lesions results in atrophic scarring.30

 FIGURE 11-8 (Continued.)

the years, specific causes of WCD have been recognized and probably will continue to be identified. For example, when revisited, cases of WCD have been reclassified as alpha-1-antitrypsin deficiency panniculitis, cytophagic histiocytic panniculitis (CHP), erythema induratum of Bazin/nodular vasculitis, erythema nodosum, factitial panniculitis, pancreatic panniculitis, subcutaneous panniculitic lymphoma, superficial thrombophlebitis, and traumatic panniculitis.30,91 Recently WCD-like symptomes and findings were found in patients with detected mutations in the TNFRSF 1A gene, coding for the p55 TNF receptor. Mutations in this gene are the cause of tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS), with an unbalanced TNF alfa action.92 Beyond acknowledging WCD as a historical entity, the term should probably be abandoned. If no cause of a particular panniculitis can be established, the process should be designated lobular panniculitis of unknown etiology, and the patient should continue to be evaluated and monitored. In the following section, specific causes of predominately lobular panniculitis (or mixed septal and lobular panniculitis) will be detailed. As mentioned below, many of these conditions may show septal panniculitis as the predominant finding.

Alpha-1-Antitrypsin Deficiency Severe homozygous deficiency of the protease inhibitor alpha-1-antitrypsin may result in a recurrent ulcerating lobular panniculitis thought in the past to be WCD.93-95 Alpha-1-antitrypsin, which is synthesized in the liver, is the major inhibitor of serine proteases circulating

in the blood. The deficiency of alpha-1antitrypsin is thought to result in unopposed proteolytic activity and the promotion of inflammatory reactions. CLINICAL FEATURES There is often a history of tender, recurrent, erythematous, subcutaneous nodules associated with ulceration that involves the face, trunk, buttocks, and proximal extremities30,35,92-94 (Table 11-10). The nodules commonly follow trauma and exhibit drainage of clear or serosanguineous material. There also may be an exudate similar to necrotic

Table 11-10 Alpha-1-Antitrypsin Deficiency

Clinical Features Tender recurrent erythematous nodules Ulceration Drainage Cellulitis-like presentation Trunk, buttocks, proximal extremities Emphysema Hepatitis Acquired angioedema Histopathologic Features Lobular panniculitis Fat necrosis Neutrophilic infiltrates Septal panniculitis Liquefactive necrosis of septa, dermis Neutrophilic and macrophage infiltrates Laboratory Evaluation Reduced serum alpha-l-antitrypsin activity Differential Diagnosis Infection Physical and factitial panniculitis

CHAPTER 11 ■ PANNICULITIS

G

HISTOPATHOLOGIC FEATURES Two patterns of panniculitis have been described: (1) a lobular panniculitis with fat necrosis and (2) a septal panniculitis with proteolysis of collagen and necrosis of the fibrous trabeculae94 (see Table 11-10). The first pattern is commonly characterized by neutrophilic infiltration of fat lobules that may be focal but often is indistinguishable from other forms of lobular panniculitis. The entire fat lobule may be destroyed. The septal pattern of panniculitis also shows neutrophilic infiltration of fibrous septa of the reticular dermis but usually is accompanied by prominent numbers of macrophages.30 Concomitant lobular involvement with fat necrosis may or may not be present. An important feature is the presence of liquefactive necrosis of the dermis, which, along with a similar pattern in the fibrous septa, is thought to be characteristic of alpha-1antitrypsin deficiency panniculitis. As the necrosis progresses and scar formation ensues, the number of neutrophils and macrophages found on biopsy decreases.96 Having well-demarcated edges and being well localized are other unique features of alpha-1-antitrypsin deficiency.30 Vasculitis usually is not present on biopsy except in the necrotic areas surrounding the panniculitis.30 DIFFERENTIAL DIAGNOSIS The lobular form of alpha-1-antitrypsin deficiency may be indistinguishable from other lobular panniculitides, particularly those associated with infection and physical or factitial agents. Cultures, special stains, polaroscopy, clinical history, and laboratory evaluation of serum alpha-1-antitrypsin activity are needed to sort out these possibilities. Marshall syndrome is considered part of the clinical spectrum of alpha1-antitrypsin deficiency.30

Cytophagic Histiocytic Panniculitis and Subcutaneous Panniculitic Lymphoma For years these disorders have been poorly understood and classified. Until

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recently, it was believed that CHP was an early finding in a spectrum of diseases that eventuated in a subcutaneous lymphoma. However, cytophagic panniculitides presently are classified into two separate conditions.30 One is a genuine panniculitis, which retains the original name cytophagic histiocytic panniculitis.30 It is a prolonged systemic disease state that lasts from months to years.30 Complications may include recurrent ulcerating subcutaneous nodules, fever, generalized lymphadenopathy, hepatosplenomegaly, pancytopenia, liver dysfunction, a hemorrhagic diathesis, and purpura.30,97-105 Generally, these patients do not have evidence of active or dormant Epstein-Barr virus (EBV), and they respond well to prednisone or cyclosporine.30 The second condition is called subcutaneous panniculitic lymphoma.30 Patients with subcutaneous panniculitic lymphoma do not suffer from an actual panniculitis, although the clinical findings suggest panniculitis.30 This rare form of peripheral T-cell lymphoma presents as subcutaneous nodules mimicking conventional panniculitis in both children and adults.106-110 There is a slight predominance among females (1.4:1) but no major difference in the median age between genders.111 Patients usually experience a rapidly progressive clinical course often ending in death from a hemophagocytosis syndrome, but it may be protracted with multiple recurrences.30 Treatment with radiation or chemotherapy is usually not effective in altering the course.30 There is also a common association with EBV infection, whether active or latent.30 Subcutaneous panniculitic lymphoma is also known as subcutaneous panniculitic (or panniculitislike) T-cell lymphoma, panniculitis-like subcutaneous lymphoma with cytophagocytosis, and subcutaneous T-cell lymphoma.30,112-114 The Revised European-American Classification of Lymphoid Neoplasms (REAL) in the year 1997 classified subcutaneous panniculitic T-cell lymphoma as a “peripheral or mature T-cell neoplasm.”114 Patients with this lymphoma have less than 3-year median survival.114

Table 11-11 Cytophagic Histiocytic Panniculitis

Clinical Features Hemophagocytic syndrome often Immunosuppression, immune dysregulation Recurrent subcutaneous nodules—extremities commonly involved Fever Lymphadenopathy Hepatosplenomegaly Pancytopenia Liver dysfunction Hemorrhagic diathesis Often fatal Associated diseases Infections, particularly viral Lymphoproliferative disorders, usually T-cell Connective tissue disease Histopathologic Features Lobular panniculitis Monocyte-macrophage infiltration Phagocytosis of erythrocytes, platelets, lymphocytes by macrophages (“beanbag” cells) Extravasation of erythrocytes Infiltration by other cell types Septal panniculitis Atypical infiltrates in lymphoproliferative disorders Differential Diagnosis Infection Connective tissue diseases Lymphoproliferative disorder

and T-lymphocyte inflammatory infiltrates with “beanbag cells” (macrophages with erythrocytes and leukocytes within their cytoplasm) surrounding fat lobules in a mostly lobular panniculitis.30 The epidermis and dermis usually are uninvolved. In most cases of either CHP or subcutaneous panniculitic lymphoma, the principal finding is a lobular infiltration of the subcutaneous fat by T-lymphocytes and benign monocytes/macrophages (histiocytes) (Fig. 11-9). On occasion, the panniculitis shows a mainly septal pattern. This infiltrate shows phagocytosis of other cellular elements, for example, erythrocytes, platelets, lymphocytes, and neutrophils, and may extend to bone marrow30,97105,115,116 (see also Table 11-11). Histologically, the lymphoid cells most commonly infiltrate the fat lobules in a lacelike pattern or in sheets. This cellular population is cytologically banal in CHP but represents malignant T-lymphocytes in subcutaneous panniculitic lymphoma, which may originate from delta or gamma T cells.30,114 These atypical lymphocytes may be found forming a halo around necrotic adipocytes and express CD3, CD8, and other cytotoxic proteins but lack CD4.30 A cytokine phagocytosisinducing factor (PIF) secreted by other Tlymphocytes, which are CD4-positive, may be responsible for the prominent phagocytic properties of monocytes/ macrophages in this syndrome.116 These changes usually are accompanied by prominent extravasation of erythrocytes in the fat lobules, karyorrhectic debris,

CLINICAL FEATURES Patients with either CHP or subcutaneous panniculitic lymphoma usually present with recurrent large erythematous nodules involving the extremities but also occasionally the face and trunk (Table 11-11). The nodules may ulcerate and show ecchymoses.

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HISTOPATHOLOGIC FEATURES The original description of CHP included the following, which still applies today: histiocytic

 FIGURE 11-9 Cytophagic histiocytic panniculitis. High magnification shows phagocytosis of erythrocytes and leukocytes by macrophages in a fat lobule.

variable infiltration by other cells (such as lymphocytes, lipophages, plasma cells, and granulocytes), and possibly some fat necrosis. Hemophagocytosis occurring in association with other malignancies, such as acute leukemia, is usually minimal.115-119

Pancreatic Panniculitis A syndrome including pancreatic disease, subcutaneous fat necrosis, arthritis, lytic bone lesions, eosinophilia, and polyserositis has been recognized for over a century.120-128 This syndrome is associated most commonly with alcoholrelated acute pancreatitis but also has been associated with chronic pancreatitis, cholelithiasis, traumatic panniculitis, pancreatic cysts and pseudocysts, calculi of the pancreatic duct, acinar cell carcinoma, pancreatic adenocarcinoma, pancreatic divisum, unusual pancreatic infections (including a syphilitic gumma and tuberculosis), vasculopancreatic fistulas, and ingestion of sulindac.30 Pancreatic panniculitis has also been described in a child with nephrotic syndrome, caused by hypertriglyceridemia.127 The clinical lesions occurring in various organs are secondary to widespread or metastatic fat necrosis. The pathogenesis of these lesions, including those in the panniculus, is poorly understood but thought secondary to lipolytic enzymes released into the systemic circulation from the diseased pancreas.122 In particular, elevations of serum lipase and, to a lesser extent, amylase and other enzymes have been reported. Support for this etiology is twofold: First, pancreatic lipase has been found in areas of subcutaneous necrosis in these patients, and second, antilipase antibodies in these necrotic areas are reactive.30 Yet in vitro experimentation did not replicate panniculitis when serum high in pancreatic enzymes was incubated with subcutaneous fat.30 Since pancreatic panniculitis does not

CLINICAL FEATURES In contrast to other forms of panniculitis, pancreatic panniculitis is more common in men than in women (3:1) and generally presents as a tender, erythematous nodule or nodules on the lower extremities resembling or indistinguishable from EN4,120-125 (Table 11-12). The nodules often measure about 1 to 2 cm and commonly involve the anterior shins. The distribution of lesions, however, is often more wide-

Table 11-12 Pancreatic Panniculitis

Clinical Features Men > women Age 30-50 years Alcohol-related pancreatitis Pancreatic carcinoma Traumatic pancreatitis Fluctuant tender erythematous nodules Extremities, especially pretibial Buttocks Arthritis Polyserositis Histopathologic Features Early septal panniculitis with perivascular lymphocytic infiltrates Fat necrosis with ghost cells Basophilic alteration (saponification) Calcification Neutrophilic infiltration of fat lobules Mononuclear cells later Laboratory Evaluation Elevated lipase, amylase levels Differential Diagnosis Early septal panniculitides Infection

spread than typical EN. These lesions also may break down and drain a creamy, oily substance resulting from liquefactive necrosis.30 The ages of patients most commonly afflicted are in the range of 30 to 50 years. Patients commonly exhibit systemic involvement with fever, arthralgias, arthritis, and occasionally, widespread necrosis of fat, including the bone marrow. HISTOPATHOLOGIC FEATURES In the fully developed state, the histologic findings in pancreatic panniculitis are diagnostic4,120-125 (see Table 11-12). The fat lobules show a characteristic form of necrosis with formation of “ghost cells” (Fig. 11-10). The latter finding refers to necrotic adipocytes with intact but thickened eosinophilic cell walls and absence of nuclei. At the peripheries of necrotic foci with ghost cells, there is variable calcification, resulting in a basophilic lamellation that constitutes saponification, that is, formation of calcium soaps from the reaction of free fatty acids with ionizable calcium. Neutrophilic infiltration of fat lobules accompanies the fat necrosis and later gives place to mononuclear cells and granulomatous inflammation. The earliest lesions have been reported to show perivascular lymphocytic infiltrates without evidence of fat necrosis in a pattern resembling EN.121 Still other early lesions show what appears to be a mostly septal panniculitis thought to be initiated by vascular damage from pancreatic enzymes.30 Once damaged, endothelial leakage of these enzymes into the perivascular space allows enzymatic attack of adjacent fat lobules, causing the lobular pattern.30

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DIFFERENTIAL DIAGNOSIS Although the histologic findings of cytophagocytosis are distinctive, it is important that the patient and such lesions are assessed carefully for infection, connective tissue disease, lymphoproliferative disease, and other systemic disorders. It is important to differentiate between CHP and subcutaneous panniculitic lymphoma through cell surface protein markers and the specific histologic differences mentioned earlier. The presence of infection does not necessarily rule out malignancy.30 Patient follow-up is also important to determine the course of disease and modifications to treatment.

occur in every patient with pancreatitis, an additional underlying cause or causes for the panniculitis possibly await elucidation.30 The resemblance of the syndrome to connective tissue disease has prompted studies to identify an immune mechanism for tissue injury.123 The deposition of immunoglobulin and complement in the pleura and a reduced complement level in one patient provided some evidence for possible immune injury. The cutaneous lesions usually resolve simultaneously with cases of pancreatic inflammation.30 Subcutaneous lesions associated with cancer tend to be more chronic, recurrent, and ulcerative and may spread beyond the usual location of the lower extremities.30,128 Skin manifestations may precede the diagnosis of a pancreatic disease by several months, and with correction of the underlying pancreatic disorder the skin lesions fade away.127

DIFFERENTIAL DIAGNOSIS As mentioned earlier, early lesions may show nonspecific change suggesting a broad differential diagnosis, including vasculitides and EN.129 However, typical lesions showing fat necrosis with ghost cells and saponification are pathognomonic and should not be confused with other forms of panniculitis.129

CRYSTAL-RELATED PANNICULITIS (PANNICULITIS IN NEONATES AND CHILDREN ASSOCIATED WITH CRYSTAL FORMATION) Subcutaneous fat necrosis of the newborn (SFN),130-138 sclerema neonatorum (SN),120,133,135,139,140 and poststeroid panniculitis (PSP)141,142 are three forms of

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 FIGURE 11-10 Pancreatic panniculitis. (A) Lobular panniculitis. (B) The outlines of necrotic adipocytes are still maintained as so-called ghost cells.

panniculitis occurring in either neonates or children and showing crystallization of subcutaneous fat. The pathogenesis of this crystal formation remains poorly understood, but certain factors may contribute to its development. At least with respect to SFN and SN, the composition of the subcutaneous fat in infants differs from that in older individuals. In this age group, hydrolases that break down unsaturated fatty acids are released in unusual events, such as mild trauma.30 The large ratio of body surface area to weight combined with a higher ratio of saturated to unsaturated fatty acids compared with adults favors this release.30 Since saturated fatty acids have a higher melting point than unsaturated fatty acids, solidification (or crystallization) of fat may occur at lower temperatures. Additional factors that have some bearing on this phenomenon include prematurity, trauma, infection, fetal asphyxia, hypothermia, and other stresses. It should be pointed out that none of the latter factors have been consistently implicated in precipitating these diseases.

Subcutaneous Fat Necrosis of the Newborn CLINICAL FEATURES Full-term or postmature infants develop variably sized red to violaceous indurated nodules that are reasonably well circumscribed and not bound down to deep tissue (Table 11-13). The lesions are localized primarily to the

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B

cheeks, shoulders, back, buttocks, and thighs. The lesions usually develop in the first few days or weeks of life and generally resolve over 3 to 5 months with an excellent outcome in most newborns. Occasional infants develop an associated hypercalcemia that potentially can result in extensive calcification. This hypercalcemia has been suggested to be caused from increased prostaglandin E, parathormone, or extrarenal 1,25-dihydroxyvitamin D.143 It may be preceded by hypocalcemia in the first day of life and has been

reported up to 7 weeks after the onset of SFN.143 HISTOPATHOLOGIC FEATURES The epidermis and dermis generally are uninvolved. The most characteristic findings are patchy fat necrosis with crystallization of fat (Fig. 11-11; see also Table 11-13). Typically, macrophages and, to a lesser extent, lipocytes contain radially oriented needle-shaped clefts that correspond to triglyceride crystals dissolved during processing (Fig. 11-11). In addition to

Table 11-13 Crystal-Related Panniculitis SUBCUTANEOUS FAT NECROSIS (SFN) OF THE NEWBORN Clinical Features Full- or post-term Healthy Onset first few days or weeks

Reddish indurated nodules Cheeks, shoulder, back, buttocks Good prognosis Histopathologic Features Inflammation Needle-shaped clefts in macrophages and lipocytes Variable fat necrosis

SCLEREMA NEONATORUM

POSTSTEROID PANNICULITIS

Often premature Seriously ill Onset within 1 week of birth Widespread board-like induration Often fatal

Young children Healthy Onset days after stopping high-dose steroids

Little or no inflammation Crystals mainly in adipocytes

Similar to SFN

B

 FIGURE 11-11 Subcutaneous fat necrosis of the newborn. (A) There is a prominent lobular panniculitis. (B) The characteristic stellate clefting from triglyceride crystals is evident in the center of the field.

macrophages and foreign-body giant cells, other inflammatory cells, including neutrophils, lymphocytes, and plasma cells, may be observed. Early lesions may exhibit prominent neutrophilic infiltrates. The panniculitis is often septal and lobular, and it is important to emphasize that one may not detect the needle-shaped clefts in all cases of SFN. Furthermore, there may be prominent calcification of the fibrous trabeculae in some specimens. Frozen specimens or those not yet subjected to paraffin embedding show positive staining with lipid stains such as oil red O, and birefringent crystals may be observed when examined with polarized light. Later stages of SFN show septal fibrosis and calcification in fat lobules.30 DIFFERENTIAL DIAGNOSIS Poststeroid panniculitis is histologically indistinguishable from SFN, and thus one is dependent on clinical history to differentiate the two conditions. SN characteristically shows crystal formation in lipocytes and lacks inflammation. If crystals are not detected in SFN, one must exclude other forms of panniculitis, particularly infection or cold panniculitis. However, the clinical features of SFN should enable one to make the diagnosis without too much difficulty.

Sclerema Neonatorum CLINICAL FEATURES Neonates developing SN are often premature and develop the process within 1 week of birth (see Table 11-13). These newborns are usually seriously ill at the onset of SN, and many are dehydrated or undernour-

ished. In general, a widespread yellowwhite boardlike induration involves the entire cutaneous surface except the palms, soles, and scrotum.30 The process commonly begins on the lower extremities and progresses upward, causing immobility of limbs.30 There is a high mortality rate, often resulting from sepsis. Patients who recover from SN in the first week of life have no lasting complications or residual cutaneous manifestations of their illness.30 HISTOPATHOLOGIC FEATURES The findings in SN are fairly distinctive although there may be considerable histologic overlap with SFN. On gross examination, the subcutaneous fat is greatly thickened and has a firm, lardlike consistency. The expanded fat lobules are separated by thickened fibrous trabeculae. Histologically, the expanded fat lobules show lipocytes containing the characteristic needle-shaped clefts with a radial or starburst pattern, as described earlier for SFN. In general, there is little or no associated inflammation. However, occasional neutrophils, lymphocytes, eosinophils, macrophages, and multinucleated giant cells, some containing the needle-shaped clefts, are observed. Older lesions may show thickening of fibrous trabeculae and rarely calcification. DIFFERENTIAL DIAGNOSIS As discussed earlier, SFN differs from SN by showing radial clefts predominately in macrophages, greater inflammation, and fat necrosis in contrast to SN, which shows crystals primarily in lipocytes and little or no inflammation or fat necrosis.

Poststeroid Panniculitis This is an extremely rare form of panniculitis, thus far only observed in young children 1 to 13 days after the rapid discontinuation of high doses of oral corticosteroids141,142 (see Table 11-13). Subcutaneous nodules develop particularly in areas of fat accumulation, especially the cheeks, secondary to steroid therapy. The lesions generally are asymptomatic and resolve without scarring over a period of weeks to months, unless they ulcerate, in which case they heal with atrophic scarring.30 The histologic findings are similar to SFN, with needle-shaped clefts occurring within both macrophages and adipocytes.

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Infection-Related Panniculitis Infection is a relatively frequent cause of panniculitis.144,145 Bacterial organisms are probably the most common agents, including Staphylococcus, Streptococcus, and both conventional and atypical mycobacteria.30 They are followed in incidence by fungi, Nocardia, and recently, Acanthamoeba. A particularly important predisposing factor to infection-related panniculitis is immunosuppression. Many such patients have undergone organ transplantation and have received immunosuppressive agents such as systemic corticosteroids and other cytotoxic drugs. Other conditions associated with this form of panniculitis include diabetes mellitus, AIDS, cancer, and connective tissue disease. CLINICAL FEATURES Most patients are adults, but individuals of any age may be

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Table 11-14 Infection-Related Panniculitis

Clinical Features Immunosuppression Organ transplantation Corticosteroid and cytotoxic therapy Cancer Connective tissue disease Diabetes mellitus Inflammatory nodules—lower extremities most common Histopathologic Features Epidermal and dermal changes common Neutrophil-rich infiltrate Edema Septal and lobular panniculitis often Septal changes frequent with bacterial infection Neutrophilic infiltrates Abscess formation Basophilic necrosis Hemorrhage Granulomatous inflammation in nonbacterial panniculitis Vascular damage and vasculitis Differential Diagnosis Acute neutrophilic panniculitis (erythema nodosum syndromes) Neutrophilic dermatoses Sweet syndrome Pyoderma gangrenosum Inflammatory bowel disease—metastatic Crohn disease Physical and factitial panniculitis

affected. Patients present most commonly with inflammatory subcutaneous nodules involving the lower extremities, but any site may be affected (Table 11-14). Lesions may be primary (sites of inoculation) or secondary (sites of direct or hematogenous spread).30 The most common route of infectious entry is via the respiratory tract.30 HISTOPATHOLOGIC FEATURES Epidermal and dermal changes are more frequent in infection-related panniculitis than in the other panniculitides (Table 11-14). Often there is parakeratosis, acanthosis, and spongiosis. In addition, dermal edema and a neutrophil-rich inflammatory infiltrate are encountered commonly in the dermis. In general, the panniculitis is both septal and lobular. A predominantly septal panniculitis with infiltration of fibrous trabeculae and the peripheries of fat lobules may be noted with bacterial infection. Other notable features include a prominent neutrophilic infiltrate with occasional abscess formation, hemorrhage, basophilic necro-

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sis (Fig. 11-12A and B), and associated necrosis of sweat glands. Bacterial panniculitis as a general rule does not exhibit granulomatous inflammation. However, granulomatous inflammation is a common finding in other forms of infectionrelated panniculitis, particularly those with mycobacterial infection (Fig. 11-12C). Both small and medium-sized vessel vasculitis may be observed. In the case of atypical mycobacteria, suppurative granulomas inside the fat lobules contain histiocytes surrounding groups of neutrophils.30 In primary lesions, the superficial dermis is the center of the inflammation, whereas secondary lesions are deeper and involve the reticular dermis and subcutaneum.30 Blood vessels are thrombosed and are expanded with large numbers of the infective organism.30 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes causes of acute neutrophilic panniculitis such as might be associated with short-lived hypersensitivity reactions (the EN reaction pattern), vasculitis, a primary neutrophilic dermatosis (as in Sweet syndrome and pyoderma gangrenosum), inflammatory bowel disease, and physical and factitial forms of panniculitis. One recent case report demonstrates a neutrophilic panniculitis in an infant as a manifestation of juvenile rheumatoid arthritis.146 Infection can be confirmed by special stains, cultures, and possibly special techniques, including immunostaining and the polymerase chain reaction (PCR).

Erythema Induratum and Nodular Vasculitis (Bazin Disease) Erythema induratum of Bazin and nodular vasculitis should be used interchangeably when discussing this most frequent form of lobular panniculitis associated with vasculitis.30 Since the description of this entity by Bazin in 1861,148 there has been continued controversy as to its relationship to tuberculosis as a “tuberculide,” the relationship to and the nature of the vasculitis described in many cases (“nodular” vasculitis), and its very legitimacy. Nonetheless, many clinicians maintain that erythema induratum/ nodular vasculitis is a distinctive clinical entity characterized by tender, dusky, bluish nodules, principally localized to the posterior calves of obese adult women.30 These nodules seem to have some relationship to cold exposure, as does ulceration of the nodules.30 When ulceration occurs, healing is slow and

usually results in atrophic scars. Other features and possible predisposing factors are cutis marmorata, erythocyanosis, and column-like, weighty calves.30 Variants that are clearly related to cold exposure have been termed erythema induratum of Whitfield and are likely to a form of perniosis (Whiting DA, personal communication, 1996). A pattern of livedo reticularis has been described in many cases. Recurrence can last decades.30 An atypical variant occurs in men, in whom the lesions are unilateral involving the shins and thighs most commonly.30 The relationship of erythema induratum/nodular vasculitis to Mycobacterium tuberculosis (MTB) has remained controversial over the past century.148-152 Some authors have provided convincing evidence for a relationship to MTB based on documentation of tuberculosis at other sites, positive Mantoux (tuberculin-purified protein derivative) tests, and response to antituberculous therapy. Others have disavowed any relationship, and Montgomery et al emphasized the presence of vasculitis in these lesions and proposed the term nodular vasculitis to describe nodules not having any clear association with MTB.64 A relationship to perniosis was suggested for some lesions. Nonetheless, recent studies using molecular diagnostic techniques (PCR) have isolated MTB DNA from 25% to 77% of lesions considered to be erythema induratum.30,153 Using newly developed primers for PCR, bacille Calmette-Guérin was ruled out as a source of false-positive results, as reported in one study.153 Furthermore, patients with these lesions have responded to treatment for MTB. HISTOPATHOLOGIC FEATURES The histopathologic features described in these lesions are entirely nonspecific and often are related to the age of the lesion biopsied. In early lesions, small collections of mostly neutrophils are interspersed throughout the fat lobules, where extensive ischemic necrosis may be found.30 Foamy macrophages are likely to be present depending on the stage of the lesion.30 The fat lobules are affected by extensive inflammatory infiltrates consisting of lymphocytes, multinucleated giant cells, and epithelioid histiocytes contributing to granulomatous inflammation and caseation necrosis.30 The caseous process may extend to the dermis and epidermis, causing ulceration and exudation of the necrotic, liquefied fat.30 Vasculitis is not always identified but is accepted as one of the histopathologic criteria.30 Still, controversy exists as to

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C  FIGURE 11-12 Infection-related panniculitis. (A and B) Bacterial panniculitis. There is granular basophilic necrosis of fat. (C) Septal and lobular panniculitis with caseation necrosis. These changes are nonspecific but may be associated with infectious agents such as mycobacteria.

whether the involved vessels are small and medium-sized arteries or veins since both have been observed.30 A prevailing belief is that venous vessels are involved primarily, and the arteries are affected as they become trapped within the areas of caseation.30 Some authors have concluded that venous structures are involved almost exclusively and that those vessels labeled as arteries in past years were largely misclassified.154 Montgomery et al reported features similar to polyarteritis nodosum in some lesions.64 Recently, lesions have been categorized histopathologically into two types.155 Type I, also called focal panniculitis, is distinguished by only one artery or nonspecific blood vessel involved with a neutrophilic vasculitis in the fat lobule.155 Type II, also called diffuse panniculitis, differs in that more than one vessel is involved with the neutrophilic

vasculitis, and both the septa and fat lobule are affected.155 Also, type II has more pronounced inflammation.155 However, since vasculitis is not an absolute finding in every case of erythema induratum/ nodular vasculitis, this classification scheme is not always used.30 Taken together, there is increasing evidence that many cases of erythema induratum are likely to be a form of infection-related panniculitis in which a florid hypersensitivity reaction probably has resulted in the death of MTB organisms, since they cannot be cultured from such lesions. Nonetheless, the structure of some organisms remains intact because they can be detected by PCR amplification. Since MTB has been reported to also be associated with EN and possibly cutaneous periarteritis nodosa, further studies are needed to confirm the infectious etiology of erythema induratum.156,157

The author recommends that the terms erythema induratum and nodular vasculitis be abandoned in favor of more objective morphologic descriptions. For example, such panniculitides are best designated as granulomatous panniculitis associated with MTB detection, granulomatous panniculitis without specific cause (failure to detect an infective agent), or panniculitis associated with small or medium-sized vessel vasculitis. Patients should have a thorough evaluation for a local or systemic cause of their panniculitis.

Erythema Nodosum Leprosum CLINICAL FEATURES Erythema nodosum leprosum (ENL) is characterized by multiple, tender, violacious, erythematous papules or nodules on the extremities of patients with lepromatous or borderline

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lepromatous leprosy.30 It usually begins after initiating treatment for leprosy, although it has been reported as the presenting complaint.158 Sometimes referred to as a type 2 leprosy reaction, ENL is a serious complication of patients with multibacillary leprosy.159 Regional—not worldwide—prevalence has been established within various populations of leprosy patients and varies from population to population.159 It is more common with dapsone monotherapy and less common in patients undergoing multidrug therapy, especially the regimens that include clofazimine.160 ENL is also associated with bacterial or viral infections.161 Pregnancy has been reported as a precipitant to ENL, with no resolution of lesions after delivery, continuing through lactation.162 Risk factors include bacterial index greater than 4+ and age over 40 years, according to one study.160 HIV has been reported as a risk factor in another study.159 Recurrence has been reported in 45% to 60% of patients.159,160 Patients who have a diffuse form of lepromatous leprosy can develop a necrotizing vasculitis called Lucio phenomenon.30 This is an infarctive, hemorrhagic, ulcerative process that is painful.30 The course involves serious systemic symptoms and has an associated mortality.30 HISTOPATHOLOGIC FEATURES A small-vessel vasculitis with fibrinoid necrosis and associated neutrophilic infiltrates usually involves the dermis and/or subcutis.30 The panniculitis is often septal and lobular with variable fat necrosis. Although macrophages generally contain lepra bacilli, the vasculitis appears to be Arthus-type, immune-complex related.158 Direct immunofluorescence demonstrates complement and IgG deposits in the wall of the associated blood vessels.30 Fine-needle aspiration cytology shows neutrophils, foamy macrophages, and Ziehl-Neelsen staining for acid-fast bacilli.158 A current theory is that immune-complex formation leads to vasculitis and secretion of tumor necrosis factor alpha (TNF-α) from macrophages.160 Whether or not T cells augment the secretion of TNF-α is still being defined.160 Patients with a polymorphism in the TNF-α gene are at a higher risk of lepromatous leprosy and possibly increased risk for ENL.160 The vasculitis of Lucio phenomenon is usually confined to the upper and middle dermis with subsequent epidermal ulceration, but it also may extend into the subcutaneous fat involving the small vessels.30 There is also a slight perivascular inflammation comprised of

foamy histiocytes.30 The latter histiocytes, as well as the endothelial cells of the involved vessels, contain acid-fast bacilli.30 The inflammation is not as pronounced as in ENL lesions.30

PHYSICAL AND FACTITIAL PANNICULITIS This category of panniculitis refers to injury to fat secondary to various physical insults, such as cold, pressure, external trauma, chemical agents, and selfinduced injury.

Cold Panniculitis Cold-related panniculitis was first described in 1902 by Hochsinger in children 4 to 10 years of age, primarily involving the face.106-110,163,164 The propensity to develop cold panniculitis is inversely correlated with age. Thus, as with crystal-associated panniculitis, cold panniculitis has been attributed to a higher ratio of saturated to unsaturated fatty acids and generally presents in infants and young children. Because of a higher melting point, saturated fatty acids will crystallize more rapidly when exposed to cold temperature than unsaturated fatty acids.165 These crystals disrupt the normal architecture of the fat and cause the panniculitis.165 CLINICAL FEATURES The exposed skin, especially the cheeks and submental area of the chin, of neonates and young children is affected most commonly (see Table 11-15). Individuals wearing thin, tight clothing particularly on the buttocks in cold weather are also susceptible.30 Typically patients develop tender, often indurated, erythematous plaques and nodules without well-defined margins about 2 to 3 days after cold exposure from cold air, ice cubes, cold fluids, ice packs, or “popsicles.”30 The lesions will soften and then heal without scarring in a few days to 2 weeks if maintained at a warm temperature.30,165 HISTOPATHOLOGIC FEATURES In general, the epidermis and dermis are unaffected. The most prominent findings often are perivascular lymphocytic infiltrates at the dermal-subcutaneous interface with features observed in chilblains, that is, the “fluffy” edema involving the walls of blood vessels (see Table 11-15). However, as with many other insults to the fat, the panniculitis is nonspecific, with variable fat necrosis and inflammatory cell infiltrates, including neutrophils,

Table 11-15 Cold Panniculitis

Clinical Features Infants and young children Young women Exposed skin, cheeks Tender, indurated plaques, nodules Onset 2-3 days after cold exposure Histopathologic Features Perivascular lymphoid infiltrates Histologic features of chilblains Dermal-subcutis interface “Fluffy” edema of vessels Lobular and septal panniculitis Fat necrosis Mixed infiltrates Differential Diagnosis Other physical panniculitides

lymphocytes, macrophages, and other inflammatory cells involving fat lobules and, to a lesser extent, fibrous trabeculae. Cryoglobulins and cold agglutinins have not been shown to be a factor in cold panniculitis.165

Trauma-Related Panniculitis Physical trauma, whether self-inflicted (factitial) or otherwise, is a major cause of injury to fat (Fig. 11-13A).1-5,166,167 Common locations include the breasts of women and accessible sites, such as the extremities. Purpura and scarring may be important clinical features. Secrétan syndrome and l’oedeme bleu are forms of factitial panniculitis resulting from blunt trauma to the dorsal hand and forearm and upper arm, respectively, or any site. Clinically, one observes traumatic edema and hemorrhage, often resulting in brawny, discolored, indurated plaques or nodules that may have a peau d’orange appearance, especially when located on the breast.30 Healing of trauma-related panniculitis to the breast usually occurs, but it may resolve with lipoatrophy.30 Lipoatrophia semicircularis is possibly a variant of trauma-related panniculitis that occurs when individuals, particularly women, bump one of their thighs on a hard object.30 It manifests as a semicircular ring of atrophic subcutaneous fat around half the anterolateral thigh.30 Nodularcystic fat necrosis, also known as encapsulated fat necrosis or encapsulated lipoma, is also a possible variant of trauma-related panniculitis.30 These subcutaneous, wellcircumscribed, movable nodules are induced by trauma and are located on the elbows, lower extremities, and hips.30

B

 FIGURE 11-13 Traumatic fat necrosis. (A) These changes are nonspecific and may follow a number of insults. (B) Encapsulated fat necrosis. Small nodule of adipose tissue compartmentalized by fibrous tissue “capsule.”

Histologically, the subcutaneous nodules show organizing hematoma, granulation tissue, fibrosis and hemosiderin often in the late stage, and focal fat necrosis and prominent hemorrhage surrounding cyst-filled fat lobules.30 These cysts are of various shapes and sizes.30 They are bordered by foamy histiocytes and lymphocytes.30 Mobile encapsulated lipomas differ from normal lipomas in that they are bordered by nucleated, necrotic adipocytes.30 Their thin, fibrous capsule completely or almost completely surrounds normal-appearing adipocytes (Fig. 11-13B).30 They are likely formed in association with vascular insufficiency or trauma.30

Chemical and Factitial Panniculitis Injection of various foreign or organic substances and medications is also a common cause of panniculitis.166-172 Sclerosing lipogranuloma is a term used to describe the reaction of adipose tissue to various mineral, animal, and vegetable oils, silicone, and other hydrocarbons injected into the subcutaneous fat for cosmetic and other reasons. Almost every conceivable substance, including milk, feces, and blood, has been injected into the subcutis. Many medications have been associated with panniculitis, including meperidine, pentazocine, povidone-iodine, morphine, corticosteroids, vitamin K, tetanus toxoid, and augmentation substances such as paraffin, silicone, PMMA microspheres, and polymethylsiloxane.30,34 A recent case report demonstrates a patient with several years history of recurrent areas of panniculitis and hospital admissions

that was self-induced and an expression of Munchausen syndrome.173 CLINICAL FEATURES The injection or implantation of various oils, paraffin, and other hydrocarbons may involve any site (Table 11-16). However, particularly common locations include the male genitalia, face and scalp, female breasts, and hands (“greasegun granuloma”). Such lesions are often indurated and

Table 11-16 Chemical and Factitial Panniculitis

Clinical Features Injection of foreign or organic substances, oils, paraffin, silicone, medications Psychiatric history Health care professionals Unusual or bizarre manifestations Indurated lesions—drainage Histopathologic Features Sclerosing lipogranuloma Variable-size vacuoles (“Swiss cheese” pattern) Foreign body reaction Dense hyalinized fibrous tissue Variable inflammation Fat necrosis Microcyst formation Mixed and granulomatous inflammation Fibrosis Calcification Birefringent material, often Differential Diagnosis Infection Alpha-l-antitrypsin deficiency Pancreatic panniculitis

may break down with drainage of oily material. The clinical manifestations associated with injections of other substances, for example, feces, or medications are related to the properties of the particular substance. Many such patients have health profession backgrounds and psychiatric histories and exhibit unusual or bizarre manifestations. There may be systemic signs, such as fever and, in some instance, a liquefying panniculitis. HISTOPATHOLOGIC FEATURES Sclerosing lipogranuloma shows a rather characteristic constellation of findings involving fat lobules: the so-called Swiss cheese pattern, with variably sized vacuoles corresponding to lipid removed with tissue processing, variable foreign-body giant cell reaction associated with vacuolated spaces, dense hyalinized fibrous tissue, and variable inflammatory cell infiltrates (see Table 11-16). The histologic features associated with injection or implantation of other substances is in general nonspecific but varies with the particular agent (Fig. 11-13A). Commonly, there is patchy, sometimes focal fat necrosis accompanied by microcyst formation and inflammatory infiltrates composed of neutrophils, especially early lesions; mononuclear cells; and granulomatous elements, more specifically in late-stage lesions.30 Birefringent material may be demonstrated with polarized light. Some agents such as meperidine may result in exuberant fibrotic reactions. Various methods can be used to identify the offending material, such as slide polarization or special staining techniques.20

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DIFFERENTIAL DIAGNOSIS In many instances the cause of physical panniculitis is obvious. However, factitial panniculitis may present considerable difficulties in diagnosis. Unusual forms of panniculitis, particularly persistent or recurrent, should raise suspicion for factitial etiologies. The differential diagnosis includes infection, alpha-1-antitrypsin deficiency, pancreatic panniculitis, and superficial thrombophlebitis. Evaluation for birefringent material and calcification may provide evidence for self-administered local injections.

Lupus Panniculitis (Lupus Profundus) The first recorded observation of subcutaneous nodules in lupus erythematosus (LE) was by Kaposi in 1883.174-181 Reports over the past half century have confirmed the rarity of lupus profundus (incidence about 1%-30% of patients with LE).30,182 Lupus panniculitis occassionally occurs without evidence of systemic lupus erythematous (SLE).30 Patients with systemic involvement seem to have a milder course, often exhibiting only arthralgias, polyserositis, and Raynaud phenomenon. Trauma to the subcutaneum often occurs to sites where lesions later arise, for example, injection, biopsy, or excision sites.30 Recent evidence suggests a close relationship of lupus panniculitis to subcutaneous lymphoma, an observation that requires further study and clarification.30 CLINICAL FEATURES In general, lupus panniculitis is a chronic disease of adults aged 20 to 60 years, but children as young as 3 years may be affected183 (Table 11-17). Women are afflicted two to four times as often as men.183 Patients commonly present with multiple indurated, deep-seated subcutaneous nodules or plaques involving the proximal extremities, particularly the upper extremities, as well as the shoulders, breasts (lupus mastitis), buttocks, trunk, or face.30,182 There also have been reports of lupus profundus associated with the subcutaneum of the orbit and periparotid area.30 Ulceration may develop, and the lesions often heal with lipoatrophy and depressed scars. Cutaneous manifestations overlying the panniculitis may include discoid LE (DLE), poikiloderma, atrophy, telangiectasia, and dyspigmentation. HISTOPATHOLOGIC FEATURES The epidermis and dermis may or may not show features typical of LE, such as hyperkeratosis,

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Table 11-17 Lupus Panniculitis

Clinical Features Women > men Age 20-60 years Multiple indurated subcutaneous nodules or plaques—proximal extremities, buttocks, breasts, trunk, or face Ulceration Overlying discoid lupus erythematosus, poikiloderma Lipoatrophy, depressed scars late Histopathologic Features Epidermis and dermis may or may not show features of lupus erythematosus Septal and lobular panniculitis Hyaline necrosis of fat lobules Hyalinization of adipocytes, connective tissue, blood vessels (“onion-skin” pattern) Karyorrhectic material Lymphocytic infiltrates and nodules at peripheries of fat lobules Plasma cells often Lymphocytic vasculopathy and vasculitis Occasional fibrin thrombi Mucin deposition Variable fibrous thickening of septa Differential Diagnosis Septal panniculitis Panniculitis in connective tissue disease Morphea/scleroderma Eosinophilic fasciitis Dermatomyositis Lipoatrophy, not otherwise specified Borreliosis Necrobiosis lipoidica

follicular plugging, epidermal atrophy, basal layer vacuolization, basement membrane thickening, perivascular and periadnexal lymphoid infiltrates, and dermal mucin. Most cases show changes consistent with DLE, including epidermal atrophy, increased thickness of the basement membrane, vacuolar change within the junction of the dermis and epidermis, mucin among bundles of collagen in the dermis, and a lymphocytic perivascular dermal inflammatory infiltrate that may be superficial and/or deep.30 The remainder of the cases are characterized by changes confined to the subcutaneous fat only.30 In general, lupus panniculitis shows distinctive changes involving septal and lobular areas (Fig. 11-14; see Table 11-17). The principal findings include (1) hyaline necrosis (Fig. 11-14C involving primarily

fat lobules but extending to the fibrous trabeculae in many instances, (2) lymphocytic infiltrates often forming nodules and occasionally containing germinal centers looking very much like lymphoid follicles (Figs. 11-14A, B), and (3) nuclear dust within the infiltrates, which is not seen in most other forms of panniculitis.30 The presence of such lymphoid follicles in the subcutaneum is highly suggestive of lupus profundus but not diagnostic because of their presence in other panniculitides such as erythema induratum of Bazin, panniculitis in dermatomyositis, deep morphea, and EN.30 The hyaline necrosis refers to the degeneration of fat lobules and connective tissue with development of a progressive glassy eosinophilic appearance. This alteration is often accompanied by karyorrhectic debris and mucin deposition. The fat lobules are commonly characterized by the formation of hyalinized microcysts (Fig. 11-14C), and involved blood vessels exhibit a characteristic onion skin-like concentric layering of eosinophilic fibrils. The lymphocytic infiltrates are variable and primarily localized to the peripheries of fat lobules or septal-lobular interface but rarely may involve the entire lobule. The lymphocytic infiltrates often are present between vessels, as well as having a perivascular disposition. Almost without exception, plasma cells are an integral part of the infiltrate, often surrounding it.30 Lesions in later stages likely will reveal membranocystic changes.30 Immunohistochemistry reveals IgM and C3 linear deposition at the dermal-epidermal junction.30 Some studies have shown atypical lymphocytes with clonal proliferation within the infiltrate as well.184 Variable degrees of vascular injury are observed commonly, with lymphocytic vasculitis the most frequent finding. Fibrinoid necrosis and fibrin thrombi are noted on occasion. Other more variable features include fibrous thickening of septa, deposition of elastic fibers in the septa, calcification that may be extensive, mucin deposition, granulomas involving septa, and occasional eosinophils in the infiltrate. On occasion, the histopathologic findings are nonspecific. DIFFERENTIAL DIAGNOSIS Early lesions of lupus panniculitis may be confused with septal patterns of panniculitis (the EN reaction pattern). However, the major entities to be considered include connective tissue disease-related panniculitis, that is, morphea, eosinophilic fasciitis, and allied conditions; dermatomyositis;

B

CHAPTER 11 ■ PANNICULITIS

A

C  FIGURE 11-14 Lupus panniculitis. (A) A septal and lobular panniculitis is present. There is some hyalinization of the fibrous septa and fat lobules. Fat lobules also exhibit infiltration by rather dense mononuclear cell infiltrates. (B) Lupus panniculitis. Higher magnification shows hyalinizing necrosis of fat with mononuclear infiltrates. (C) Lupus panniculitis. There is hyalinization of the fat lobule accompanied by lymphocytic infiltrates.

necrobiosis lipoidica; lipoatrophy; and borreliosis. The greatest difficulty may be distinguishing lupus panniculitis from morphea profunda/eosinophilic fasciitis. Both may present as clinically indurated plaques or nodules, and both exhibit prominent lymphoplasmacellular infiltrates, thickening of fibrous septa, lymphocytic vasculitis, mucinosis, and occasional eosinophilic infiltrates. As discussed earlier (see “Morphea Profunda, Scleroderma, Eosinophilic Fasciitis”), lupus panniculitis is distinguished from morphea by the frequent presence of the epidermal changes of hyperkeratosis, atrophy, basal layer vacuolopathy, basement membrane thickening, prominent dermal mucin, hyalinizing necrosis of adipose tissue, and less prominent sclerosis of the subcutis and dermis compared with morphea profunda (and eosinophilic fasciitis). Subcutaneous T-cell lymphoma must be excluded

because of commonly found peripheral rimming of atypical lymphocytes around the fat lobules and the evidence of clonality.184

Panniculitis in Dermatomyositis and Polymyositis Pure panniculitis is rarely observed in both children and adults with dermatomyositis.30,179-181,185-187 In fact, since 1924, only 10 adults and 2 children have been reported in the literature.188 It is more common for these patients to have an association with deep tissue and muscle calcification.30 Regardless of how pure the panniculitis is, these patients may present with painful, erythematous, indurated nodules or plaques on the buttocks, thighs, and arms, or the panniculitis may be asymptomatic and diagnosed coincidentally with skin or muscle biopsy.189

CLINICAL AND HISTOPATHOLOGIC FEATURES Histologically, one often observes features noted in the other connective tissue diseases, especially lupus panniculitis.30 A mostly lobular panniculitis with lymphoplasmacytic infiltrates of variable density affecting the fat lobules is commonly found.30 The pannicular septa exhibit hyaline sclerosis, and fibrous tissue replaces the adipose tissue.30 Other features noted less commonly include hyaline necrosis of fat, mucinosis, thickening of the vessels supplying the fat lobules, neutrophilic or lymphocytic vasculitis, and calcification.30 Vacuolar change may be found, and as the lesion progresses, membranocystic changes may occur.30 There may be overlying features of dermatomyositis affecting the epidermis and dermis. Immunofluorescence studies have been inconclusive thus far.30 Patients generally have a good prognosis

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and a decreased incidence of cancer versus patients with only dermatomyositis.30

Connective Tissue Panniculitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Winkelmann and Padilha-Goncalves reported an unusual form of panniculitis that they considered to be closely related to lupus panniculitis and morphea.189,190 However, connective tissue panniculitis was distinguished from the latter conditions by florid lymphocytic infiltration and extensive caseation necrosis of fat lobules. There was no hyaline necrosis or vasculitis according to these authors, and the lesions resolved with lipoatrophy.

LIPOATROPHY AND LIPODYSTROPHY This category includes a highly heterogeneous and confusing group of conditions perhaps only related by the clinical finding of loss of subcutaneous fat. 2,179,190-198 This atrophy or disappearance of fat may be localized, partial, or generalized (total) (Table 11-18). Specifically, lipoatrophy is the loss of a previously inflamed subcutaneum, whereas lipodystrophy is a similar condition but lacks a preceding inflammatory episode of the panniculus.30 Much more work is needed to characterize the pathogenesis of these various disorders. Various classifications have been proposed, but until a more definitive nosology is devised, this text will continue with the current classification: localized, partial, and generalized or total lipoatrophy.30,199 Recent studies in this area have

shown mutations in several genes in patients with inherited lipodystrophies. In patients with partial lipodystrophies, mutations in LMNA, PPARG, and ZMPSTE24 and in total lipodystrophy BSCL2 and AGPAT2 have been noticed.200 The localized lipoatrophies probably encompass the most heterogeneous grouping of conditions. One well-recognized outcome of panniculitis occurring in connective tissue disease, for example, lupus panniculitis and morphea profunda, is localized lipoatrophy, which has been designated atrophic connective tissue panniculitis. However, other autoimmune diseases such as diabetes mellitus, Hashimoto thyroiditis, and juvenile rheumatoid arthritis may result in localized lipoatrophic panniculitis. Localized lipoatrophy may be secondary to a variety of local insults to fat, such as injections of depot corticosteroids, antibiotics, vasopressin, human growth hormone, and insulin, and factitial disease.30 Other unusual and poorly understood variants include centrifugal lipodystrophy and the annular and semicircular lipoatrophies. Centrifugal lipodystrophy is characterized by round, depressed lesions having a raised erythematous border, often involving the trunk and groin areas of children. The annular and semicircular variants show circumscribed bands of lipoatrophy involving the upper extremities and thighs, respectively, of adult patients. Annular lipoatrophy of the ankles is typified by a broad (~10 cm) annulus of lipoatrophy involving the distal leg above the ankle. It is often induced secondarily by compression of tightly fitted clothing on the

abdomen, sacrum, and extremities, especially the thighs and ankles.30 The partial lipodystrophies most commonly show progressive loss of facial fat that may extend gradually to the upper trunk and arms (cephalothoracobrachial lipodystrophy). They are more common in female than male children.199 Many patients have reduced serum complement (C3) levels, a circulating immunoglobulin that activates C3 (the C3 nephritic factor), membranoproliferative glomerulonephritis, SLE, scleroderma, Sjögren syndrome, sicca syndrome, dermatomyositis, recurrent infections, high thyroid autoantibody titers, hypertriglyceridemia, insulin resistance, and diabetes.30 The generalized or total lipodystrophies may present at birth or develop later in life. They are more common in females and show a number of cutaneous signs, including acanthosis nigricans, hypertrichosis, and hyperpigmentation. Endocrine abnormalities, including diabetes and hypothalamic dysfunction, often are present. Patients with human immunodeficiency virus 1 (HIV-1) infection have been reported with lipodystrophy while undergoing combination antiretroviral therapy that has specifically included protease inhibitors.199 The most commonly areas affected are the gluteal region, face, and extremities.199 HISTOPATHOLOGIC FEATURES All forms of lipoatrophy are characterized by loss of subcutaneous fat in their established or fully developed stages; that is, fat lobules are greatly diminished in size and

Table 11-18 Lipoatrophies And Lipodystrophies CONDITION Localized lipoatrophies Atrophic connective tissue panniculitis; lipoatrophic panniculitis Secondary localized lipoatrophies Centrifugal lipodystrophy (lipodystrophia centrifugalis, abdominalis infantilis) Annular lipoatrophy, semicircular lipoatrophy, annular lipoatrophy of the ankle Localized lipoatrophy Partial lipoatrophies, dystrophies; cephalothoracic lipodystrophy

Generalized lipodystrophies

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CLINICAL FEATURES Children or adults with connective tissue and autoimmune diseases Localized lipoatrophy secondary to local processes such as injections, factitial disease Annular erythematous lesions involving abdomen and other sites of children, possibly related to Kawasaki disease Circumferential band of lipoatrophy affecting circumscribed areas of the extremities Localized lipoatrophy without evidence of inflammation Progressive loss of fat from the face and upper trunk; relationship to hypocomplementemia, C3 nephritic factor, glomerulonephritis, and diabetes; often inherited Congenital or acquired; generalized loss of fat; diabetes and other endocrine abnormalities; often inherited

Table 11-19 Eosinophilic Panniculitis

 FIGURE 11-15 Lipoatrophy. Note prominence of microvessels associtated with diminished overall size of fat lobule.

associated with prominent microvessels and myxoid alteration (Fig. 11-15). Mostly, small fat lobules are surrounded by lipophagic granulomas and perilobular fibrosis.30 Early lesions, particularly those associated with inflammation and autoimmune or connective tissue disease in localized lipoatrophy, have been reported to show infiltration of fat lobules by lymphocytes, plasma cells, and macrophages with little change to the surrounding adipocytes or blood vessels. Direct immunofluorescence highlights the walls of blood vessels or the basement membrane at the junction of the dermis and epidermis.30 An involutional phase of localized lipoatrophy has been described and may or may not have a relationship to antecedent inflammation. This stage is characterized by diminished sizes of fat lobules, variation in the sizes of adipocytes, prominent vascularity, and a hyaline or myxoid stromal alteration. The latter findings greatly resemble fetal adipose tissue. Part of the clinical differential diagnosis consists of SHORT syndrome (short height, hyperextensability of limbs, ocular depression, Reiger anomaly, and teething delay), Werner syndrome, Wiedemann Rautenstrauch syndrome, leprechaunism, and Cushing syndrome.199

Eosinophilic Panniculitis Eosinophilic panniculitis is the improperly used term to describe a distinctive but nonspecific histopathologic reaction pattern associated with a wide variety of processes that may be localized or systemic.21,30,201-203 Reviews of many patients with eosinophilic panniculitis have included the following associations: asthma, atopy, bacterial infections, cancer (particularly leukemia and T- and B-cell lymphomas), deep insect bites, deep morphea, drug dependency with injection granuloma, EN, glomerulonephiritis, leukocytoclastic and systemic vasculitides, local injections, lupus panniculitis, parasitic infection (eg, Toxocara canis and Gnathostoma), parotitis, psychiatric diseases, radiotherapy, sarcoidosis, Sjögren syndrome, thyroid disease, and Wells syndrome (eosinophilic cellulitis, a closely related nonspecific reaction).30,204 With so many disorders in which eosinophilic panniculitis may be found, patients with this pattern should be evaluated for associated systemic processes.30 CLINICAL AND HISTOPATHOLOGIC FEATURES Eosinophilic panniculitis may show a lobular or septal panniculitic pattern, but

CHAPTER 11 ■ PANNICULITIS

Clinical Features Many etiologies Atopy Local injections Cancer (especially lymphoma) Vasculitis Borrelial infection Inflammatory subcutaneous nodules Vesicles, pustules, urticarias Histopathologic Features Infiltration of fat lobules by eosinophils Other inflammatory cells to variable extent Occasional “flame figures” Occasional eosinophilic cellulitis and fasciitis Laboratory Evaluation Special stains and serologic evaluation for Borrelial infection Differential Diagnosis Lymphoma

it is not a true panniculitis.30 In general, adults are affected and present with inflammatory nodules, occasionally associated with other cutaneous findings, including vesicles, pustules, and urticaria (Table 11-19). The panniculitis is characterized by prominent infiltration of fat lobules by eosinophils, possibly with an admixture of other inflammatory cells, including lymphocytes, neutrophils, plasma cells, and macrophages. Vasculitis, “flame figures” (deposition of eosinophilic granules on connective tissue), and palisading granulomas may be seen in some instances. Associated eosinophilic cellulitis and fasciitis also may be present. If relevant, silver stains (eg, Warthin-Starry) and serologic evaluation may be considered to rule out borrelial infection.

Neutrophilic Dermatitides and Vascular Reactions The neutrophilic dermatitides, including Sweet syndrome and pyoderma gangrenosum, may involve the panniculus.16,28 These conditions often show varying degrees of septal and/or lobular infiltration by neutrophils and possibly microvascular injury. There may be some admixture of other inflammatory cells.

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Infections must be excluded by special stains and culture. These disorders are discussed in more detail in Chap. 9.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Noninfectious Granulomatous Panniculitis A number of (presumed) noninfectious processes may involve the subcutaneous fat, eventuating in varying degrees of septal and/or lobular panniculitis, in addition to the palisading/necrobiotic granulomatous disorders.2,4 These conditions include metastatic Crohn disease, sarcoidosis, granulomatous reactions secondary to arthropod bites, rupture of pilosebaceous units, granulomatous angiopanniculitis (GAP), and epithelial cysts.205 In Crohn disease, the lesions may resemble EN clinically and usually are located on the lower extremities.30 Histologically, they may show noncaseating granulomas in the subcutaneous septa or within the fat lobules accompanied by a lymphocytic vasculitis in the medium-sized vessels at the dermalpannicular junction.30 In sarcoidosis, deep subcutaneous nodules are present on the lower extremities, but there are usually no visible indications of an inflammatory process except for pink to tan coloration.30,34 Microscopically, these small noncaseating granulomas are associated with the subcutaneous septa and fat lobules but show only a few lymphocytes around their perimeter (“naked” granulomas).30,34 Occasionally, these sarcoid granulomas will undergo necrosis in their centers, and calcification may develop.30 GAP may appear microscopically similar to carcinoma, as in GAP of the breast, but close inspection will reveal granulomas lacking involvement of breast lobules and ducts.205 Because a possible infectious etiology still exists in patients with panniculitis and Crohn disease or sarcoidosis, noninfectious granulomatous panniculitis must be a diagnosis of exclusion.30

panniculitis.14 The number of leukemic cells in such infiltrates varies from none to many. It has recently been shown that drug-associated lymphomatoid hypersensitivity reactions can show cytologic atypia, clonality, and an immunophenotypic profile that can simulate CTCL. This may of course cause diagnostic difficulties. Performing TCR-beta gene rearrangement on these cases showed that monoclonality on TCR was a reliable finding in CTCL and that polyclonality indicated a benign process.206

FASCIITIS Fasciitis needs to be differentiated from panniculitis and eosinophilic fasciitis, which is a specific clinical entity. Fasciitis, on histologic grounds, is a marked inflammation and thickening of the deep fasciitis. The term, fasciitis panniculitis syndrome (FPS) as previously discussed in this chapter (see Morphea Profunda, Scleroderma, Eosinophilic Fasciitis (Shulman Syndrome)), has recently been proposed as a new category of fasciitis and includes eosinophilic fasciitis (EP).207 EP (Shulman syndrome) has been described to have a consistent eosinophilia, with eosinophilic infiltrate of the lesion. FPS on the other hand does not show consistent findings of eosinophilia. The major histologic findings are dermal thickening, inflammation and thickening of the panniculus, fibrosis and thickening of the fascia, and inflammation of the muscle. Often FPS patient are resistant to corticosteroid treatment and the treatment of choice has been shown to be cyclophosphamide together with prednisolone.207 Necrotizing fasciitis (NF) is a serious and potential life-threatening bacterial infection associated with progressive necrosis of the superficial fascia. The overall mortality ranges from 25% to 73%. (This entity is discussed in greater detail in Chapter 19.)

Lymphoma and Leukemia Cutaneous lymphoid infiltrates, lymphoma, and leukemia may involve the subcutaneous fat. These entities are discussed in more detail in Chap. 34. Nonetheless, because of its importance in differential diagnosis, subcutaneous T-cell lymphoma was discussed earlier. Patients with leukemia on occasion may develop erythematous subcutaneous nodules (resembling EN) that histologically suggest an inflammatory septal

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CHAPTER 12 Cutaneous Drug Eruptions A. Neil Crowson Cynthia M. Magro

IMMUNOLOGIC DRUG REACTIONS Allergic reactions to drugs encompass immediate hypersensitivity (type I) reactions, type II reactions in which antibodies are directed against cell surface antigens, immune-complex-mediated (type III) reactions, and delayed-type hypersensitivity (type IV) reactions. Since the histomorphology of each pattern is distinctive, the pathogenetic basis of the reaction often can be inferred. The first step in the evolution of the cutaneous drug reaction is primary sensitization, often via topical exposure to contactants that cross-react with an offending oral agent. Following primary sensitization, a reaction may occur within seconds to hours after subsequent antigenic rechallenge. Factors that influence the development of hypersensitivity include the nature of the allergen (ie, lipid versus water solubility), the antigenic load (ie, drug dose), individual genetic variations in absorption or metabolism of the drug, immunomodulatory effects of concurrently administered drugs or systemic diseases, environmental factors such as sun exposure, and route of administration.

Immediate Hypersensitivity (Type I) Reactions Most dramatic are the drug reactions of immediate hypersensitivity type (type I),

mediated by the in vivo cross-linkage by polyvalent drug-protein complexes of IgE molecules on the surface of sensitized mast cells or basophils, provoking the release of histamine, leukotrienes, and other proinflammatory molecules that result in vasodilatation, increased vascular permeability, angioedema, pruritus, urticaria, bronchospasm, laryngeal edema, and in some cases, death. The prototype is that due to penicillin.16

Antibody-Mediated (Type II) Reactions Antibody binding to cells leads to damage through complement-mediated lysis. One example is hemolytic anemia associated with methyldopa, mediated by the induction of autoantibodies directed against red blood cell antigens; another is autoimmune thrombocytopenic purpura, mediated through antibodies against platelets and provoked by pyrazolone derivatives (ie, phenylbutazone and allopurinol), sulfonamides, penicillin, salicylates, thiazides, diuretics, and chloramphenicol.

Immune-Complex-Mediated (Type III) Reactions Immune-complex-mediated reactions encompass urticaria; the Arthus reaction, a localized form of immune-complexmediated leukocytoclastic vasculitis (LCV); urticarial vasculitis; Henoch-Schonlein purpura; and serum sickness.

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

In consequence of polypharmacy in an aging population and the continuous stream of novel drugs being brought to market in the modern era, systemic drug reactions are increasing in frequency and complexity and are thus a constant challenge to clinicians and pathologists.1,2 Adverse clinical manifestations resulting from administration of medicinal agents account for 2% of hospital admissions,3 affect 1% to 2% of the population, and are said to generate roughly $3 billion of annual expense in the United States.4 Although many organ systems may be involved, cutaneous manifestations are frequent and offer a window for diagnosis. Drug reactions may be immunologic or nonimmunologic, the latter consisting of overdosage, intolerance, teratogenicity, facultative effects that result from disruption of bacterial flora in mucous membranes and skin, and toxicity, the latter either delayed (ie, carcinogenic) or cumulative (ie, pigmentary disturbances due to deposition of gold or silver). Other nonimmunologic mechanisms of drug toxicity include anaphylactic reactions due to agents that degranulate mast cells (ie, opiates) or impair arachidonic acid metabolism (ie, cyclooxygenase inhibitors such as acetylsalicylic acid or other nonsteroidal anti-inflammatory agents). Recent advances in our understanding of perturbational effects of drugs on the immune system indicate that classes of drugs that alter immune function may dramatically modify the cutaneous response to exogenous antigens, including drugs of alternate classes.5 Cutaneous drug reactions also can be exacerbated in the setting of immune dysregulation caused by infection with agents such as human immunodeficiency virus (HIV),6,7 cytomegalovirus (CMV),8,9 and human herpesvirus 6 (HHV-6) in the context of the idiopathic drug hypersensitivity syndrome consisting of erythroderma, facial edema, lymphadenopathy, hepatopathy with circulating atypical lymphocytes, and a rash with a mycosis fungoides (MF)like histology.9-11 Drug interactions reflect pharmacokinetic and pharmacodynamic factors, the

former operative when one drug alters the effective serum concentration of another by interfering with its absorption, secretion, or metabolism and the latter reflecting changes induced in one drug by another without alteration of its serum concentration.1,12 Synergistic and cumulative effects of different agents may exacerbate the cutaneous manifestations of a drug reaction, often making it difficult to implicate one agent in isolation. The diagnosis of a cutaneous drug reaction is thus challenging and requires a thorough history, often aided by clinical algorithms. In particular, it is essential to know whether the drug in question has an established adverse effect, whether an alternative explanation for an eruption is possible, whether the timing of the eruption plausibly can be attributed to drug ingestion, whether the eruption resolves after drug therapy is stopped, and whether the rash recurs following rechallenge.3,4,13-15 Confirmatory drug rechallenge is not without risk; patch testing is generally better tolerated than is a systemic (ie, oral or parenteral) challenge.15

Delayed-Type Hypersensitivity (Type IV) Reactions The initial event in the delayed-type hypersensitivity (DTH) or cell-mediated immune response, endocytosis by Langerhans cells of an exogenous antigen (hapten) of drug, viral, or other derivation, is followed by complexing with tissue proteins. The latter leads to the recruitment of a subset of skin-seeking T lymphocytes that attach to high endothelial venules via interaction between lymphocyte function antigens and their respective endothelial receptors.17,18 These T cells, in turn, migrate into the perivascular dermis, where they may encounter antigen-presenting Langerhans cells. The sensitized lymphocytes then migrate to the peripheral lymph nodes, where proliferation of memory and effector cells occurs. The circulating effector lymphocytes return to sites of cutaneous sensitization via homing receptors for

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tissue-specific endothelial ligands. The expression of these ligands is upregulated, as is that of corresponding endothelial adhesion markers, in sites of DTH reactions19; memory or previously activated lymphocytes return to the tissue or lymphatic bed in which they were first activated. Drug reactions in which this mechanism is likely to be operative include erythema multiforme and morbilliform, fixed, eczematous, pustular, lichenoid, lymphomatoid, and pigmentary purpura-like drug reactions.

282

CLINICAL FORMS OF DRUG REACTIONS AND THEIR HISTOPATHOLOGIC EXPRESSION The types of clinical drug reactions are listed in Table 12-1.1-3,20,21

Exanthematous (Morbilliform) Drug Eruptions CLINICAL FEATURES Accounting for up to 95% of all cutaneous drug eruptions, the exanthematous or morbilliform eruptions are characterized by red to salmoncolored macular or papular eruptions that may form polycyclic, gyrate, or reticular patterns resembling a viral exanthem (Fig.12-1 A)1,22 (Table 12-2). Lesions often appear first on the trunk and spread peripherally in a symmetric fashion with dependent areas such as the lower extremities manifesting purpura. Lesions clear with withdrawal of the causative agent but may progress to a generalized exfoliative dermatitis if the drug is continued. Pruritus and fever may be present. Lesions may fade following drug cessation or resolve with a residuum of postinflammatory hyperpigmentation. The commonly implicated agents are listed in Table 12-3. One unusual cause is the lymphocyte recovery state in patients receiving chemotherapeutic drugs for leukemia and lymphoma following the nadir of their peripheral lymphocyte counts.23 HISTOPATHOLOGIC FEATURES Findings include a cell-poor lymphocytic interface dermatitis with basilar and suprabasilar vacuolopathy in an epidermis of normal thickness surmounted by a basketweave pattern of orthokeratinization (Fig. 12-1B). Scattered cytoid bodies may be seen along the lower layers of the epithelium with patchy parakeratosis and slight acanthosis in lesions of several days’ duration. Scattered eosinophils, histiocytes, and plasma cells are seen

Table 12-1 Clinical Forms of Drug Reactions

Table 12-2 Exanthematous Drug Reactions

Exanthematous (maculopapular) Lichenoid Fixed Photosensitivity Pustular Eczematous Bullous Porphyria and pseudoporphyria Drug-induced pemphigoid Drug-induced pemphigus Erythema multiforme and Stevens-Johnson syndrome Toxic epidermal necrolysis Psoriasiform Pityriasiform Lymphomatoid Drug-induced lupus erythematosus Collagen and elastic tissue alterations Elastosis perforans serpiginosa Sclerodermoid Alopecia Ichthyosiform Purpuric Annular erythema Erythrodermic/exfoliative Urticarial or anaphylactic Pigmentary abnormalities Vasculitis Serum sickness Halogenoderma Eosinophilia-myalgia syndrome Erythema nodosum Erythromelalgia Drug-induced hypertrichosis Drug-induced nail abnormalities Drug-induced oral abnormalities Acanthosis nigricans Hidradenitis Panniculitis Dermatomyositis

Clinical Features Salmon-colored macular or papular eruption Often polycyclic, gyrate, or reticular patterns Trunk → acral areas in symmetric distribution Dependent areas may manifest purpura Clear following drug withdrawal May progress to exfoliative erythroderma if drug continued Histopathologic Features Cell-poor lymphocytic interface dermatitis with basilar vacuolopathy Basket-weave orthokeratosis overlying epidermis of normal thickness Mixed lymphohistiocytic, eosinophilic, and/or plasmacellular dermal infiltrate Papillary dermal edema Differential Diagnosis Viral exanthemata Erythema multiforme

it should be easily excluded by clinical history, may be indistinguishable histologically from a drug eruption or viral exanthem. Acute graft-versus-host disease typically manifests a sparse perivascular lymphocytic infiltrate lacking eosinophils. Rashes of systemic connective tissue disease typically produce perivascular and periadnexal lymphoid infiltrates in concert with epidermal atrophy and dermal mucinosis.24

Table 12-3 Drugs Causing Exanthematous (Morbilliform) Eruptions

around the superficial vascular plexus (Fig. 12-2), often accompanied by papillary dermal edema. Some examples, particularly the scarlatiniform eruptions, may show no epithelial alterations. DIFFERENTIAL DIAGNOSIS Viral exanthemata and erythema multiforme reactions closely mimic exanthematous drug eruptions. Tissue eosinophilia is unusual in the former two entities, except in the context of erythema multiforme-like drug reactions. The presence of individually necrotic keratinocytes would point toward an erythema multiforme reaction. Acute graft-versus-host disease, although

Penicillin and synthetic derivatives Phenylbutazone Sulfonamide Phenytoin and carbamazepine Gold Amphotericin B Oral hypoglycemic agents Thiazides Barbiturates Benzodiazepines Phenothiazines Allopurinol Quinidine Captopril Nonsteroidal anti-inflammatory agents Gentamicin Lithium

A

B

 FIGURE 12-1 Morbilliform drug eruption. (A) Characteristic diffuse erythematous macular and papular eruption. (B) A basket-weave pattern of orthokeratinization surmounts a slightly acanthotic epidermis showing a cell-poor lymphocytic interface dermatitis.

CLINICAL FEATURES Lichenoid drug eruptions (Table 12-4) resemble lichen planus by virtue of a violaceous papular eruption with or without oral involvement. Eruptions develop in weeks to months, tend to be extensive, and often develop a psoriasiform appearance. Resolution following cessation of therapy is slow, with postinflammatory pigmentation being more pronounced than in idiopathic lichen planus. Implicated drugs are listed in Table 12-5.1,3,25-27 Lichenoid dermatitis also may be caused by ingestion of gold-containing liquor.28

HISTOPATHOLOGIC FEATURES A bandlike lymphocytic infiltrate along the dermalepidermal junction associated with vacuolopathic basal layer keratinocyte degeneration and colloid body formation is cognate to lichen planus (Fig. 12-3). Eosinophils and plasma cells frequently are present. DIFFERENTIAL DIAGNOSIS Compared with lichen planus, acanthosis is often less striking in the lichenoid drug eruption, and the wedge-shaped hypergranulosis of lichen planus, although present in some cases (see Fig. 12-3), is uncommon. Eosinophils and parakeratosis, common

 FIGURE 12-2 Morbilliform drug eruption due to fluvoxamine, an antidepressant. A vacuolar lymphocytic interface dermatitis is associated with a superficial, perivascular, lymphohistiocytic, and eosinophilic infiltrate.

in lichenoid drug eruptions, are rare in lichen planus, as is middle or deep dermal perivascular extension of the infiltrate. Lichenoid inflammation may be seen in

Table 12-4 Lichenoid Drug Reactions

Clinical Features Extensive violaceous papular eruption, sometimes with psoriasiform appearance Individual lesions resemble lichen planus Postinflammatory hyperpigmentation more pronounced than lichen planus Clear following drug withdrawal Histopathologic Features Bandlike lymphocytic infiltrate hugs dermal-epidermal junction Basilar vacuolopathy of keratinocytes and colloid body formation Patchy parakeratosis often seen Mixed lymphohistiocytic, eosinophilic, and/or plasmacellular dermal infiltrate Middermal perivascular extension Differential Diagnosis Lichen planus Connective tissue diseases with lichenoid infiltrates Subacute cutaneous lupus erythematosus Discoid lupus erythematosus Systemic lupus erythematosus in the setting of anti-Ro antibodies Mixed connective tissue disease Postherpetic eruptions Other lichenoid hypersensitivity reactions, including: Some insect bite reactions Lichenoid contact reactions (ie, color photodeveloper fluids) Erythema multiforme

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

Lichenoid Drug Eruptions

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Table 12-5 Causes of Lichenoid Drug Eruptions Beta blockers Captopril Methyldopa Thiazides Lasix Gold Antimalarials Quinidine Oral hypoglycemic agents Phenytoin and carbamazepine Antituberculous agents Phenylbutazone Antipsychotics (including phenothiazines) Bismuth p-Aminosalicylic acid Lithium

 FIGURE 12-3 Lichenoid drug eruption due to a beta blocker. Wedge-shaped hypergranulosis overlying an acanthotic epidermis with a lichenoid lymphocytic infiltrate. the setting of hepatobiliary disease such as that induced by hepatitis C infection29 and with connective tissue diseases including mixed connective tissue disease, some cases of discoid and subacute cutaneous lupus erythematosus (SCLE), and cases of systemic lupus erythematosus (SLE) in the setting of anti-Ro antibodies.24,30 However, such cases typically manifest at least focal epidermal atrophy and only exhibit tissue eosinophilia when seen in the context of drug-induced lupus erythematosus (DIL)24,25. A novel form of lichenoid drug reaction consisting of a lichenoid and granulomatous dermatitis may be seen in patients receiving sulfa drugs and other antibiotics, angiotensinconverting enzyme inhibitors, lipid-lowering agents, antihistamines, and beta blockers.31

Fixed Drug Eruption

284

CLINICAL FEATURES Fixed drug eruptions (Table 12-6) are associated with the drugs listed in Table 12-7.1-3,20,21,25,27,31-35 Over-the-counter preparations such as pseudoephedrine may go unreported to the clinician and so obscure the diagnosis.36,37 The eruptions characteristically recur in the same locations following antigenic rechallenge, with areas of involvement often increasing in size and distribution with each recurrence. The mechanism appears to reflect upregulated keratinocyte expression of intercellular adhesion molecule (ICAM)-1 and endothelial expression of E-selectin and vascular adhesion molecule-1.38 Lesions occur more often on acral and anogenital sites than on the trunk. The acute lesion, a sharply circumscribed round or oval

patch of violaceous or dusky erythema, generally arises within 30 minutes to several hours following drug administration. Vesiculation or blistering may ensue.33

Table 12-6 Fixed Drug Eruption

Clinical Features Oval or round, sharply demarcated violaceous or dusky macule Arises 30 minutes to several hours after drug ingestion Anogenital areas, especially glans penis, and acral sites most common Vesiculation and blistering may ensue Areas of involvement tend to expand and multiply with drug rechallenge Postinflammatory hyperpigmentation Clear following drug withdrawal Histopathologic Features Variably bandlike lymphocytic interface infiltrate Basilar vacuolopathy of keratinocytes and colloid body formation, often accentuated at tips of retia Acanthosis more pronounced than erythema multiforme Patchy parakeratosis often seen Mixed lymphohistiocytic, eosinophilic, plasmacellular, and neutrophilic dermal infiltrate, often superficial and deep Differential Diagnosis Erythema multiforme Viral exanthema Connective tissue disease Graft-versus-host disease

Multifocal and extensive eruptions may resemble erythema multiforme and toxic epidermal necrolysis, respectively. Lesions may progress to scaling and resolve with striking postinflammatory pigmentary alteration. HISTOPATHOLOGIC FEATURES The fixed drug eruption manifests a lymphocytic

Table 12-7 Drugs Associated with Fixed Drug Eruptions Antibiotic agents Sulfonamides Tetracycline Penicillin and synthetic penicillins Trimethoprim Antifungal agents Dapsone Arsenicals p-Aminosalicylic acid Antimalarials Flagyl Sedatives Barbiturates Opiates Benzodiazepines Anticonvulsants Dextromethorphan Nonsteroidal anti-inflammatory agents Acetylsalicylic acid Phenylbutazone Ibuprofen Miscellaneous agents

eosinophilic, neutrophilic, and plasma cellular infiltrates, inclusive of intraepithelial eosinophilic microabscesses. The cytoid bodies in erythema multiforme tend to be scattered across the breadth of a 3- or 4-mm punch biopsy as opposed to clustered around rete ridges, as seen in the fixed drug eruption. Graftversus-host disease and viral exanthemata are usually pauci-inflammatory and lack granulocytes.

Photosensitivity Drug Eruptions

 FIGURE 12-4 Fixed drug eruption. A lymphocytic interface dermatitis is present showing focal accentuation at tips of retia associated with striking colloid body formation and a dermal, perivascular, and bandlike lymphocytic and eosinophilic infiltrate.

interface dermatitis with rete ridge accentuation associated with marked colloid body formation, often with a superficial and deep dermal perivascular lymphocytic and eosinophilic infiltrate (Fig. 12-4). Clusters of colloid bodies are seen in the damaged retia. There may be an admixture of neutrophils or plasma cells or both. Later in lesional evolution, more pronounced epithelial necrosis

and pigment incontinence may be seen (Fig. 12-5). Neutrophilic fixed drug eruptions occur rarely.39 DIFFERENTIAL DIAGNOSIS Fixed drug eruptions can be distinguished from erythema multiforme by virtue of relatively greater epithelial hyperplasia, pigment incontinence, deeper extension of lymphoid infiltration, and more frequent

 FIGURE 12-5 Fixed drug eruption in a patient on Premarin. More pronounced epidermal necrosis and colloid body formation are seen, and a bandlike dermal lymphocytic and eosinophilic infiltrate are associated with pigment incontinence.

Table 12-8 Photosensitivity Drug Reactions

Clinical Features Erythematous macular, papular, or vesicular eruptions in a photodistribution, sparing submental and retroauricular areas Phototoxic: occur 5-20 hours after exposure to drug and light Photoallergic: occur within 24 hours of repeat antigenic challenge with drug and sunlight and may occur on non-sun-exposed skin Combined phototoxic/photoallergic eruptions common Histopathologic Features Phototoxic Keratinocyte injury (apoptosis or reticular degeneration) at all levels with architectural disarray and dysmaturation Neutrophilic epidermotropism at sites of injury Perivascular lymphocytic infiltrate in dermis Superficial vasculature ectatic with endothelial swelling Photoadaptive: hypergranulosis, hyperkeratosis, and melanocytic hyperplasia Photoallergic Spongiosis and vesiculation with adherent scale-crust Mixed lymphohistiocytic and eosinophilic dermal infiltrate Papillary dermal edema Differential Diagnosis Phototoxic Viral exanthemata Erythema multiforme Graft-versus-host disease Photoallergic: delayed-type hypersensitivity reactions of diverse cause

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

CLINICAL FEATURES Drugs that induce photosensitivity absorb electromagnetic radiation in the ultraviolet (UV) and visible ranges, the former mainly consisting of UVA (320-400 nm) and UVB (290-320 nm) (Table 12-8). In phototoxic

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reactions, the drug absorbs radiation and enters an excited state, producing species that react with other cellular constituents, including reactive oxygen species. In photoallergic reactions, the drug is converted into an immunologically active compound. Interactions between drugs and UV light produce eruptions in a photodistribution, sparing the submental and retroauricular areas and upper eyelids. Phototoxic eruptions characteristically occur within 5 to 20 hours of first exposure to a drug and resemble an exaggerated sunburn reaction, being characterized by erythema with blistering, vesiculation, desquamation, and hyperpigmentation of sun-exposed skin. Photoallergic eruptions require a latent period for sensitization and characteristically appear within 24 hours of repeat antigenic challenge with both drug and UV light. Unlike purely phototoxic reactions, photoallergic eruptions also may be seen on non-sun-exposed sites. Most drugs associated with photoallergy, if given in sufficient quantities, can induce

a phototoxic reaction. Combined photallergic-phototoxic eruptions are common. Implicated drugs are listed in Table 12-9.1-3,20,21,40,41 HISTOPATHOLOGIC FEATURES The phototoxic eruption manifests keratinocyte injury at all levels of the epidermis with architectural disarray and dysmaturation (Fig. 12-6). Parakeratosis may surmount areas of epithelial injury, the patterns of which include apoptosis and reticular degeneration. Neutrophils may infiltrate the epidermis at sites of injury. There is a variable perivascular mononuclear cellpredominant infiltrate that is accentuated around the superficial vascular plexus and manifests exocytosis. Blood vessels usually are dilated and show endothelial swelling or necrosis that diminishes in the depths of the biopsy and is accompanied by hemorrhage. The photoadaptive reaction (Fig. 12-7) shows hypergranulosis, hyperkeratosis, melanocytic hyperplasia, suprabasilar melanization, and transepidermal elimination of melanin. Photoallergic features consist of epidermal spongiosis and vesiculation, which frequently eventuates in an adherent

plasma-rich scale crust. Eosinophils are a frequent component of the infiltrate. In eruptions of combined phototoxicphotoallergic type, variable expressions of these two prototypic morphologies are seen. Some patients develop persistent photosensitivity at exposed and nonexposed skin sites. If accompanied by skin infiltration by transformed lymphocytes, the designation chronic photosensitivity dermatitis may be appropriate. Histologically, the presence of intraepithelial cerebriform lymphocytes arranged into groups surrounded by a clear halo reminiscent of Pautrier microabscesses results in a histologic pattern mimicking mycosis fungoides. DIFFERENTIAL DIAGNOSIS Subacute and chronic dermatitides of diverse causes mimic photoallergic eruptions but generally lack the scattered epidermal cytoid bodies and vascular alterations of phototoxic states and the photoadaptive changes in melanocytes. The nodular perivascular distribution of the infiltrates, psoriasiform hyperplasia, multinucleated stromal giant cells, and perivascular elastolysis, in concert with the clinical history,

Table 12-9 Drugs Associated with Photosensitivity Eruptions Common Amiodarone (PA) Phenothiazines (PA, PT, pigmentation) Psoralens (PT) Sulfonamides Tetracyclines (PT) Thiazide diuretics (lichenoid, LE-like) Nonsteroidal anti-inflammatory agents (PA, PT, PCT-like) Nalidixic acid (PA, PT, PCT-like) Coal tar Quinidine (lichenoid, eczematous) Uncommon Antihistamines (PA) Synthetic penicillins Antidepressants (PA, PT) Antifungal agents (PA) Beta blockers Anticonvulsants (PA) Benzodiazepines (PA) Methyldopa Oral contraceptives (PA) Antimalarials (PA, PT) Retinoids (PA, PT) Sun screens (PA) Oral hypoglycemics (PA) PA = predominately photoallergic. PT = predominately phototoxic. PCT = porphyria cutanea tarda. LE = lupus erythematosus.

 FIGURE 12-6 Phototoxic drug eruption. Cytoid bodies are present along the basal layer, in suprabasilar epidermis, and in the cornified layer. Ectasia of superficial blood vessels, associated with endothelial swelling, is characteristic.

neutrophilic dermal infiltrate unaccompanied by leukocytoclastic vasculitis.52-56

Eczematous Drug Reactions enable distinction of the chronic photosensitivity dermatitides from mycosis fungoides.

With respect to drug-induced pustular Sweet-like eruption, biopsies show massive papillary dermal edema and a diffuse

CLINICAL FEATURES Oral ingestion, inhalation, or transcutaneous application of a drug to which a person has been previously sensitized via contact exposure may

Pustular Eruptions CLINICAL FEATURES Acute generalized exanthematous pustulosis (AGEP) is a distinctive generalized toxic pustular erythema associated with reactions to drugs, including calcium channel blockers, nonsteroidal anti-inflammatory agents, anticonvulsants, b-lactam and macrolide antimicrobials, and antifungal agents.42-50 Less common associations are with antiarrhythmic agents, including quinidine, and contact with mercury. Typically, patients present with a generalized scarlatiniform eruption of sudden onset that is studded with sterile pustules, is associated with fever, and follows a self-limited course of 4 to 17 days.51 A drug-induced eruption mimicking Sweet syndrome has been described in the setting of therapy with diltiazem, sulfamethoxasole-trimethoprim, minocycline, oral contraceptives, and nonsteroidal anti-inflammatory agents and in patients receiving colony-stimulating factors for therapy of leukemic or congenital neutropenic states.52-56 HISTOPATHOLOGIC FEATURES Biopsies of AGEP lesions show spongiform pustulation of the epidermis typically with follicular and acrosyringeal accentuation (Fig. 12-8). An accompanying leukocytoclastic vasculitis may be seen but is not typical in our experience.

 FIGURE 12-8 Pustular drug eruption. Spongiform pustulation involving a hair follicle is accompanied by a subcorneal pustule in the adjacent interfollicular epidermis and a perivascular and diffuse dermal infiltrate of lymphocytes and eosinophils.

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

 FIGURE 12-7 Photoallergic drug eruption in a patient on amiodarone. Hypergranulosis, hyperkeratosis, and acanthosis are seen, and a plump photoactivated melanocyte is present in the basal layer.

DIFFERENTIAL DIAGNOSIS The main considerations include variants of pustular psoriasis, infection, and neutrophilic dermatoses, including Sweet syndrome. A leukocytoclastic vasculitis is not seen in lesions of psoriasis, except in the setting of concomitant hypersensitivity reactions, such as due to drugs. When a psoriasiform diathesis is seen in concert with a leukocytoclastic vasculitis, Reiter disease merits strong consideration.57 It has been suggested that some patients with AGEP have latent psoriasis58 or underlying immune dysregulation, such as that due to HIV infection.51,59 Pustular IgA vasculitis is also seen in patients with mucosal infections.60 Other pustular eruptions such as Sneddon-Wilkinson syndrome or impetigo show broad subcorneal pustulation or admixed bacteria, respectively; both lack acrosyringeal centricity.

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Table 12-10 Eczematous Drug Reactions

Clinical Features Erythematous, papular, or vesicular eruption in patients exposed to an agent to which they were previously sensitized Sites often correspond to those previously affected Histopathologic Features Spongiosis and intraepidermal vesiculation Moderately dense dermal lymphocytic and eosinophilic infiltrate with variable exocytosis Differential Diagnosis Other delayed-type hypersensitivity reactions of diverse cause

elicit an eczematous drug reaction61 (Table 12-10). Affected sites frequently correspond to those involved in a prior contact dermatitis, with symptoms arising 2 to 24 hours after an oral dose. The term baboon syndrome has been used to describe bright-red, well-demarcated anogenital lesions associated with a symmetric eczematous eruption involving elbow flexures, axillae, eyelids, and the sides of the neck. Drugs commonly associated with eczematous reactions include antibiotics and ethylenediaminecontaining antihistaminic and aminophylline preparations.1,2,20,21 HISTOPATHOLOGIC FEATURES Biopsies show spongiosis with intraepidermal vesiculation and a moderately dense lymphoeosinophilic infiltrate with variable exocytosis of lymphocytes and eosinophils.61 DIFFERENTIAL DIAGNOSIS Hypersensitivity reactions to a variety of antigenic triggers will look similar.

Blistering Drug Eruptions The blistering drug eruptions include pseudoporphyria cutanea tarda, bullous erythema multiforme, bullous fixed drug eruption, and drug-induced pemphigus, pemphigoid, and linear IgA dermatosis.62-64

Drug-Induced Pseudoporphyria Cutanea Tarda

288

Pseudoporphyria cutanea tarda is a blistering disorder reminiscent of porphyria cutanea tarda by virtue of clinical, histologic, and immunofluorescent findings64 but in which porphyrin metabolism is normal. Patients often have an underlying

connective tissue disease.63 This process is discussed in Chap. 7.

Drug-Induced Pemphigus CLINICAL FEATURES AND PATHOGENESIS In idiopathic pemphigus, autoantibodies are directed at antigenic targets that include a 130-kDa glycoprotein complexed to an 85-kDa cytoplasmic plaque protein called plakoglobin to form the adhesion molecule desmoglein III in pemphigus vulgaris and a 165-kDa cell adhesion molecule termed desmoglein I in pemphigus foliaceus.64,65 The distribution of desmoglein I in buccal mucosa, scalp, and lower torso correlates with lesional distribution. Drug-induced blistering eruptions may present as a superficial pemphigus state, as grouped annular plaques mimicking pemphigus herpetiformis, or with a picture cognate to pemphigus vulgaris. A preblistering prodrome, either a morbilliform or an urticarial eruption similar to a morbilliform or urticarial drug rash, helps to distinguish drug-induced from idiopathic pemphigus. The main agents implicated include those which contain a thiol (sulfhydryl) group, such as angiotensinconverting enzyme inhibitors, penicillamine, and gold sodium thiomalate, and nonthiol drugs such as penicillin and its derivatives, cephalosporins, pyrazolone derivatives such as phenylbutazone, and miscellaneous drugs. It is postulated that sulfhydryl groups of offending drugs bind to the disulfide bond-rich intercellular junctions and so render them antigenic. The drug-induced autoantibodies have similar specificities to those seen in idiopathic pemphigus.66 Thiols also can induce a superficial IgA pemphigus state mimicking idiopathic subcorneal pustular dermatosis of Sneddon-Wilkinson.67 In some patients in whom antibodies are not demonstrable, the blisters may reflect a direct toxic chemical effect on intercellular junctions. HISTOPATHOLOGIC FEATURES Early lesions may exhibit nondiagnostic parakeratosis, spongiosis, and a lymphoeosinophilic dermal infiltrate. The fully-evolved blistering lesions are identical to their idiopathic counterparts (ie, superficial pemphigus, pemphigus vulgaris, or subcorneal pustular dermatosis). Direct immunofluorescence (DIF) microscopy reveals pericellular deposition of immunoreactants in the perilesional epidermis in 90% of cases64 in a distribution that does not reliably correlate with antibody specificity or pemphigus subtype. Some 70% of patients have circulating antibodies by indirect immunofluorescence testing.

Drug-Induced Pemphigoid CLINICAL FEATURES AND PATHOGENESIS Bullous pemphigoid (BP) is an autoimmune blistering dermatosis typically seen in elderly patients who manifest tense blisters on an erythematous or urticarial base involving the trunk, extremities, and intertriginous areas. Typical are IgG antibodies directed at antigenic targets of 230 and 180 kDa localized to the lamina lucida of the basement membrane zone (BMZ) that are components of the hemidesmosome.64,68 Circulating antibodies usually are detectable in sera. A drug-induced BP syndrome is seen in patients receiving furosemide, penicillamine, penicillins, salicylazosulfapyridine, sulfasalazine, and phenacetin. Case-control studies show enhanced relative risk with diuretic and neuroleptic agents.68 Clinical presentations range from classical BP-like lesions to scarring plaques affecting mucosal sites in the fashion of cicatricial pemphigoid,69 an erythema multiforme-like picture, and a pemphigus-like morphology. HISTOPATHOLOGIC FEATURES Skin biopsies show a subepidermal eosinophilrich blister reminiscent of that seen in BP, and DIF testing shows linear IgG and C3 in the BMZ of the dermal-epidermal junction in a fashion indistinguishable from idiopathic BP.

Drug-Induced Linear IgA Disease CLINICAL FEATURES AND PATHOGENESIS Classic linear IgA disease presents as a vesiculobullous eruption of the trunk, inner thighs, and pelvic region that may resemble dermatitis herpetiformis and/or BP but is never symmetric, is inconstantly pruritic, and exhibits mucosal involvement in up to 50% of patients. Some patients manifest mucosal scarring, as seen in cicatricial pemphigoid, typically in the setting of IgA antibodies directed at type VII collagen.70,71 Linear IgA disease has been associated with such drugs as antibiotics (vancomycin, penicillins, cetriaxone, metronidazole, Septra, and rifampicin), lithium, Dilantin, lipid-lowering agents, furosemide, angiotensin-converting enzyme inhibitors, granulocyte colony-stimulating factor, piroxicam, and diclophenac.72-83 While drug-associated linear IgA disease clears with drug cessation, a rechallenge may generate a more severe eruption with a shorter latent period.72-75 HISTOPATHOLOGIC FEATURES Characteristic is a neutrophil-rich interface dermatitis with effacement of the epidermal

Table 12-11 Drug Classes Associated with Drug-Induced Lupus Erythematosus Antihypertensive Antipsychotic Anticonvulsant Anti-inflammatory Antimicrobial Immunosuppressive Antihormonal Recombinant cytokines

vary somewhat with drugs from different classes, skin disease in general is less frequent and pulmonary manifestations more common than in idiopathic LE. A systemic LE-like syndrome is characteristic, although some cases resemble discoid LE clinically. A form of drug-induced SCLE is seen in the setting of therapy with calcium channel blockers and antihistaminic preparations.25,92 The prototypical drugs associated with DIL generate two distinctive serologic profiles; chlorpromazine and hydralazine are associated with antihistone antibodies, and procainamide and quinidine generate anti–H2a-H2b-DNA antibodies, the latter directed at a histone-DNA complex. Predisposition to the development of DIL tends to be in part genetically determined; patients are often slow acetylators and thus metabolize hydralazine and

procainamide slowly. Although the mechanisms by which these agents provoke DIL are not fully elucidated, we know that procainamide and hydralazine inhibit T-cell DNA methylation, provoking autoreactivity in cloned T-helper (Th) lymphocytes, and perhaps share the capacity to induce autologous B-cell differentiation. Passive transfer of Th cells treated with procainamide or other DNA methyltransferase inhibitors causes a lupus-like illness in syngeneic mice. Agents most closely associated with DIL, including methyldopa, procainamide, chlorpromazine, and hydralazine, are known to disturb a variety of lymphocyte functions, as do calcium channel blockers and antihistaminics. This may create an immunologic milieu permissive of the development of autoantibodies against ribonucleoproteins.92 With respect to the SCLE-like eruptions, most patients are women with photoinduced annular papulosquamous lesions in whom serologic studies demonstrate a positive ANA assay with or without anti-Ro, anti-La, and anticentromere antibodies.92 HISTOPATHOLOGIC FEATURES Light microscopic and DIF studies tend to show features typical for LE,24,93 namely, SLE in the case of methyldopa, procainamide, chlorpromazine, and hydralazine and SCLE in patients receiving calcium channel blockers92 or antihistaminics25 (Fig. 12-9). The histologic features of LE

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

architecture, variable tissue eosinophilia, and subepidermal blisters containing granulocytes and fibrin. It is postulated that IgA binding to specific antigenic components of the BMZ may cause hemidesmosomes to function as a ligand for neutrophil adherence and activation. Routine DIF studies show a thin, linear band of homogeneous IgA decoration along the dermal-epidermal junction. Immuno-ultrastructural localization shows the IgA deposition to be variably in the lamina lucida or hemidesmosomal plaques and adjacent lamina lucida, below the lamina densa, or on both sides of the lamina densa.84 A 97-kDa/120-kDa antigen and a 285-kDa dermal antigen are the target antigens,85 with antibodies to the former targeting the anchoring filament protein ladinin (LAD-1) synthesized and secreted by keratinocytes.86 LAD-1 is sandwiched between the NC-16A and the carboxylterminal domains of BPAg2, a localization that also encompasses the collagenous domain of BPAg2.87,88 The NC-16A domain of BPAg2 is found within the plasma membrane of the hemidesmosomal complex, whereas the carboxyl terminus of BPAg2 is in the lower lamina lucida; thus LAD-1 and the extracellular portion of BPAg2 co-localize in the lamina lucida.89 Since the 285-kDa antigen represents the NC-1 domain of collagen type VII, there is clinical overlap with epidermolysis bullosa aquisita.85 Most patients with idiopathic or drug-induced linear IgA disease manifest antibodies of IgA and IgG classes directed against BPAg2, particularly the carboxyl-terminal portion,90 also the major target region of antibodies in cases of cicatriceal pemphigoid. The latter finding may explain the clinical overlap between the two conditions from the standpoint of cicatricial mucosal involvement. Immunoblotting techniques demonstrate antibodies to type VII collagen, LAD-1, and BPAg1 in cases of drug-associated linear IgA disease.73,91

Drug-Associated Lupus Erythematosus-Like Eruptions CLINICAL FEATURES Drug-induced lupus erythematosus (DIL) occurs with a variety of medication classes (Table 12-11) and should be suspected in patients who, in the absence of underlying lupus erythematosus (LE), develop antinuclear antibodies (ANAs) and at least one clinical manifestation of LE while ingesting a drug and in whom symptoms abate after its discontinuance.1,2,24 Although the clinical stigmata of DIL

 FIGURE 12-9 Drug-induced subacute lupus erythematosus in a patient on diltiazem. A lymphocytic interface dermatitis is associated with epidermal atrophy, vacuolar basal layer degeneration, cytoid body formation, and suprabasilar lymphocytic satellitosis around degenerating keratinocytes.

289

are discussed elsewhere24 (see Chaps. 3 and 5).

Table 12-13 Histologic Features of the Lymphomatoid Hypersensitivity Reaction

DIFFERENTIAL DIAGNOSIS Concomitant features typically associated with delayed-type hypersensitivity reactions, namely, tissue eosinophilia and epithelioid histiocytic granulomata, may be seen and are distinguishing features from idiopathic LE.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Lymphomatoid Drug Eruptions CLINICAL FEATURES Lymphomatoid drug reactions are a type of lymphomatoid hypersensitivity reaction,5 a spectrum that also encompasses aberrant and excessive immune reactions to other antigenic stimuli inclusive of insect bites,94 viruses, bacteria, contactants, and light.95 The most frequently encountered drugs are listed in Table 12-12.5,96-100 Patients often receive two or more such drugs, suggesting a synergistic or cumulative effect on lymphoid function. Although the iatrogenic causes of immune dysregulation usually reflect the ingestion of one or more drugs with immune-dysregulating properties,100 patients often have underlying systemic immune-perturbing conditions such as malignant lymphoma, HIV infection, or connective tissue disease.5 Lesions present as one or more plaques resembling mycosis fungoides, as multiple papules, or as a solitary nodule. Long-term clinical follow-up is necessary because distinction from lymphoma can be difficult and because progression from pseudolymphoma to malignant

MYCOSIS FUNGOIDES-LIKE PATTERN OF LYMPHOMATOID HYPERSENSITIVITY

FEATURES COMMON TO MYCOSIS FUNGOIDES AND LYMPHOMATOID HYPERSENSITIVITY

Infiltration of the epidermis by mildly atypical lymphocytes or by cells with a comparable cytomorphology to the small and intermediate-sized atypical dermal lymphocytes Sézary cells Directed pattern of epidermal infiltration with maximal involvement of suprapapillary plates/adnexaea Vesiculationa Papillary dermal edemaa No Pautrier’s microabscesses Vascular fibrin depositiona

Dermal Sézary cells

Atrophy Vascular ectasia Dermal fibrosis, either vertical or laminated

a

Histologic features characteristic of delayed-type hypersensitivity reactions.

lymphoma can occur.5 Immune dysregulation may persist for weeks after a drug is discontinued; failure of an eruption to resolve within several weeks should not be held to indicate a diagnosis of malignant lymphoma, although lesional persistence several months after appropriate drug modulation should prompt that consideration.5 HISTOPATHOLOGIC FEATURES Distinctive patterns seen in the context of the lymphomatoid drug reaction (Table 12-13) include the MF-like pattern (Fig. 12-10),

the lymphomatoid vascular reaction (Fig. 12-11), follicular mucinosis, and lymphocytoma cutis. The MF-like pattern combines features of epidermotropic cutaneous T-cell lymphoma (CTCL) with histologic hallmarks of delayedtype hypersensitivity,5,96,97 including basilar vacuolopathy, spongiosis, vesiculation, keratinocyte nec-rosis, and papillary dermal edema. Epithelial infiltration is frequently only mild and is of maximal intensity in suprapapillary plates and adnexae, sites of preferential antigenic processing.5 The lymphomatoid

Table 12-12 Drugs Implicated in Pseudolymphomata ACE inhibitors Alpha antagonists Anticonvulsants Antidepressants Benzodiazepines Beta blockers Calcium channel blockers H1 antagonists H2 antagonists Lithium Lipid-lowering agents Nonsteroidal anti-inflammatory agents Phenothiazines Sex steroids

290

ACE = angiotensin-converting enzyme. H1 = histamine receptor, type 1. H2 = histamine receptor, type 2.

 FIGURE 12-10 Lymphomatoid hypersensitivity reaction (mycosis fungoides-like) in a patient on amitriptyline. A bandlike dermal lymphocytic infiltrate is present and shows haphazard epidermotropism with minimal spongiosis; in other areas not shown, the epidermis was spared, unlike mycosis fungoides, where epidermal involvement is continuous in shave biopsy specimens.

drugs that can induce cutaneous sclerosis are bromocriptine, lithium, valproic acid, hydantoins, b-interferon, hydroxyurea, and L-tryptophan.1,2,106 Sclerodermoid tissue reactions localized to injection sites are associated with corticosteroids, heparin, vitamin K1, pentazocine, and prior radiotherapy. With respect to pathobiology, the ergot derivatives provoke peripheral vasoconstriction that damages capillary endothelium. A reduction in cyclic AMP levels promotes collagen synthesis and is the proposed mechanism of fibrosis in patients receiving beta blockers. Trytophan-associated eosinophilic fasciitis is addressed elsewhere.

vascular reaction manifests an angiocentric infiltrate of atypical lymphocytes that obscures the vessel architecture, usually without fibrinoid necrosis (see Fig. 12-11). DIFFERENTIAL DIAGNOSIS The mycosis fungoides-like lymphomatoid hypersensitivity reaction pattern is distinguished from MF by virtue of the architecture of the lymphoid infiltrate, the lack of intraepidermal Sézary cells, infrequent apoptosis of lymphocytes, low mitotic rates, tingible body macrophages, and often by lymphocyte polyphenotypy and polygenotypy. Recent studies have demonstrated both clonal restriction and aberrantly diminished expression of CD5 and CD7 in some cases, suggesting that a form of reversible drug-induced cutaneous T-cell dyscrasia at times may be operative.101,102 The lymphomatoid vascular reaction pattern may be seen in a variety of neoplastic and nonneoplastic lesions, including angioimmunoproliferative lesions (AILs) ranging from lowgrade lymphomatoid granulomatosis to angiocentric T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid papulosis, angioimmunoblastic lymphadenopathy, delayed-type hypersensitivity reactions, and lymphomatoid connective tissue disease.103,104

Drug-Associated Alopecia Drugs-induced alopecia occurs primarily through two mechanisms: induction of

telogen effluvium or mitotic arrest of anagen hair (anagen effluvium) (see Chap. 10). Causes of the former include anticoagulants, lithium, and boric acid, whereas chemotherapeutic agents cause the latter. Although virtually any drug may induce alopecia, only a few are associated routinely with hair loss. Exacerbation of hair loss with reexposure and hair recovery following withdrawal are the best evidence to incriminate a specific drug. Other drugs associated with diffuse hair loss through unclear mechanisms include naproxen, colchicine, thiamphenicol, amiodarone, levodopa, anticonvulsants, and estrogen therapy following withdrawal.21,105 HISTOPATHOLOGIC FEATURES Drugs associated with a lichenoid reaction, the prototype being quinidine, can produce a scarring alopecia (see Chap. 10). DIFFERENTIAL DIAGNOSIS Distinction of drug-induced alopecia from idiopathic anagen and telogen effluvium may be impossible. The lichenoid infiltrate provoked by quinidine mimics lichen planopilaris but lacks hypergranulosis of the interfollicular epidermis and may manifest eosinophilic infiltrates.

Sclerodermoid Tissue Reactions Drugs implicated in the pathogenesis of fibrosing disorders include serotonin, methysergide and other ergot alkaloids, practolol, and hydralazine. Among the

DIFFERENTIAL DIAGNOSIS The morphology is indistinguishable from idiopathic morphea and from sclerodermoid alterations associated with connective tissue disease and Borrelia infection.

Other Alterations of Collagen and Elastic Fibers Associated With Drug Therapy Cutis laxa, anetoderma, elastosis perforans serpiginosa, and pseudoxanthoma elasticum, the clinical and histopathologic features and differential diagnosis of which are considered elsewhere, can be provoked by drugs1,2 (Table 12-14).

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

 FIGURE 12-11 Lymphomatoid vascular reaction in a patient on diazepam. A perivascular and transmural infiltrate of mature and transformed lymphocytes is present and is unaccompanied by vascular fibrin deposition.

HISTOPATHOLOGIC FEATURES Scleroder-moid tissue reactions demonstrate widened collagen fibers with diminished fibrillar striations and interstitial infiltrates of lymphocytes and plasma cells.

Side Effects of Chemotherapeutic Agents CLINICAL FEATURES Chemotherapyinduced reactions include acral erythema characterized by erythema and swelling

Table 12-14 Alterations of Collagen and Elastic Fibers by Drugs Elastosis perforans serpiginosa Tiopronine D-Penicillamine Cutis laxa/pseudoxanthoma elasticum-like Penicillin Isoniazid L-Tryptophan D-Penicillamine Anetoderma Penicillamine

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 292

of the hands after administration of fluorouracil, Taxol, doxorubicin, methotrexate, and arabinoside1,107,108; neutrophilic hidradenitis109; and radiation recall dermatitis provoked by doxorubicin, oxaliplatin, and methotrexate, in which an eruption occurs in a previously quiescent radiation field.110,111 As mentioned earlier, a fibrosing dermopathy can be induced by hydroxyurea, as can the erosion of psoriatic plaques in patients treated for psoriasis over long time periods.112

tration of other drugs, such as lithium,114 or of id reactions to microbial pathogens.

HISTOPATHOLOGIC FEATURES Acral erythema manifests as basilar vacuolopathy accompanied by focal dyskeratosis107 (Fig 12-12). In radiation-recall dermatitis, an atrophying interface dermatitis characterized by basilar vacuolopathy and superficial vascular ectasia is observed (personal observation). Neutrophilic eccrine hidradenitis manifests neutrophilic infiltrates surrounding and permeating the eccrine apparatus with epithelial cell degeneration and necrosis.109 Eccrine ducts may exhibit squamous syringometaplasia, manifesting comma-shaped structures showing mat-ure squamous epithelium113 in response to a variety of chemotherapeutic agents.

HISTOPATHOLOGIC FEATURES The prototypical drug-induced vasculitis is a leukocytoclastic vasculitis confined to the superficial vascular plexus and sometimes accompanied by significant tissue eosinophilia115; the histopathology and differential diagnosis are discussed elsewhere. Older lesions of drug-associated vasculitis may be predominated by mononuclear cells. A pandermal severe LCV such as typifies systemic vasculitic syndromes is not a feature of druginduced vasculitis; granulomatous vasculitis is uncommon. A lymphocytic vascular reaction with hemorrhage can be observed in drug-induced vasculitides, but the presence of tissue eosinophilia and absence of luminal thrombosis are unlike the prototypical lymphocytic vasculitides of connective tissue disease.115 A pustular hypersensitivity vasculitis associated with vascular IgA deposition is seen in the setting of therapy with drugs including carbamazepine.116 The pigmented purpuric dermatoses, for

DIFFERENTIAL DIAGNOSIS Connective tissue diseases, erythema multiforme, and viral exanthemata mimic acral erythema lesions; the incipient lesion is often indistinguishable from acute graft-versus-host disease. Neutrophilic eccrine hidradenitis may be a manifestation of the adminis-

Drug-Associated Vasculitis Including Serum Sickness CLINICAL FEATURES Drug-associated vasculitis in the skin is expressed as palpable purpura or a maculopapular rash. Some implicated drugs and their associated vascular injury patterns are listed in Table 12-15.1,2

 FIGURE 12-12 Taxotere-induced acral erythema. There are scattered cytoid bodies within the epidermis that appear concentrated in the acrosyringia as confirmed in deeper levels.

which a lymphocyte-mediated vascular injury state is the pathophysiologic basis, are associated in some cases with the intake of sedatives, nonsteroidal anti-inflammatory drugs, and antibacterial and antifungal agents such as itraconozole.116,117 An IgA-mediated pigmented purpura has been described in the setting of therapy with captopril.118 Drug-associated atypical pigmentary purpura is a form of lymphocytic vasculopathy that represents roughly 50% of all cases of pigmentary purpura showing lymphoid atypia and epitheliotropism and so mimicking purpuric mycosis fungoides.119 The implicated drugs fall in the

Table 12-15 Drug-Associated Vasculitis Leukocytoclastic vasculitis, not otherwise specified Phenylbutazone Indomethacin Allopurinol Penicillins Erythromycin Sulfonamides Thiazide diuretics Hydantoins Henoch-Schonlein purpura Acetylsalicylic acid Penicillins Quinine Thiouracil Gold Pustular vasculitis Naproxen Penicillins Ampicillin Amoxicillin Furosemide Diltiazem Carbamazepine Mercury Pigmentary purpuras Bromhexine Carbromal Bromisoval Captopril Polyarteritis nodosa-like Acetylsalicylic acid Sulfasalazine Allopurinol Sulfamethoxazole Sulfonamides Quinidine Phenytoin Meprobamate Thiouracil Potassium

immune-dysregulating classes considered to be causal of pseudolymphomata.

Psoriasiform Drug Reactions A variety of drugs can be associated with a psoriasiform eruption and/or with the induction or exacerbation of psoriasis1,2,21 (Table 12-16).

DIFFERENTIAL DIAGNOSIS The hallmark of the psoriasiform diathesis, namely, tortuous dermal papillae capillaries in apposition to thinned suprapapillary plates, is not seen except in the context of drugs that induce or aggravate underlying psoriasis, whereby the histomorphology is indistinguishable from psoriasis, save for the presence of tissue eosinophilia.

Pityriasiform Eruptions CLINICAL FEATURES Drugs associated with eruptions resembling pityriasis rosea are listed in Table 12-17.1,2

Table 12-16 Drugs that Induce or Aggravate Psoriasiform Eruptions ACE inhibitors Acetylsalicylic acid Morphine Ibuprofen Codeine Ampicillin Chloroquin Quinidine Beta blockers Propanolol Pindolol Practolol Lithium Cyclosporine Gold Arsenic Iodine Penicillamine Interleukins Interferon Etretinate Methoxsalen

 FIGURE 12-13 Psoriasiform drug eruption in a patient of African origin. Psoriasiform hyperplasia of epidermis is present with a nodular perivascular dermal lymphocyte-predominant infiltrate; unlike true psoriasis, tortuous dermal papillae capillaries in apposition to thinned suprapapillary plates are not seen.

HISTOPATHOLOGIC FEATURES These reactions are morphologically indistinguishable from pityriasis rosea, the hallmarks of which are a subacute dermatitis with focal parakeratosis, superficial erythrocyte extravasation, dyskeratosis, and tissue eosinophilia. DIFFERENTIAL DIAGNOSIS The histopathology of pityriasis lichenoides chronica can look similar to the pityriasiform drug eruption but is usually separable by the presence of eosinophils in the latter. The epithelial injury of pityriasis lichenoides et varioliformis acuta is usually greater, and the dermal infiltrate, as in pityriasis lichenoides chronica, is usually purely lymphocytic.

Drug-Associated Ichthyosiform Dermatoses CLINICAL FEATURES Certain classes of drugs may provoke ichthyosiform reactions (Table 12-18).

HISTOPATHOLOGIC FEATURES The histopathology resembles ichthyosis vulgaris by virtue of laminated orthohyperkeratosis, a diminished or absent granular cell layer, and in some cases, attenuation of the epidermis. DIFFERENTIAL DIAGNOSIS Distinction from ichthyosis vulgaris under the microscope can be impossible, although the presence of eosinophils tends to point toward a drug-based etiology. Most other heritable ichthyosis states manifest a normal or increased granular cell layer, as discussed elsewhere (see Chap. 14).

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

HISTOPATHOLOGIC FEATURES Psoriasiform epidermal hyperplasia, granular cell layer diminution, and foci of neutrophil-imbued parakeratosis are variably accompanied by an interface dermatitis, spongiotic epithelial changes, eosinophilia, and focal dyskeratosis (Fig. 12-13). Some patients also manifest a lichenoid infiltrate, particularly those taking beta blockers.

Erythema Multiforme, Including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Drugs implicated in erythema multiforme and toxic epidermal necrolysis are listed in Tables 12-19 and 12-20.1,2 The clinical and histologic features are

Table 12-17 Drugs Associated with Pityriasiform Reactions

Table 12-18 Drugs Inducing Ichthyosiform Dermatoses

Acetylsalicylic acid Griseofulvin Metronidazole Captopril Clonidine Gold Arsenic

Allopurinol Clofazimine Hydrochlorothiazide Nicotinic acid (niacin) Dyrazine Ergocalciferol Lipid-lowering agents

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 12-19 Erythema Multiforme and StevensJohnson Syndrome Pyrazolone derivatives including phenylbutazone and oxyphenbutazone Penicillins Slowly excreted sulfonamides Ampicillin Salicylates Salazopyrin Barbiturates Phenobarbital Hydantoins Carbamazepine Phenothiazine derivatives D-Penicillamine

Table 12-20 Toxic Epidermal Necrolysis Sulfonamides Trimethoprim and sulfadoxine Trimethoprim and sulfamethoxazole Pyrazalones including phenybutazone and allopurinol Barbiturates Anti-inflammatory drugs Tetracycline Nitrofurantoin Antituberculous drugs Hydantoins Carbamazepine

Genetic factors may predispose patients to SJS in specific populations.124 There are rare reports of erythema multiforme following allergic contact dermatitis with nickel and poison ivy (ie, Rhus dermatitis). The epidermal necrosis in erythema multiforme is mediated by cytotoxic T cells of the Tc1/Tc2 subsets 125 through provocation of apoptosis via interaction between circulating soluble Fas and its receptor, FasL.126 Therapeutic application of intravenous immunoglobulin (IVIG), which binds soluble Fas, has thus been thought to have a potential role in the treatment of TEN.122,127 Synergistic action with helper T cells, including those of the Th2 subset, is implied by demonstration of the thymus- and activation-regulated chemokine (TARC).128 Antibodies directed against desmosomal plaque proteins desmoplakin I and II have been described in a subset of patients with severe erythema multiforme and suggest a humoral mechanism in the propagation of lesions in these patients. The epitope, localized at the carboxy terminal domain of desmoplakin, is responsible for the assembly of keratin filaments and desmosomes. Purified human antibody directed against the carboxy terminus of desmoplakin I and II, when injected into newborn mice, produces lesions that resemble erythema multiforme, suggesting a role for these antibodies in a subset of patients with erythema multiforme.129

Halogenodermas

294

discussed in Chap. 3. Erythema multiforme has long been considered to reflect a type 4 cellular cytotoxic reaction.120 Provocation of lesions often relates to the ingestion of drugs or to infection by microbial pathogens such as Mycoplasma sp.121 or herpes virus, including in the context of recurrent herpes labialis, in which the classical targetoid lesions are more common and disease is typically self-limited. In contrast, drug-induced erythema multiforme can be quite severe; when the eruption is extensive, there may be severe oral mucosal involvement which defines Stevens-Johnson syndrome (SJS). In SJS, greater than 10% of the body surface is affected by epidermal necrosis and detachment, in a fashion reminiscent of, but less marked than, toxic epidermal necrolysis (TEN), in which more than 30% of the skin surface is so affected.122 Case fatality rates are 1% to 5% in the former instance and 25% to 35% in the latter, where management in a dedicated burn unit is advised.123

CLINICAL FEATURES Iodides, bromides, and fluorine can induce vegetative, fungating, papulopustular, and ulcerating lesions130 (Table 12-21). Iododermas tend to manifest as a pustular facial eruption, often with ulceration. Bromodermas present as nodules or plaques with a verrucous or granulating surface, most commonly on the lower extremities; some patients manifest panniculitis.131

Table 12-21 Halogenodermas Iodides Amiodarone Potassium iodide Iodized radiographic contrast media Iodized salt Iodine in seaweed and other food Bromides Fluorides

The pathophysiology of the halogenodermas is not well understood, although underlying systemic diseases may predispose to their development.132 HISTOPATHOLOGIC FEATURES The epidermis shows pseudoepitheliomatous hyperplasia with neutrophilic intraepidermal and dermal microabscesses and superficial dermal edema.132 In lesions of iododerma, epithelial proliferation is less prominent, but vascular alterations may be more conspicuous and likely account for the ulceration that may be observed. DIFFERENTIAL DIAGNOSIS Other causes of pseudoepitheliomatous hyperplasia associated with tissue neutrophilia and intraepidermal pustulation include infections with atypical mycobacteria or fungi, which may be distinguished from halogenodermas by special stains and culture; pyostomatitis vegetans of Crohn disease, separable by clinical history and by proximity to a mucosal orifice133; and blastomycosis-like pyoderma of the immunocompromised, a bacterial infection.134

Erythroderma CLINICAL FEATURES Erythroderma due to drugs must be distinguished from other causes such as pityriasis rubra pilaris, psoriasis, seborrheic dermatitis, and cutaneous T-cell lymphoma. The common drugs associated with erythroderma are listed in Table 12-22.1,2

Table 12-22 Drugs Associated with Erythroderma Acetylsalicylic acid Sulfasalazine Fenbufen Oxytetracycline Gentamicin Nystatin Ketoconazole Sulfonamides Cotrimoxazole Clofazimine Quinidine Captopril Timolol Minoxidil Phenobarbital Methotrexate Granulocyte-macrophage colony-stimulating factor Etretinate

HISTOPATHOLOGIC FEATURES Characteristic is psoriasiform hyperplasia with granular cell layer diminution, variable spongiosis, and a diffuse parakeratotic scale that may contain neutrophils. Additional features include a vacuolopathic interface dermatitis, focal dyskeratosis, and a mixed inflammatory cell infiltrate often containing lymphocytes, eosinophils, and neutrophils.

Dilantin Hypersensitivity Syndrome CLINICAL FEATURES In addition to its perturbative effects on lymphocyte function, namely, enhancement of blast transformation and abrogation of T-suppressor function, phenytoin and its analogues also may function as antigens in some patients. In concert, these two processes promote a variety of clinical consequences, including the Dilantin hypersensitivity syndrome, which is seen in 2% to 20% of patients who consume the drug.135 The manifestations of Dilantin hypersensitivity syndrome include fever, lymphadenopathy, hepatosplenomegaly, mucositis, a rash that characteristically manifests as patchy erythema that may progress to generalized erythroderma, a folliculocentric pustular eruption, erythema multiforme, and toxic epidermal necrolysis. Lymphoma may supervene rarely. Dilantin also perturbs collagen synthesis, resulting in gingival hyperplasia in roughly 50% of patients receiving the drug. The types of phenytoin-induced exanthems are listed in Table 12-23. HISTOPATHOLOGIC FEATURES Histologic features reflect the type of eruption biopsied. The pustular lesions exhibit intraepidermal neutrophilic vesiculopustules, often accentuated in hair follicles, whereas the erythema multiforme-like eruptions manifest lymphocytic interface inflammation with keratinocyte necrosis, and the maculopapular eruptions demonstrate a mild perivascular lymphocytic infiltrate with variable interface injury.

Acneiform eruptions Exfoliative dermatitis Hyper- and hypopigmentation Maculopapular eruptions Erythema multiforme Toxic epidermal necrolysis Vasculitis Pseudolymphoma

annular array involving inner aspects of the arms, medial thighs, and intertriginous areas, prompting differential diagnoses including cutaneous T-cell lymphoma, erythema annulare centrifigum, GA, and LE. Lesions tend to resolve gradually over a 6- to 12-week period following discontinuation of the implicated drug.

DIFFERENTIAL DIAGNOSIS Depending on the type of lesion biopsied, Dilantininduced eruptions may mimic mycosis fungoides and other mycosis fungoidelike pseudolymphomata, other pustular drug eruptions and pustular bacterid, and other causes of erythema multiforme and vasculitis.

HISTOPATHOLOGIC FEATURES Characteristic is diffuse infiltration of the interstitium by lymphocytes and histiocytes (Fig. 12-14) with fragmentation of collagen and elastic fibers in concert with a vacuolar interface dermatitis. Some patients show superimposed atypical lymphoid infiltrates. This lesion is distinctive from the granulomatous drug eruption seen in erythema nodosum, namely, a granulomatous septal panniculitis in patients receiving sulfonamides, penicillin, minocycline, or oral contraceptives.

Interstitial Granulomatous Drug Reaction

Cutaneous Reactions to Targeted Biological Therapy: The Cytokines

CLINICAL FEATURES An interstitial granulomatous inflammatory process mimicking granuloma annulare (GA) at the light microscopic and sometimes at the clinical level has been associated with therapy with angiotensin-converting enzyme inhibitors, lipid-lowering agents, calcium channel blockers, beta blockers, antihistamines, anticonvulsants, and antidepressants.136 Classic lesions are asymptomatic erythematous to violaceous plaques in an

The clinical application of cytokines produced through recombinant DNA technology has been associated with cutaneous reactions in patients undergoing therapy for cancer and autoimmune disease. The most frequently reported reactions are those to injection of granulocyte-macrophage colonystimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and interferons (IFNs).

 FIGURE 12-14 Interstitial palisading granulomatous drug reaction. The interstitium shows columns of histiocytes infiltrating between collagen bundles.

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

DIFFERENTIAL DIAGNOSIS The constellation of findings diagnostic of a true psoriasiform diathesis, namely, the direct apposition of ectatic capillaries to thinned suprapapillary plates, is not seen. Tissue eosinophilia may be observed in pityriasis rubra pilaris, erythrodermic psoriasis, and cutaneous T-cell lymphoma and is not in isolation a discriminating feature. Mycosis fungoides usually can be distinguished by continuous epidermotropism of atypical lymphoid forms accompanied by epidermal atrophy.

Table 12-23 Phenytoin-Induced Exanthems

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GM-CSF and G-CSF GM-CSF and G-CSF are used to counter neutropenia in patients with HIV infection, aplastic anemia, myelodysplasia, and congenital neutropenic states. Skin reactions reported with GM-CSF and G-CSF tend to be expressed as forms of neutrophilic dermatosis: pyoderma gangrenosum, Sweet syndrome, neutrophilic folliculitis, and vasculitis.137,138 A widespread annular papular eruption described in patients receiving G-CSF after bone marrow transplantation manifests histologically as a purely mononuclear cell or mixed mononuclear cell and granulocyte dermal infiltrate.128 The pathogenesis of such lesions involves the enhanced proliferation of myelomonocytic and granulocytic precursors and possibly stimulation of dermal dendrocytes to increase in size and number and to produce cytokines such as interleukin-1 (IL-1) and tumor necrosis factor a (TNF-a).139 Upregulation of endothelial adhesion molecule expression may contribute to the propogation of vasculitis. G-CSF promotes differentiation and chemotaxis of neutrophils and prolongation of their survival and so may promote the Sweet syndrome reactions seen in neutropenic patients.138,139

Interferon-β1b Interferon-β1b (IFN-β1b), an immunomodulatory agent used in the treatment of multiple sclerosis, has been associated with the generation of sclerotic or erythematous dermal plaques and ulcers at injection sites along with a sclerodermalike syndrome consisting of sclerodactyly and digital infarction (personal observation). Lesions manifest dermal fibrosis and a pandermal pauci-inflammatory thrombogenic vasculopathy; overt vasculitis has not, to our knowledge, been documented. The pathogenesis of IFNβ–related ischemic dermopathy may reflect platelet activation and aggregation. Pustular psoriasis flares as well as otherwise typical delayed-type hypersensitivity reactions are also reported.

keratinocytes and so provoke lichenoid reactions and epidermolytic hyperkeratosis; IFN also may promote the migration of T-lymphocytes into the epidermis. The latter may cause upregulation of IL-2 production by keratinocytes and promote TNF-α production by dermal dendrocytes, which, in turn, upregulates adhesion molecule expression on keratinocytes and triggers keratinocyte proliferation.140

Cutaneous Reactions to Targeted Biological Therapy: Cytokine Receptor Blockers Epidermal Growth Factor Inhibition CLINICAL FEATURES In recent years, novel biologically targeted therapies designed to interfere with the molecular pathways of carcinogenesis have been brought forward as therapeutic options in patients who have failed other, more conventional therapies, either because those therapies have proven ineffective or because the patients were intolerant to the former chemotherapeutic regimes. New targeted therapies approved by the Food and Drug Administration141 include monoclonal antibodies and small molecular inhibitors which have significantly changed the character of cancer therapy for a small subgroup of patients.142 Such targeted therapies are frequently better tolerated than traditional chemotherapy but are associated with specific adverse effects,

including acneiform rashes, cardiac dysfunction, thrombosis, proteinuria, and hypertension.142 Furthermore, the small molecule inhibitors are frequently metabolized by the hepatic cytochrome P450 enzyme system and therefore provoke, and are subject to, multiple drug interactions. With respect to dermatologic side effects associated with epidermal growth factor receptor (EGFR) inhibitors, the majority of patients receiving such agents experience some form of cutaneous toxicity.143 Most frequently, these mucocutaneous side effects include papulopustular rashes, hair and nail changes, xerosis, pruritus, telangiectasias, hyperpigmentation, mucositis,144-149 psoriatic eruptions, erythema nodosum, and nummular eczema. Typically, blockade of the EGFR is done through the use of monoclonal antibodies of which examples include panitumumab (Vectibix), cetuximab, gefitinib, and erlotinib. In addition to specific blockade of epidermal growth factor, most of the oncogenes that impact cell cycle activities and are aberrantly regulated or mutated in malignant neoplasia function through tyrosine receptor kinase activity. Specific agents can inhibit tyrosine kinases, including sorafenib,150 have provoked a similar variety of skin erruptions in addition to localized pulmoplantar epidermal hyperplasia.150 The reactions seen in patients receiving these agents appear to act as a surrogate marker for the clinical response to drug therapy; those patients in whom skin toxicity develops have a higher response rate,151 and survivorship

Interferon-α2

296

Interferon-α2 (IFN-α2) plays a key role in the therapy of hepatitis C virus (HCV) infection. Variably reported to initiate, clear, and exacerbate lesions of lichen planus, IFN-α2b has an association with the development of oral erosive lichen planus and psoriasiform hyperplasia with epidermolytic hyperkeratosis in the setting of HCV infection. From a pathogenetic standpoint, IFN may induce expression of hidden surface antigens on

 FIGURE 12-15 Drug-induced psoriasiform eruption. A patient taking the epidermal growth factor receptor blocker erlotinib (Tarceva) developed a diffuse pustular rash with an acneiform follicular component. The biopsy shows spongioform pustulation of the epidermis with a pyodermatous dermal component.

B

 FIGURE 12-16 (A) A mycosis fungoides-like and subacute lupus erythematosus-like morphology in a patient receiving adalimumab (Humira) for rheumatoid arthritits. The epidermis is percolated in a haphazard fashion by small lymphoid forms with associated keratinocyte necrosis. (B) The same patient illustrated in Fig. 12-16(A) had infiltrative plaques which showed a granuloma annulare-like interstitial histiocytic infiltrate. Still other foci had a lichen planus-like histology. This overlap of morphologies cognate to disparate idiopathic dermatoses is an important clue, in our estimation, to a drug-based etiology.

appears to be increased.152 In consequence of the foregoing, it has been advised that agents be used at the maximum-tolerated dose to maximize the subsequent clinical benefit.151,152 HISTOPATHOLOGIC FEATURES Histopathologic studies of the papular-pustular rash show an acneiform eruption centered upon the superficial aspects of the hair folicle where intense neutrophilic inflamation is seen (Fig. 12-15); there is a rupture of the epithelial lining of the hair folicle with adjacent dermal changes. The exact mechanisms of this eruption are not known but there appears to be inhibition of epithelial cell proliferation of the follicular lining.

Bortezomib (Velcad) Bortezomib is a proteasome inhibitor developed and principally used for the treatment of myeloma.153 It inhibits the degradation of wild type p53; preservation of wild type p53 helps to down regulate the cell cycle and slows tumor growth in patients with myeloma. Among the various rashes reported with the ingestion of bortezomib include plaque-like urticarial, erythematous, and edematous eruptions.

Tumor Necrosis Factor α Tumor Necrosis Factor α (TNF-α) is a cytokine implicated in the pathogenesis of several idiopathic and/or autoimmune inflammatory disorders. Accordingly, pharmaceutical firms have developed

specific blockers of the TNF-α receptor in an attempt to modulate the activity of the immune system. Inhibitors of TNF-α include specific blockers of the receptors, such as infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), and thalidomide. These agents have been employed successfully in mediation of psoriasis, rheumatoid arthritis, and inflammatory bowel disease, and also have a role in the treatment of lymphoproliferative disorders.154 Patients may develop complications from the use of TNF-α receptor inhibitors, such as infection and dermatological reactions. Recently described are annular plaques on the trunk and extremities which show an interstitial granulomatous dermatitis in skin biopsies.154 Other cutaneous eruptions documented in the setting of TNF-α receptor blocker therapy include leukocytoclastic vasculitis, lichenoid tissue reactions, urticaria, lupus erythematosus-like eruptions, chilblains, folliculitis, and necrotizing fasciitis.155,156 The histopathology of the tissue reactions to TNF-α blockade include, in the setting of the folliculitis lesions, pustular follicular reactions, lymphocytic interface dermatitis with papillary dermal edema in the setting of chilblains eruptions, variably intense interface dermatitis in lupus erythematosus-like eruptions (Fig. 12-16A), classical features of psoriasis with superimposed tissue eosinophilia in the case of the psoriasiform eruptions,157 and lymphocytic and histiocytic interstitial infiltrates mimicking granuloma annulare in the case of the interstitial granulomatous dermatitides (Fig. 12-16B).

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134. Rongioletti F, Semino M, Drago F, et al. Blastomycosislike pyoderma (pyoderma vegetans) responding to antibiotics and topical disodium chromoglycate. Int J Dermatol. 1996;35:828-830. 135. Silverman AK, Fairley J, Wong RC. Cutaneous and immunologic reactions to phenytoin. J Am Acad Dermatol. 1988; 18:721-741. 136. Magro CM, Crowson AN, Schapiro BL. Interstitial and palisading granulomatous drug reaction: a distinctive clinical and pathological entity. J Cutan Pathol. 1998;25:72-78. 137. Prevost-Blank PL, Shwayder TA. Sweet’s syndrome secondary to granulocyte colony-stimulating factor. J Am Acad Dermatol. 1996;35:995-997. 138. Richard MA, Grob JJ, Laurans R, et al. Sweet’s syndrome induced by granulocyte colony-stimulating factor in a woman with congential neutropenia. J Am Acad Dermatol. 1996;35:629-631. 139. Glass LF, Fotopoulos T, Messina JL. A generalized cutaneous reaction induced by granulocyte colony-stimulating factor. J Am Acad Dermatol. 1996;34:455-459. 140. Elgart GW, Sheremata W, Ahn YS. Cutaneous reactions to recombinant human interferon beta-1b: the clinical and histologic spectrum. J Am Acad Dermatol. 1997;37:553-558. 141. Ross JS, Schenkein DP, Pietrusko R, et al. Targeted therapies for cancer 2004. Am J Clin Pathol. 2004;122(4):598-609. 142. Gerber de. Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 2008;77(3):294-296. 143. Boone SL, Rademaker A, Liu D, Pfeiffer C, Mauro DJ, Lacouture ME. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology. 2007;72(3-4):152-159. 144. Mitchell EP, Perez-Soler R, Van Cutsem E, Lacouture ME. Clinical presentation and pathophysiology of EGFRI dermatologic toxicities. Oncology. (Williston Park) 2007:21(Suppl 5):4-9. 145. Perez-Soler R, Van Cutsem E. Clinical research of EGFR inhibitors and related dermatologic toxicities. Oncology. (Williston Park) 2007;21(1 Suppl 5):10-16. 146. Yamazaki N, Muro K. Clinical management of EGFRI dermatologic toxicities: the Japanese perspective. Oncology. (Williston Park). 2007;21(11 Suppl 5):27-28.

147. Agero AL, Dusza SW, BenvenutoAndrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55(4):657-670. 148. Schalock PC, Zug KA. Acneiform reaction to erlotinib. Dermatitis. 2007;18(4): 230-231. 149. Delle Sedie A, Bazzichi L, Bombardieri S, Riente L. Psoriasis, erythema nodosum, and nummular eczema onset in an ankylosing spondylitis patient treated with infliximab. Scand J Rheumatol. 2007;36(5): 403-404. 150. Beldner M, Jacobson M, Burges GE, Dewaay D, Maize JC Jr, Chaudhary UB. Localized palmar-plantar epidermal hyperplasia: a previously undefined dermatologic toxicity to sorafenib. Oncologist. 2007;12(10):1178-1182. 151. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345. 152. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22(7):1201-1208. 153. Sanchez-Politta S, Favet L, Kerl K, Dietrich PY, Piguet V. Bortezomibinduced skin eruption. Dermatology. 2008; 216(2):156-158. 154. Deng A, Harvey V, Sina B, Strobel D, et al. Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor α inhibitors. Arch Dermatol. 2006;142:198-202. 155. Devos SA, Van Den Bossche N, De Vos M, Naeyaert JM. Adverse skin reactions of anti-TNF-α monoclonal antibody. Dermatology. 2003;206:388-390. 156. Chan ATY, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J. 2002;78:47-48. 157. Seneschal J, Lepreux S, Milpied B, Schaeverbeke T, Taieb A. Psorasiform eruptions during anti TNF-alpha treatment: psoriasis or not? Arch Dermatol. 2007;143(2):223-231.

CHAPTER 13 Cutaneous Reactions to Exogenous Agents Raymond L. Cornelison A. Neil Crowson

REACTIONS TO TRAUMA AND IRRITATION

HISTOPATHOLOGIC FEATURES The histology associated with trauma and irritation follows the continuum observed clinically. Minimal trauma may result in parak eratosis, crust, mild spongiosis, superficial vasodilatation, and mild papillary dermal inflammation. More severe changes

DIFFERENTIAL DIAGNOSIS Most of the pathologic features associated with external trauma and irritation require clinical correlation because the histologic patterns are not diagnostic in isolation. Certain clinical and histologic features such as a deep decubitus ulcer on the sacrum of an elderly person may favor a more precise diagnosis.

 FIGURE 13-1 Decubitus ulcer. Ulcerated epidermis with impetiginized neutrophilic scale-crust, underlying acute and chronic inflammation, and granulation tissue formation.

REACTIONS TO RADIATION Ionizing radiation can affect the skin. For the purposes of this text, radiation dermatitis is subclassified as acute, subacute, and chronic radiation dermatitis (Table 13-1). Rarely, a form of fibrosing dermopathy can be seen after diagnostic radiation. Termed radiation-induced morphea, it has a variable time of onset ranging from 1 month to 30 years after fluoroscopy, does not appear to be dose-dependent, and unlike radiation fibrosis, does not always remain confined to the radiation port.2 CLINICAL FEATURES Acute radiation dermatitis follows exposure to a threshold dose of ionizing radiation. The multiphasic response is dose- and timedependent and is characterized initially by transient redness, hair loss, and sometimes by vesiculation. In the second phase, redness develops 7 to 9 days following radiation exposure. Redness and pigmentary changes may recur weeks after radiation exposure. Intense exposure may produce ulceration that

Table 13-1 Radiation Dermatitis

Clinical Features Acute Erythema Hair loss Vesicle formation Chronic Atrophy Telangiectasia Pigmentary changes Histopathologic Features Acute Spongiosis Epidermal necrosis Dermal edema Vascular ectasia and thrombosis Chronic Epidermal hypoplasia and/or hyperplasia Squamous epithelial atypia Dermal sclerosis/hyalinization Deeply located elastotic material in dermis Loss of adnexae Bizarre “radiation fibroblasts” Hyalinization of vessel walls and thrombosis Differential Diagnosis Scar Thermal burn Lichen sclerosus Morphea/scleroderma Chronic graft-versus-host reaction

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

CLINICAL FEATURES The skin interfaces with and protects from an array of external irritants and other stimuli that range from minimal to severe, with objective results that follow the same continuum. Minimal stimuli may result in redness, mild scale, and symptoms such as pruritus and burning. More severe irritation can lead to vesicles, eczematous changes, ulceration, and necrosis. Artifactual dermatitis, ulceration, friction blisters, and calcaneal petechiae are examples of clinical patterns seen in response to trauma and irritation.

include prominent intracellular edema, spongiosis with vesicle formation and overlying parakeratotic scale-crust, ulceration, and polymorphous dermal inflammation with hemorrhage. The histopathology of ulceration is not specific as to etiology and consists of a polymorphous inflammatory infiltrate, varying degrees of vascular damage, hemorrhage, dermal necrosis, scale-crust formation, and fibrin deposition (Fig. 13-1). Nodular primary localized cutaneous amyloidosis has been reported after blunt trauma to the skin.1 If foreign material is part of the process, it may be detected within the necrotic mass or in the adjacent dermis. Foreign material may be detected through the use of special stains and by polarized light microscopy. Location may be helpful in arriving at a clinicopathologic cor-relation; for example, transepidermal elimination of hemorrhage with intracorneal collections in a biopsy specimen from a plantar site would be compatible with the shear injury that produces calcaneal petechiae.

301

typically occurs after several weeks. The National Cancer Institute common toxicity criteria version 3.0 is the standard for evaluation of acute radiation dermatitis.3

changes (Fig.13-2A). Late radiation necrosis can occur over bony prominences, generally beginning 1 or more years after exposure and often precipitated by trauma.

Grade:

HISTOPATHOLOGIC FEATURES The location of the pathologic change in radiationinduced cutaneous injury will depend on the radiation penetration. In acute radiation dermatitis, keratinocytes show intracellular edema, variation in nuclear size and tinctorial qualities, and individual cell necrosis in an epidermis that manifests spongiosis and vacuolar change. Dermal injury is variable and includes degenerative effects in the adnexae, dermal edema, ectasia of vessels, and scattered endovascular fibrin thrombi. Variably intense mononuclear and/or granulocytic inflammatory infiltrates may be seen. In subacute radiation dermatitis, epidermal changes include vacuolar alteration with necrosis and focal atypia of keratinocytes, hypergranulosis, and compact hyperkeratosis. Dermal changes may contain a variably dense infiltrate of lymphocytes and histiocytes in the papillary dermis, telangiectatic vessels, and reparative changes.4 Chronic radiation dermatitis manifests epidermal changes that range from slight

• 0—None • 1—Faint erythema or dry desquamation

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

• 2—Moderate to brisk erythema or patchy moist desquamation, mostly confined to skin folds and creases; moderate edema • 3—Confluent moist desquamation, equal to 1.5 cm diameter, not confined to skin folds; pitting edema • 4—Skin necrosis or ulceration of fullthickness dermis; may include bleeding not induced by minor trauma or abrasion Healing in the acute phase occurs with scaling and pigmentary changes. Subacute radiation dermatitis develops several months following exposure and produces scaling with postinflammatory alterations.4 Chronic radiation dermatitis develops months to years following exposure and is associated with induration, atrophy, telangiectasia, and pigmentary

A

302

alterations in the stratum corneum, edema, atrophy and/or acanthosis, and vacuolar basal layer alteration to ulceration (Fig. 13-2B). There may be cytologic atypia of keratinocytes, dyskeratosis, and loss of the rete-ridge pattern. The dermis may be hyalinized and sclerotic. Dermal fibroblasts may exhibit variation in the size and tinctorial qualities of their nuclei (Fig. 13-3). Blood vessels manifest variable ectasia, proliferative change, hyalinization of media, and thrombosis. Adnexal structures may be diminished or absent. Radiation-induced fibrosis extends deep into subcutaneous fat, fascia, and muscle.2 Inflammatory infiltrates are variable and may be associated with dermal pigmentary alteration. DIFFERENTIAL DIAGNOSIS The histology of radiation dermatitis provokes a number of differential diagnostic considerations depending on the specific findings in a given biopsy. An interface injury, if present, raises consideration to cytotoxic effects from chemotherapy, burn injury, lupus erythematosus, lichen sclerosus, erythema multiforme, fixed drug eruption, acute graft-versus-host disease, and dermatomyositis. Dermal changes mimic cicatrices, scleroderma, morphea, and lichen sclerosus. The dermal changes in

B

 FIGURE 13-2 Chronic radiation dermatitis. (A) Well-defined indurated plaque demonstrating atrophy, telangiectasia, both hypo- and hyperpigmentation, and scaling. (B) Hyperkeratotic and parakeratotic epidermal hyperplasia with vacuolar interface change. Full-thickness dermal sclerosis with lymphatic dilation and loss of adnexa is characteristic.

Table 13-2 Thermal Burns

 FIGURE 13-3 Chronic radiation dermatitis. Bizarre-appearing “stellate” fibroblast with features of radiation effect: pleomorphic hypochromatic nuclei, abundant cytoplasm, and intranuclear and intracytoplasmic vacuoles.

the late stages of burns may be indistinguishable from those in chronic radiation dermatitis, except that “radiation fibroblasts” are present in the latter. Markedly atypical nucleolated dermal fibroblasts may raise the possibility of neoplasia. The array of histologic findings seen with radiation change usually enables accurate diagnosis.

(Fig. 13-5). Lesions result from coldinduced spasm of dermal arterioles. Subsequent upregulation of endothelial adhesion molecules is felt to be associated with an efflux of mononuclear cells

at reperfusion. The diagnosis is suggested by the temporal relationship between symptom onset and cool weather or immersion in cold liquids5,6 in patients without occlusive peripheral arterial disease. Spontaneous resolution follows removal of the cold insult. The association with wet climates and with cold fluids is held to be a physical one, in

REACTIONS TO HEAT AND COLD Thermal stress and electrical injury can produce tissue damage. These external stresses have been studied in animal systems, and the histologic changes associated with the degree of damage have been identified. CLINICAL FEATURES The clinical appearance of thermal burns ranges from faint erythema to vesiculation and necrosis (Table 13-2). Electrical injury produces three zones: a central zone of carbonization, a pale ischemic intermediate zone, and an erythematous peripheral zone. Cold injury presents in a similar fashion to thermal injury, the clinical lesion ranging from mild redness to vesiculation and necrosis (Fig. 13-4). Chilblains (perniosis) are itchy, burning, red vesicular, or ulcerative patches or plaques that occur symmetrically in acral locations, particularly toes, following exposure to cold, especially in a wet environment5

 FIGURE 13-4 Frostbite. Coagulative necrosis of epidermis and dermis to the deep reticular dermal compartment with an inflamed scale-crust. These changes are identical to those seen with full-thickness burns.

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

Clinical Features Erythema Vesiculation Necrosis Histopathologic Features Degree and thickness of injury are highly variable Epidermal necrosis Necrosis and “mummification” of dermis Reepithelialization of epidermis in less severe burns Differential Diagnosis Cicatrix resulting from trauma or iatrogenic injury Lichen sclerosus Morphea/scleroderma Radiation dermatitis

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

limited differential diagnosis of perivascular lymphoid infiltrates; the presence of deep vascular thrombosis should provoke consideration of a systemic connective tissue disease, of procoagulant states such as those seen with antiphospholipid antibody syndrome or cryoprecipitates,14 or of (Hutchinson) chilblains lupus erythematosus.15 In the latter condition, a cellpoor lymphocytic interface inflammatory infiltrate is also present, and deep involvement of the eccrine coil is unusual.5,8,15,16 Some chilblains lupus erythematosus patients are seropositive for antibodies to Ro/SSA.17,18

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REACTIONS TO LIGHT

 FIGURE 13-5 Perniosis (chilblains). There is marked papillary dermal edema in this biopsy of acral skin. A lymphocytic perivascular infiltrate shows directed migration into the epidermis, unlike the haphazard infiltration of cutaneous T-cell lymphoma or the vacuolar interface injury of lupus erythematosus. There is dilatation of dermal papillae capillaries, in which platelet-fibrin thrombi are seen.

that moisture serves to augment heat extraction from the skin surface. Females are affected more commonly than males. There is an association with the intake of certain immune-perturbing drugs such as fluoxetine. HISTOPATHOLOGIC FEATURES Mild thermal and cold injuries produce epidermal and dermal edema, vacuolated keratinocytes, and vascular dilatation.7 More severe injury leads to necrosis of keratinocytes, vesiculation, dermal thrombosis, and hemorrhage. The severity of cutaneous injury following a burn correlates with depth and traditionally has been categorized as first degree (epidermal damage only), second degree (both epidermal and partial dermal injury), or third degree (full-thickness necrosis of the epidermis and dermis). The histopathologic features of burns correlate with the severity of the thermal insult and thus vary from focal epidermal cell necrosis, vascular ectasia, and dermal edema to full-thickness necrosis of the dermis. Second-degree burns are characterized by subepidermal bulla formation. In thirddegree burns, extensive necrosis of the dermis is present. Some lesions show carbonized debris. Severe burns may be associated with a “mummified” appearance of the dermis; dermal collagen fibers are swollen and eosinophilic, and stromal cell nuclei are absent. In concert with

necrosis of the overlying epidermis, these changes constitute evidence of thermal injury. In lesions with significant inflammation, superinfection should be considered, and special stains and/or cultures for microbial pathogens should be preformed. Frostbite produces a histology identical to a burn, with the level and extent of tissue destruction correlating with the degree of thermal tissue injury (see Fig. 13-4). Electrical burns produce vascular thrombosis in the intermediate and peripheral zones and necrosis in the central area that varies in degree and depth depending on the severity of the injury. Perniosis manifests perivascular and periadnexal lymphoid infiltrates with striking extension around the deep eccrine coils,5,8 edema and thickening of blood vessel walls, marked subepidermal edema, and vascular thrombosis accentuated in the superficial vascular plexus5,9,10 (see Fig. 13-5). Sometimes present is a lymphocytic vasculitis,11 endothelial proliferation with necrosis,12 and leukocytoclastic vasculitis.13 DIFFERENTIAL DIAGNOSIS The overlapping histologic features of thermal, electrical, and cold injury are similar and raise consideration to external trauma; the latter is suggested in limited injuries by necrosis of keratinocytes limited to the upper stratum spinosum. The histologic picture of perniosis provokes consideration of a

Light-related eruptions offer a spectrum of clinical morphologies and histologic patterns, often augmented by drug intake or a coexisting connective tissue disease diatheses. Recognized syndromes related to light exposure include phototoxic reactions, photoallergic reactions,19 and entities where the precise etiologic basis is unknown. Drugs that induce photosensitivity reactions absorb electromagnetic radia in the ultraviolet (UV) and visible ranges to produce an excited state that is injurious to the skin. Light-induced eruptions have a characteristic photodistribution that spares the submental and retroauricular areas and upper eyelids. Phototoxic eruptions typically occur within 5 to 20 hours of first exposure to a drug and resemble an exaggerated sunburn with erythema, blistering, vesiculation, desquamation, and hyperpigmentation of sun-exposed skin. Photoallergic eruptions require a latent period for sensitization and appear within 24 hours of repeat antigenic challenge. Unlike the purely phototoxic reactions, photoallergic eruptions also may occur in non-sun-exposed sites. Combinations of phototoxic, photoallergic, and photoadaptive change are common. The common thread for the photodermatoses is that light exposure provokes lesional development in all of hydroa vacciniforme, polymorphous light eruption, actinic prurigo, chronic photodermatoses, persistent light reactions, photosensitive eczema, and actinic reticuloid.19 The use of sunscreens will produce variable benefit in the photodermatoses. The addition of topically applied antioxidants in patients with polymorphous light eruption has shown beneficial effects that imply a pathogenic role for oxidant injury in pathogenesis.20 CLINICAL FEATURES Clinical features of these light-related eruptions are listed in

Table 13-3 Reactions to Light CLINICAL FINDINGS

HISTOPATHOLOGIC FEATURES

Polymorphous light eruption

Acquired; recurrent; worse in spring and early summer; in sun-exposed areas hours to days after exposure; burning or pruritus; lesions vary from papules to plaques and vesicles

Photoallergic dermatitis

Acute or chronic papular and/or vesicular eruption following exposure to photosensitive agent and light; pruritic

Hydroa vacciniforme

A chronic eruption with redness, vesicles, necrosis, and varicelliform scars generally in children; absence of laboratory abnormalities; eye involvement has been reported; resolves in adolescence Nonimmunologic; can be elicited in majority of persons exposed; redness, burning, edema in affected areas, possibly with vesiculation Familial in Native Americans; acute and chronic phases; eczematous; cheilitis and pruritus are common

Spectrum of changes; epidermal changes ranging from minimal to spongiotic; dermal changes range from superficial and deep perivascular cuffed lymphocytoid patterns to polymorphous infiltrates with neutrophils and other cell types; prominent papillary dermal edema may be present Variable epidermal changes including edema and spongiosis; a superficial polymorphous infiltrate including lymphocytes, eosinophils, neutrophils, and edema Intraepidermal reticular degeneration and cellular necrosis; spongiosis and epidermal necrosis with dense lymphohistiocytic infiltrates with hemorrhage and thrombosis of small vessels

Phototoxic eruption

Actinic prurigo

Chronic photodermatoses

Present for 3 months or longer; decreased MED to UVA, UVB, or both

Persistent light reaction

May be a form of photoallergic contact dermatitis; musk ambrette and oxybenzone are frequently implicated; the MED is shortened Severe variant of chronic actinic dermatitis; persistent infiltrated papules and plaques, often extending to covered areas; broadbanded photosensitivity; usually, a prominent component of lichen simplex chronicus is present

Photosensitive eczema Actinic reticuloid

Table 13-3. Photoaccentuation in exposed skin areas is typical. Polymorphous light eruption is a common, acquired. nonscarring photodermatosis with an incidence of at least 10% that is held to reflect a delayed-type hypersensitivity reaction to UV-altered cutaneous antigens.21 Both UVA and UVB and visible light play a role in photoprovocation of lesions.22 Lesions are polymorphous from patient to patient but monomorphous in any individual patient. The eruption frequently is recurrent, may resolve spontaneously, and often shows reduced activity from spring to summer. Hydroa vacciniforme primarily affects children, can be induced by UVA,23-25 and heals with scarring. Actinic prurigo is an idiopathic familial photodermatosis classically seen in Amerindians that uncommonly affects Caucasians and Asians26,27 (Fig. 13-6). The face is affected most commonly, and in chronic cases it

Variable epidermal changes including edema and spongiosis; there is minimal inflammatory infiltrate; neutrophils may be present Epidermal spongiosis with a superficial and deep lymphocytic perivascular infiltrate and dermal edema; chronic forms show hyperkeratosis, acanthosis, and signs of tissue repair and/or photoadaptations A dermal infiltrate of lymphocytes and macrophages, with or without epidermal spongiosis and atypical mononuclear cells in the dermis and epidermis The histology is that of a spongiotic dermatitis and similar to that seen in photoallergic and allergic contact dermatitis Usually, a prominent component of lichen simplex chronicus; dermal lymphoid infiltrate with atypical cells; CD8+ lymphoid cells dominate in the infiltrate; reversed CD4+ to CD8+ ratio in peripheral blood

manifests leonine or swarthy coarsening of features. A coexisting cheilitis occurs commonly. The latter has been termed follicular cheilitis or actinic prurigo cheilitis.28 Chronic photodermatosis or chronic actinic dermatitis is a poorly defined group in which there is a persistent eczematous eruption in sun-exposed sites; cases are defined by the following: (1) presence for greater than 3 months, (2) decreased minimal erythema dose to either UVA and/or UVB, and (3) histologic changes, including an infiltrate of lymphocytes and macrophages, with or without epidermal spongiosis and atypical mononuclear cells in the dermis and epidermis.29 Actinic reticuloid is the most severe variant of chronic actinic dermatitis.30 There may be multiple etiologies, including chronic contact dermatitis, photoallergic contact dermatitis, and phototoxic, immunologic, and other factors.

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

DISORDER

A clinical diagnosis of actinic reticuloid should be made in patients who manifest photo-induced plaques and infiltrated papules that may extend to sun-protected areas, sometimes with erythroderma,31 a broad spectrum of photosensitivity, and an infiltrate that contains atypical lymphoid cells. HISTOPATHOLOGIC FEATURES There is an overlapping spectrum of histopathologic findings in light-related eruptions that makes subclassification challenging (see Table 13-3; see also Chap. 5). Our approach is to specifically identify phototoxic, photoallergic, and photoadaptive effects. Phototoxic eruptions are characterized by keratinocyte injury at all levels of the epidermis but particularly the cornified layer. These so-called sunburn cells differ from the apoptotic keratinocytes

305

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 306

 FIGURE 13-6 Actinic prurigo in an Amerindian. There are overlapping features of phototoxic injury (the necrotic keratinocytes in the superficial statum spinosum, unaccompanied by lymphocyte satellitosis), photoadaptive changes (the psoriasiform hyperplasia and hypergranulosis), and photoallergy (the nodular superficial perivascular lymphocytic infiltrates).

of connective tissue disease or graft-versus-host diseases by virtue of absent lymphocyte satellitosis in apposition to their cellular debris. Often present is architectural disarray, keratinocyte dysmaturation, and parakeratosis (see Fig. 13-6). Neutrophils may infiltrate the epidermis at sites of injury in response to cytokine release by injured keratinocytes. A variable perivascular mononuclear cell-predominant infiltrate is accompanied by dilatation, edema, and mural swelling of the superficial vascular plexus, whose endothelia may show cytoplasmic vacuolation. This vascular injury diminishes in the depths of the biopsy. The photoallergic response consists of epidermal spongiosis and vesiculation that frequently eventuates in an adherent plasma-rich scale-crust. Eosinophils are often a component of the infiltrate. Features of the photoadaptive response consist of hypergranulosis, hyperkeratosis, melanocytic hyperplasia, suprabasilar melanization, and transepidermal elimination of melanin. Some patients develop persistent photosensitivity at exposed and nonexposed skin sites that, if accompanied by skin infiltration by transformed lymphocytes, defines chronic photosensitivity dermatitis or actinic reticuloid. The presence of intraepithelial

cerebriform lymphocytes arranged as groups surrounded by a clear halo reminiscent of Pautrier microabscesses results in a histology that mimicks mycosis fungoides. Recently described in an actinic reticuloid patient receiving methotrexate was a neutrophilic eccrine hidradenititis;32 the eccrine inflammation was most likely a secondary effect of chemotherapy, but the case serves to illustrate the issue of overlapping pathophysiologic effects complicating interpretation of biopsies in patients with photo-induced eruptions. Eruptions of combined phototoxic, photoallergic, and photadaptive types are common and manifest as variable expressions of the above-described prototypic morphologies (see Fig. 13-6). Hydroa vacciniforme is an accelerated phototoxic/photoallergic reaction that consists of keratinocytic edema, spongiosis, and necrosis that may progress to panepidermal necrosis. There is a variable infiltrate of lymphocytes and mononuclear phagocytes that occasionally is associated with hemorrhage and vascular thrombosis. The histology of actinic prurigo includes spongiotic epidermal changes and a lymphohistiocytic nodular perivascular infiltrate in the superficial dermis; the acute form is indistinguishable from polymorphous

light eruption. Chronic lesions of actinic prurigo exhibit hyperkeratosis, acanthosis, and signs of photoadaptation.33,34 Lymphocyte function and adhesion molecule studies in actinic prurigo indicate that it is a form of delayed-type hypersensitivity reaction in a genetically predisposed host, with different HLA associations in distinct populations.35,36 The resistance of Langerhans cells to UVinduced suppression may play a role.37 In consequence of dominant T-helper lymphocyte type 1 (Th1) function,38 therapies targeted at down-regulating Th1 tone, such as thalidomide, have proven successful in isolated cases.39 Lesions of actinic prurigo are reputed to heal with atrophic scars, perhaps reflecting anomalous fibroblast responses to UVA.40 Chronic actinic dermatitis has a nonspecific pattern including a dermal perivascular and sometimes bandlike infiltrate of lymphocytes and macrophages, with or without epidermal spongiosis and atypical mononuclear cells in the dermis and epidermis.29 Actinic reticuloid may have a pattern similar to chronic actinic dermatitis and, by definition, must have atypical lymphoid cells within the infiltrate. There is usually a prominent component of lichen simplex chronicus. Multinucleated giant cells often are noted in the papillary dermis and may be associated with perivascular elastolysis; immunophenotyping of the infiltrate shows dominance of CD8+ cells.30 DIFFERENTIAL DIAGNOSIS The differential diagnosis for this group lies mainly in the spectrum of either spongiotic or superficial dermal inflammatory processes. The spongiotic forms of light-related eruptions are not distinguishable histologically from other forms of spongiotic dermatitis. Photo-induced eruptions characterized by minimal epidermal changes and welldefined cuff-like perivascular lymphoid infiltrates need to be differentiated from gyrate erythemas, dermal contact reactions, and connective tissue disease. The severe phototoxic reactions may show significant epidermal necrosis and so raise consideration to erythema multiforme and pityriasis lichenoides, whereas the release of chemokines from the damaged epidermis may provoke tissue neutrophilia and so bring to mind the neutrophilic dermatoses. The dermal components of phototoxic and photoallergic dermatitis may dominantly consist of perivascular infiltrates of mononuclear cells and so be similar; an eosinophilic component would implicate photoallergy. The differential diagnosis of the latter would include insect bite reactions, dermal

contact reactions, and other hypersensitivity states.

REACTIONS TO MARINE AGENTS The array of potential interactions between the marine environment and skin includes granulomatous reactions to foreign materials such as sea urchin

spines (Fig. 13-7), envenomations, toxic exposures following discharge of nematocysts (Portuguese man-of-war stings), contact allergic dermatitis to many agents such as coral and infections. The clinical and histologic pictures vary depending on the inciting agent. CLINICAL FEATURES The clinical features of the most common marine reactions are presented in Table 13-4. Seabather’s

HISTOPATHOLOGIC FEATURES Histopathologic changes of seabather’s eruption include a dermal infiltrate around superficial and deep vessels composed of lymphocytes, neutrophils, and eosinophils. The histopathology of sea urchin spine penetration is that of a polymorphous inflammatory infiltrate consisting of neutrophils, eosinophils, and mononuclear cells, including plasma cells with occasional foreign-body giant cells and foreign material (see Fig. 13-7). Prominent edema and hemorrhage may be present.

Table 13-4 Reactions to Marine Agents DISORDER

ETIOLOGY

CLINICAL FEATURES

HISTOPATHOLOGIC FEATURES

Seabather’s eruption

Cnidarian larvae of the thimble jellyfish, Linuche unguiculata

Sea urchin spines

Penetration by the spines of the sea urchin (Echinoidea)

Portuguese man-of-war

Physalia physalis

Confined to bathing suit areas; chills and fever may be present; erythema, macules, and papules may be present There is immediate burning pain and bleeding, variable swelling, and tender red swollen papules and nodules at site of penetration; delayed reactions can follow 2-4 months after injury At points of contact, there is burning, pain, redness, and whealing; systemic signs also may be present

Swimmer’s itch

Cercariae of avian and mammalian forms of Trichobilharzia

There is a superficial and deep perivascular infiltrate of lymphocytes, neutrophils, and eosinophils Polymorphous inflammation with foreign-body granuloma; foreign material may be identified; a wide spectrum of pathologies, including sarcoidal granulomas Nematocysts may be present in the stratum corneum; superficial vascular dilatation, focal hemorrhage, and lymphocytoid infiltrate Dermal edema with a polymorphous infiltrate containing eosinophils

Itching as water evaporates; urticarial reaction progresses to itchy papules

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

 FIGURE 13-7 Granulomatous tissue reaction to sea urchin spine. There is a nodular granulomatous infiltrate consisting of lymphocytes admixed with histiocytes, including multinucleated foreign body giant cells. Some cases show a polarizable spine in the middle dermis, which this biopsy does not demonstrate.

eruption is a highly pruritic eruption under swimwear that occurs after bathing in the ocean.41 The average duration of the eruption and pruritus is 10 days. Tiny larvae of the thimble jellyfish Linuche unguiculata appear to be the cause in Floridian and Caribbean waters, where sporadic epidemics are seen. Reaction to the coelenterate Physalia physalis reflects the extrusion of nematocysts from tentacles that adhere to the skin and inject toxin.42 Acute lesions are painful, red, and edematous, with a linear array marking the path of the tentacle. The lesions may resolve with hyperpigmentation. In contrast to seabather’s eruption, swimmer’s itch affects only exposed parts and is produced by cutaneous penetration by shistosomal cercariae.43 Transient urticarial lesions evolve into pruritic papules. A wide array of additional potential reactions can follow exposure to venomous marine agents; however, histologies of these reactions have been poorly documented.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Portuguese man-of-war stings exhibit vascular dilatation, hemorrhage, and a lymphoid infiltrate. Nematocysts are found rarely in the stratum corneum. The pathologic changes of swimmer’s itch include dermal edema and a polymorphous infiltrate containing eosinophils.43 DIFFERENTIAL DIAGNOSIS While seabather’s eruption, swimmer’s itch, and envenomation can produce nonspecific histologic features characterized by polymorphous inflammatory infiltrates, the presence of exogenous material, such as a portion of nematocyst or sea urchin spine, coupled with the appropriate history, leads to the specific diagnosis. In these cases, the history is most important. The histopathologic features of contact allergic dermatitis such as from coral exposure are nonspecific and include a spongiotic dermatitis with dermal, perivascular, lymphocytic, and eosinophilic infiltrates (see Chap. 2).

REACTIONS TO ARACHNIDS Three orders of arachnids produce cutaneous reactions: spiders, scorpions, and ticks and mites. The arachnids are distinct from insects in that they do not

have wings or antennae, and the body is not divided into distinct segments. CLINICAL FEATURES The constellation of signs and symptoms that follows a spider bite is called arachnidism. In the United States, arachnidism most often follows the bite of either the black widow spider (Latrodectus mactans) or the brown recluse spider (Loxosceles reclusa) (Fig. 13-8). In general, pain and redness develop rapidly at the site of a spider bite, although the patient may not recall the inciting event, particularly in the setting of nocturnal brown recluse spider envenomation. Tissue injury is usually trivial but can progress to induration and necrosis.44-48 Systemic signs such as nausea, fever, and vomiting may be present. Scorpions carry a venom apparatus in their tails. There is rapid onset of burning pain and induration and sometimes tissue necrosis at the site of the sting. Systemic signs and symptoms include diaphoresis, vomiting, and nausea. Tick bite reactions follow implantation of an ectoparasite of the Ixodoidea superfamily.45,46 There are two family groups: soft-bodied ticks and hard-bodied ticks. The species of tick will vary based on geographic and exposure characteristics.

The tissue reaction to implantation represents a response to salivary antigens secreted by the tick after implantation. In the saliva is an adhesive that cements the mouthpart to the tissue. Attachment sites manifest edematous, erythematous, and sometimes persistent inflammatory reactions. Mites from a variety of families are capable of producing dermatitis by biting and sensitizing their targets. Baker’s itch, grocer’s itch, copra itch, and other colorful names have been applied to the clinical syndrome that follows the bite of a mite.49 Diagnosis is made by recognition of the occupational exposure that explains the distribution. Cheyletiella dermatitis is an infrequently reported eruption caused by an ectoparasite, Cheyletiella, whose normal hosts are household pets.50,51 Because the mites do not remain on human skin, support for the diagnosis is obtained by identification of mites on the patient’s pet. Trombiculid mites, known as chiggers, feed on humans only in their larval stage. The larvae, which are very small, attach to a host and seek a soft area, constricted by clothing in humans. The lesion is a macule that evolves into a pruritic red papule that may vesiculate. HISTOPATHOLOGIC FEATURES The histopathologic changes that follow a spider bite are those of infarctive and liquefactive tissue necrosis with thrombosis, vascular injury, hemorrhage, and inflammation consisting of a pan-dermal infiltrate of lymphocytes and neutrophils with variable numbers of eosinophils. The histopathology of a tick attachment site may include sections through the attached ectoparasite (Figs. 13-9 and 13-10). There are varying degrees of spongiosis, dermal edema, and an intense polymorphous superficial and deep lymphohistiocytic and eosinophilic infiltrate with hemorrhage. Mast cells may be increased.46 Epidermal hyperplasia and dense lymphoid infiltrates may persist at the attachment site. DIFFERENTIAL DIAGNOSIS Spider bites need to be separated from the large spectrum of causes associated with focal necrosis, including infections, pyoderma gangrenosum,52 vasculitis, trauma, and thrombotic or embolic infarction.

REACTIONS TO INSECTS

308

 FIGURE 13-8 Brown recluse spider bite. There is focal full-thickness necrosis of the epidermis. The dermal vasculature shows a mixed lymphohistiocytic and leukocytoclastic vasculitis with thrombosis, and there is lysis of the collagen table.

Although the outcome of an insect bite is usually trivial, occasionally bites result in clinically significant reactions. The mosquito bite is the most common clinical

 FIGURE 13-9 Tick bite reaction. Dense superficial and deep perivascular and periadnexal lymphohistiocytic infiltrate with scattered eosinophils.

lesion. It follows contact with a female mosquito whose mouth-parts have penetrated the dermis, where a complex array of salivary antigens is deposited. Depending on the species of insect, a

number of biochemical reactions may ensue, including local anticoagulation, protease release, and cellular infiltration. The type and degree of tissue reaction depend on the immunologic state of the

 FIGURE 13-10 Tick mouthpart. Refractile mouthparts are embedded in the superficial dermis. There is an associated marked lymphoeosinophilic infiltrate and reactive fibrosis.

CLINICAL FEATURES Infestation with either the head or body louse produces pruritus with excoriations. There may be matting of hair and secondary infection. Diagnosis of head lice is made by identifying the oval egg capsules attached to hair shafts. Mobile head lice are seen frequently. The bite site of the body louse is macular and red. Persistent wheals and papules may develop. Eggs are laid in clothing, and infestation is transmitted by clothing and bedding. Diagnosis is made by identifying lice and their eggs in the seams of clothing. Pubic lice produce blue-gray macular lesions on the lower abdomen and upper thighs, often with bacterial superinfection. Cutaneous myiasis occurs on exposed skin, with lesions consisting of either a furuncular or a tortuous red line of papules and vesicles if clinical lesions represent a creeping eruption. Flea bites in a sensitized person produce pruritic papules that may be clustered and sometimes are bullous. The sand flea, T penetrans, generally penetrates the skin on the toes or between the toes. The flea appears initially as a black dot; eventually, inflammation and pustules develop. HISTOPATHOLOGIC FEATURES The histopathology of these lesions almost always consists of edema with superficial and middle-to-deep dermal inflammation in a perivascular and wedge-shaped distribution. The components of the infiltrate may vary; however, the presence of eosinophils, particularly in an interstitial pattern, is a helpful feature. If the biopsy is taken from the vicinity of mouthpart penetration, there will be a vertical area

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

individual. Particularly florid reactions occur, for example, in patients with chronic lymphocytic leukemia. Pediculosis is produced by infestation with either of two species, Phthirus pubis or Pediculus humanus. Pediculus humanus exists as either the body louse or the head louse. Bed bugs are members of the family Cimicidae and are blood-sucking insects about 3 to 4 mm in size. The bed bug emerges from crevices in floors, walls, and furniture to feed in darkness. They are attracted to the body temperature of the host, feed for several minutes, and then depart. A number of species of Cimicidae will attack humans. Myiasis is the infestation by larvae of Diptera. There are numerous genera capable of producing myiasis in humans, including Dermatobia, Callitroga, Chrysomyia, Cordylobia, and Wohlfahrtia. Tungiasis is caused by infestation of the skin by a fertilized female sand flea, Tunga penetrans.

309

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 310

of amphophilic tissue necrosis extending vertically from the cornified layer for a variable distance into the dermis, sometimes with attendant hemorrhage. Epidermal changes vary from mild acanthosis through intraepidermal vesicle formation to pustulonecrotic lesions seen with flea, gnat, and mosquito bite puncta. Most reactions have some degree of epidermal spongiosis, occasionally with exocytosis of eosinophils (eg, eosinophilic spongiosis). Rarely, there will be both intraepidermal and subepidermal vesicle formation simultaneously in the same section; this is a strongly supportive finding for an insect bite reaction. The histology of tungiasis may contain portions of the ectoparasite surrounded by a dense polymorphous host response with epidermal spongiosis and acanthosis. DIFFERENTIAL DIAGNOSIS Because these reactions represent a response to a potpourri of toxic and immunologic stimuli, the possible histologic diagnoses are legion. Generally, a superficial and deep infiltrate coupled with the presence of eosinophils suggests an insect bite reaction but does not exclude other forms of hypersensitivity reactions.

REFERENCES 1. Kalajian AH, Waldman M, Knable AL. Nodular primary localized cutaneous amyloidosis after trauma: a case report and discussion of the rate of progression to systemic amyloidosis. J Am Acad Dermatol. 2007 Aug; 57(2 suppl):S26-S29. 2. McClelland M, VanLock JS, Patterson JW, Greer KE. Radiation-induced morphea occurring after fluoroscopy. J Am Acad Dermatol. 2002;47:962-964. 3. From National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3. 4. LeBoit PE. Subacute radiation dermatitis: a histologic imitator of acute cutaneous graft-versus-host disease. J Am Acad Dermatol. 1989;20:236-241. 5. Crowson AN, Magro CM. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases. Hum Pathol. 1997;28:474-484. 6. Price RD, Murdoch DR. Perniosis (chilblains) of the thigh: report of five cases, including four following river crossings. High Alt Med Biol. 2001;2:535538. 7. Schoning P. Frozen cadaver: antemortem versus postmortem. Am J Forens Med Pathol. 1992;13:18-20. 8. Cribier B, Djeridi N, Peltre B, Grosshans E. A histologic and immunohistochemical study of chilblains. J Am Acad Dermatol. 2001;45:924-929. 9. Vayssairat M. Chilblains. J Mal Vasc. 1992; 17:229-231. 10. Wall LM, Smith NP. Perniosis: a histopathologic review. Clin Exp Dermatol. 1981;6: 263-271.

11. Herman EW, Kezis JS, Silvers DN. A distinctive variant of pernio. Arch Dermatol. 1981;117:26-28. 12. McGovern T, Wright IS, Kruger E. Pernio: a vascular disease. Am Heart J. 1941;22: 583-606. 13. Klapman MH, Johnston WH. Localized recurrent postoperative pernio associated with leukocytoclastic vasculitis. J Am Acad Dermatol. 1991;24:811-813. 14. Weston WL, Morelli JG. Childhood pernio and cryoglobulins. Pediatr Dermatol. 2000;17:97-99. 15. Crowson AN, Magro CM. The cutaneous pathology of lupus erythematosus. J Cutan Pathol. 2001;28:1-23. 16. Crowson AN, Mihm MC Jr, Magro CM. The cutaneous vasculitides: a review. J Cutan Pathol. 2003;30:161-173. 17. Francheschini F, Calzavara-Pinton P, Quinzanini M, et al. Chilblain lupus erythematosus is associated with antibodies to SSA/Ro. Lupus. 1999;8:215-219. 18. Magro CM, Crowson AN. The cutaneous pathology associated with seropositivity for antibodies to Ro/SSA: a clinicopathological study of 23 adult patients without subacute cutaneous lupus erythematosus. Am J Dermatopathol. 1999;21:129-137. 19. Millard TP, Hawk JL. Photosensitivity disorders: cause, effect and management. Am J Clin Dermatol. 2002;3:239-246. 20. Rippke F, Wendt G, Bohnsack K, et al. Results of photoprovocation and field studies on the efficacy of a novel topically applied antioxidant in polymorphous light eruption. J Dermatol Treat. 2001;12:3-8. 21. Stratigos AJ, Antoniou C, Katsambas AD. Polymorphous light eruption. J Eur Acad Dermatol Venereol. 2001;16(3):193-206. 22. Boonstra HE, van Weelden H, Toonstra J, van Vloten WA. Polymorphous light eruption: a clinical pathobiologic, and follow-up study of 110 patients. J Am Acad Dermatol. 2000;42:L199-L207. 23. Halasz CLG, Leach EE, Walther RR, et al. Hydroa vacciniforme: induction of lesions with ultraviolet A. J Am Acad Dermatol. 1983;8:171-176. 24. Leenutaphong V. Hydroa vacciniforme: an unusual clinical manifestation. J Am Acad Dermatol. 1991;25:892-895. 25. Goldgeier MH, Nordlund JJ, Lucky AW, et al. Hydroa vacciniforme: diagnosis and therapy. Arch Dermatol. 1982;118:588-591. 26. Lane PR, Hogan DJ, Martel MJ, et al. Actinic prurigo: clinical features and prognosis. J Am Acad Dermatol. 1992;26: 683-692. 27. Crouch R, Foley P, Baker C. Actinic prurigo: a retrospective analysis of 21 cases refereed to an Australian photobiology clinic. Australas J Dermatol. 2002;43:128-132. 28. Vega-Memije ME, Mosqueda-Taylor A, Irigoyen-Camcho ME, et al. Actinic prurigo cheilitis: clinicopathologic analysis and therapeutic results in 116 cases. Oral Med Oral Surg Med Oral Pathol Oral Radiol Endod. 2002;94:83-91. 29. Lim HW, Morison WL, Kamide R, et al. Chronic actinic dermatitis: an analysis of 51 patients evaluated in the United States and Japan. Arch Dermatol. 1994;130:1284-1289. 30. Toonstra J. Actinic reticuloid. Semin Diagn Pathol. 1991;8:109-116. 31. Healy E, Rogers S. Photosensitivity dermatitis/actinic reticuloid syndrome in an Irish population: a review and some

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46. 47.

48. 49. 50. 51. 52.

unusual features. Acta Derm Venereol (Stockh). 1995;75:72-74. Tojo M, Iwatsuki K, Furukawa H, et al. Neutrophilic eccrine hidradenitis in actinic reticuloid syndrome. Eur J Dermatol. 2002; 12:198-200. Lane PR, Murphy F, Hogan DJ, et al. Histopathology of actinic prurigo. Am J Dermatopathol. 1993;15:326-331. Wiseman M, Magro CM, Toole JWP, Crowson AN. Actinic prurigo: a clinical and dermatopathological study of 7 Inuit and 7 Cree Indian patients (abstract). Lab Invest. 1998;78:54A. Umana A, Gomez A, Duran MM, Porras L. Lymphocyte subtypes and adhesion molecules in actinic prurigo: observations with cyclosporin A. Int J Dermatol. 2002;41:139-145. Grabczynska SA, McGregor JM, Kondeatis E, et al. Actinic prurigo and polymorphous light eruption: common pathogenesis and the importance of HLA-DR4/DRB*0407. Br J Dermatol. 1999;140:232-236. Torres-Alvarez B, Baranda L, Fuentes C, et al. An inmmunohistochemical study of UV-induced skin lesions in actinic prurigo: resistance of Langerhans’ cells to UV light. Eur J Dermatol. 1998;8:24-28. Arrese JE, Dominguez-Soto L, HojyoTomoka MT, et al. Effectors of inflammation in actinic prurigo. J Am Acad Dermatol. 2001;44:957-961. Ng JC, Foley PA, Crouch RB, Baker CS. A case of severe actinic prurigo treated with thalidomide. Australas J Dermatol. 2001; 42:192-195. Kuno Y, Sato K, Hasegawa K, Tsuji T. A case of actinic prurigo showing hypersensitivity of skin fibroblasts to ultraviolet A (UVA). Photodermatol Photoimmunol Photomed. 2000;16:38-41. Wong DE, Meinking TL, Rosen LB, et al. Seabather’s eruption: clinical, histologic and immunologic features. J Am Acad Dermatol. 1994;30:399-406. Ioannides G, Davis JH. Portuguese man-ofwar stings. Arch Dermatol. 1965;91:488-451. Brackett S. Pathology of schistosome dermatitis. Arch Dermatol Syphilol. 1940;42: 410-418. Norment BR, Foil LD. Histopathology and physiological action of venom from the brown recluse spider, Loxosceles reclusa. Toxicon. 1979;17(suppl 1):131. Pucevich MV, McChesney T. Histopathologic analysis of human bites by the brown recluse spider. Arch Dermatol. 1983;119:851. Winer LH, Strakosch EA. Tick bites: Dermacentor variabilis (Say). J Invest Dermatol. 1941;4:249. Sams HH, Hearth SB, Long LL, et al. Nineteen documented cases of Loxososceles reculsa envenomation. J Am Acad Dermatol. 2001;44:603-608. Sams HH, Dunnick CA, Smith ML, King LE. Necrotic arachnidism. J Am Acad Dermatol. 2001;44:561-573. Krinsky W. Dermatoses associated with the bites of mites and ticks (Arthroposi: Acari). Int J Dermatol. 1983;22:75-91. Rivers JK, Martin J, Pukay B. Walking dandruff and Cheyletiella dermatitis. J Am Acad Dermatol. 1986;15:1130-1133. Lee BW. Cheyletiella dermatitis. Arch Dermatol. 1981;117:677-678. Crowson AN, Mihm MC, Jr, Magro CM. Pyoderma gangrenosum: a review. J Cutan Pathol. 2003;28:1-13.

2 PART Predominantly Noninflammatory Conditions

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CHAPTER 14 Alterations of the Stratum Corneum and Epidermis Michael W. Piepkorn

INTRODUCTION

HYPERKERATOSIS WITHOUT EPIDERMOLYTIC CHANGE: THE NONBULLOUS ICHTHYOSES AND RELATED DISORDERS The designation ichthyosis is fundamentally a descriptive term covering a variety of keratinization disorders that are usually genetic in nature. Although their

genetic bases are heterogeneous, all of them share the common feature of scaling skin, which is usually generalized, but as in the instances of the palmoplantar keratodermas and the erythrokeratodermas, they may also be localized. This section covers disorders with significant hyperkeratosis due to defective keratinization but with no cytolytic (epidermolytic) alterations. The organization of these hyperkeratotic disorders, which has been adapted from the work of Traupe,1 follows the diagnostic algorithm presented in Fig. 14-1. This scheme focuses initial attention on whether the predominant mode of keratinization is ortho- or parakeratotic and secondarily on the morphologic status of the stratum granulosum. The features that assist with the differential diagnosis of the entities are summarized in Table 14-1.

DISORDERS WITH HYPERORTHOKERATOSIS AND REDUCED TO ABSENT STRATUM GRANULOSUM The following entities share the common features of hyperorthokeratosis and a general thinning or absence of the stratum granulosum.

Ichthyosis Vulgaris Ichthyosis vulgaris was first discriminated from X-linked recessive ichthyosis,

Mode of hyperkeratosis

Hyperorthokeratosis

Reduced stratum granulosum

Prominent stratum granulosum

Ichthyosis vulgaris acquired ichthyosis Refsum syndrome Tay syndrome X-linked dominant ichthyosis Harlequin ichthyosis

X-linked recessive ichthyosis Lamellar ichthyosis, autosomal recessive Lamellar ichthyosis, autosomal dominant Neutral lipid storage disease KID syndrome Sjögren-Larsson syndrome Palmoplantar keratoderma Erythrokeratoderma variabilis Acanthosis nigricans IFAP inherited pityriasis rubra pilaris Refsum syndrome, some

Parakeratosis

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

An exceptionally diverse group of disorders that are both heterogeneous in their genetic bases and pleiotropic in their phenotypic expression can be assembled under the general category of alterations of the stratum corneum and epidermis. These disorders reflect a wide range of acquired and hereditary pathologic processes. Two distinct themes, however, unite many of the entities described here. One common pathophysiologic feature reflects defects in the keratinization process that manifest clinicopathologically as ichthyoses; the other involves molecular defects in keratin genes and other genes yet to be determined that confer defective epidermal integrity and that present clinically as the mechanobullous disorders. Many of the disorders collated here, particularly the ichthyoses, have similar

microscopic features, complicating the histopathologic differential diagnosis and highlighting the importance of clinical correlation. Accurate diagnosis may also involve special procedures, including immunocytochemistry. Indeed, for the hereditary cytolytic (mechanobullous) disorders, immunolabeling of basement membrane components or electron microscopy to delineate the level of the separation within the tissue is necessary for adequate diagnosis. The histopathologic algorithms offered here, therefore, only serve in many situations to resolve the differential diagnosis to a limited level, beyond which one must resort to supplemental strategies. The organization of this chapter follows the two major schema of defects in the process of keratinization and defective epidermal integrity often due to mutations in keratin genes. Pathways for differential diagnosis of the nonbullous ichthyoses are discussed first followed by disorders with epidermolytic changes.

Ichthyosis vulgaris, some lamellar ichthyosis, some Comèl-Netherton CHILD syndrome porokeratosis

 FIGURE 14-1 Hyperkeratosis without epidermolytic change: diagnostic algorithm for the nonbullous ichthyoses and related disorders. The pathway for differential diagnosis is dichotomized on the preponderant mode of hyperkeratosis, whether ortho- or parakeratotic, and if the former, whether the stratum granulosum is reduced or retained. CHILD = congenital hemidysplasia, ichthyosiform erythroderma, limb defects; IFAP = ichthyosis follicularis with atrichia and photophobia; KID = keratitis, ichthyosis-like hyperkeratosis, and deafness.

313

Table 14-1 Differential Diagnosis of Nonbullous Ichthyoses and Related Disorders HISTOLOGIC FEATURE DISORDER

HYPERKERATOSIS

ACANTHOSIS

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Disorders with Hyperorthokeratosis and a Reduced Granular Layer Ichthyosis vulgaris + to ++ 0 Refsum syndrome + 0 to + Tay syndrome + to ++ + X-linked dominant ichthyosis + to ++ + to ++ Harlequin ichthyosis +++ +

314

FOLLICULAR KERATOSIS

SPONGIOSIS

PERIVASCULAR INFILTRATES

+ 0 0 + to ++ +

0 0 0 + 0

0 to + 0 + + to ++ +

0 0 + 0 + 0 Variable 0

+ to ++ + + Variable + + + to ++ + +

0 +

0 to + ++

Disorders with Hyperorthokeratosis and a Normal to Thickened Granular Layer X-linked recessive ichthyosis + to ++ + 0 to + Lamellar ichthyosis + + + Dorfman syndrome + + + KID syndrome + to ++ Variable + to ++ Sjögren-Larsson syndrome + to ++ 0 to + + Palmoplantar keratoderma ++ + − Erythrokeratoderma variabilis + ++ − IFAP syndrome ++ 0 ++ Pityriasis rubra pilaris ++ to +++ ++ ++ Disorders with Hyperparakeratosis CHILD syndrome + to ++ + 0 Comèl-Netherton syndrome ++ to +++ + to ++ 0

OTHER

Vacuolized keratinocytes Follicular atrophoderma (late) Parakeratosis (some cases)

Foamy keratinocytes

Keratolysis in some cases Follicular atrophy Alternating parakeratosis

PAS-positive debris and neutrophils in corneum

CHILD = congenital hemidysplasia, ichthyosiform erythroderma, limb defects; IFAP = ichthyosis follicularis with atrichia and photophobia; KID = keratitis, ichthyosis-like hyperkeratosis, and deafness; PAS = period acid Schiff.

the other common form of ichthyosis, in the 1960s by Wells and Kerr2 on the basis of inheritance and clinical appearance. The disorder is the most common ichthyosis, with an estimated prevalence of between 1 in 250 and 1 in 5300. 2 Ichthyosis vulgaris is a retention hyperkeratosis disorder inherited as an autosomal dominant trait. Granular layer abnormalities by microscopic examination have led to investigations of the role of profilaggrin, the predominant keratohyalin protein in the human epidermis, in ichthyosis vulgaris. Profilaggrin expression in the affected epidermis is decreased or absent, depending on the disease severity. A subset of individuals with the clinical findings of ichthyosis vulgaris and with no granular layer has been identified; keratinocytes cultured from such individuals have very little detectable profilaggrin protein, and the profilaggrin mRNA level is reduced by approximately 50% in these cells.3 A mouse model, known as flaky tail, presents a clinical phenotype resembling that of the human condition, and at the histologic level, keratohyalin granules are absent from the epidermis; molecular analysis has suggested a defect in the processing of profilaggrin to filaggrin as the potential basis for the phenotype.4 Following from the animal models and

genetic linkage analyses, subsequent mutational analyses have identified specific mutations in the profilaggrin gene that cause ichthyosis vulgaris and predispose individuals to atopic dermatitis, presumably mediated by defects in barrier function.5 CLINICAL FEATURES The disorder presents early in life, usually within the first year, but is rarely present at birth (Table 14-2). Fine, white scales are found on the trunk and extensor surfaces of the extremities in association with superficial fissuring in severe cases (Fig. 14-2A). The central face and cheeks may be involved, but the sides of the neck are almost always spared. The condition is associated with atopy and keratosis pilaris. Hyperlinearity and chafing of the palms and soles are often present, but whether this is linked to the atopy or the ichthyosis is disputed. Because of the overlap in clinical phenotype, ichthyosis vulgaris and X-linked recessive ichthyosis are often confused clinically; the usual mistake in diagnosis is labeling X-linked recessive ichthyosis as ichthyosis vulgaris.6 Assay for reduced levels of steroid sulfatase activity, however, can be used to confirm the diagnosis of X-linked recessive ichthyosis.

HISTOPATHOLOGY Microscopic examination of the stratum corneum in patients with ichthyosis vulgaris reveals compact hyperorthokeratosis.1 The degree of hyperkeratosis varies from mild to moderate. This alteration is associated with a uniformly reduced granular layer that is absent in at least some foci (Fig. 14-2B). Parakeratosis is generally not observed. Follicular dilatation and hyperkeratosis are regularly present. The epidermis is usually of normal thickness,7 but on occasion, acanthosis or even atrophy may be present. The rete ridge pattern is not accentuated. The sebaceous glands are atrophic. No or slight perivascular inflammation is found in the papillary dermis. DIFFERENTIAL DIAGNOSIS The differential diagnosis may include lamellar ichthyosis and X-linked recessive ichthyosis in cases in which the granular layer is not especially thinned. However, the usual patient manifests an absent (or at least a clearly thinned) granular layer. Keratohyalin granules appear crumbly or degenerated by electron microscopy, allowing distinction from the other ichthyoses in which the granular layer is thinned. In the differential diagnosis of nonbullous

Table 14-2 Ichthyosis Vulgaris

ichthyosis with a reduced granular layer, many of the remaining disorders, such as Refsum disease and X-linked dominant ichthyosis,1 are syndromes in which the ichthyotic change is one component associated with other signs and symptoms in a recognizable pattern that collectively allows assignment of the diagnosis. The diagnostic consideration of an acquired ichthyosis is discussed in the next section.

Acquired Ichthyosis Acquired ichthyosis, with onset usually beyond the childhood years, has been

A

CLINICAL FEATURES The clinical findings are reported to resemble those of ichthyosis vulgaris, although large platelike or hyperpigmented scales are sometimes observed. Hyperlinearity of the palms and soles is not a feature, but palmar–plantar keratoderma has been described. HISTOPATHOLOGY The histologic pattern also resembles that of ichthyosis vulgaris with hyperorthokeratosis, compaction of the stratum corneum, and thinning of the granular layer in some cases.10 No cases of a totally absent granular layer have been reported, and staining with antiprofilaggrin or filaggrin antibody demonstrates the presence of profilaggrin or filaggrin. DIFFERENTIAL DIAGNOSIS Clinicopathologic overlap exists between ichthyosis vulgaris, acquired ichthyosis, and dry skin (xerosis). A distinction between ichthyosis vulgaris and acquired ichthyosis is essentially founded on the clinical history and physical examination findings. Xerosis is

poorly understood and loosely defined; other than an association with winter weather and aging, few distinguishing features are present. The distinction of the dry skin seen in atopic eczema from ichthyosis vulgaris has been made on the basis of other clinical findings associated with the two disorders and appears distinct histologically.

Refsum Syndrome (Heredopathia Atactica Polyneuritiformis) Refsum syndrome is an uncommon disorder associated with peroxisomal dysfunction. It affects the eyes, nervous system, and skin.11 The condition is inherited as an autosomal recessive trait. Accumulation of phytanic acid from phytol present in chlorophyll results in altered epidermal metabolism, with an increased thymidine labeling index, increased incorporation of precursors into DNA and protein, and altered lipid metabolism.12,13 It is unclear how accumulation of the long-chain, branched fatty acid effects such changes. The underlying defect lies in the alphaoxidation of phytanic acid, the basis for which is genetically heterogeneous; mutations in one of two AAA ATPases, PEX1 or PEX614 or in phytanoyl-CoA hydroxylase may be etiologic15 in selected kindreds. CLINICAL FEATURES Patients with Refsum syndrome initially present with night blindness caused by retinitis pigmentosa. Sequential involvement with relapsing sensory neuropathy, cerebellar ataxia, cataracts, and nerve deafness is associated with phytanic acidemia.16 Skin changes occur after the eye and neurologic changes and vary from mild scaling of the palms and soles to a presentation

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

Clinical Features Onset within the first year of life Fine, white scales on the trunk and extensor extremities, sparing the sides of the neck Hyperlinearity and chafing of the palms and soles Associated with atopy and keratosis pilaris Histopathology Mild to moderated compact hyperorthokeratosis Generally no parakeratosis Diminished to absent stratum granulosum Follicular dilatation and hyperkeratosis Epidermis usually of normal thickness Differential Diagnosis Acquired ichthyosis Xerosis Syndromes with associated ichthyosis: Refsum syndrome, ichthyosis, and trichothiodystrophy, X-linked dominant ichthyosis with chondrodysplasia punctata

described in association with a number of systemic disorders (including thyroid disease, sarcoidosis, systemic lupus erythematosus, graft-versus-host disease after bone marrow transplantation, malnutrition, HIV), drugs, and malignancies.8-10 Nearly half of people with insulin-dependent diabetes clinically show ichthyosiform changes. Although solid tumors have occasionally been found, lymphoproliferative disorders, particularly Hodgkin disease, prevail. Speculation regarding the possible role of vitamin A deficiency caused by liver involvement or malabsorption has not been substantiated. Thus, the cause of the disorder is unknown.

B

 FIGURE 14-2 Ichthyosis vulgaris. (A) Diffuse fine white scale on the extremity. (B) A moderately hyperorthokeratotic stratum corneum overlies a mildly acanthotic spinous layer without an intervening stratum granulosum.

315

resembling ichthyosis vulgaris and occasionally to widespread, severe scaling resembling lamellar ichthyosis.1

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

HISTOPATHOLOGY The stratum corneum exhibits slight hyperorthokeratosis, which is associated with a thinned to normal granular layer. Slight acanthosis may be present. Vacuolization of basal and suprabasal keratinocytes due to lipid accumulation with phytanic acid may not be evident by routine histologic examination, but is shown with histochemical lipid stains such as Sudan red.

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DIFFERENTIAL DIAGNOSIS The routine histopathologic findings resemble those of ichthyosis vulgaris and related disorders. The accumulation of phytanic acid within keratinocytes and other cutaneous cells such as melanocytes, however, is the hallmark of the disorder and can be demonstrated by lipid staining. Its presence serves to discriminate Refsum disease from most other ichthyoses with similar histologic features, although neutral lipid storage disease shows similar lipid accumulations.

Syndromes of Ichthyosis and Trichothiodystrophy The syndromes of ichthyosis and trichothiodystrophy are a heterogeneous group of overlapping phenotypes with no firm criteria allowing for absolute categorization.1 These conditions include Tay syndrome, BIDS (brittle hair, intellectual impairment, decreased fertility, and short stature), IBIDS (ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature), and PIBI(D)S (photosensitivity, brittle hair, intellectual impairment, decreased fertility, and short stature). All of these disorders are thought to be inherited as autosomal recessive traits. The nucleotide excision repair defect in PIBI(D)S, which is associated with photosensitivity, may fall into the same complementation group as xeroderma pigmentosum group D, with a mutation in the repair gene XPD that encodes helicase subunits of the repair factor transcription factor II H (TFIIH).17,18 At the biochemical level, the cystine content of the hair is decreased. CLINICAL FEATURES The syndromes have in common the features of ichthyosis, brittle hair, and short stature. The ichthyosis varies from mild to severe congenital erythroderma with a collodion membrane, which evolves to more platelike scaling with little erythema, similar to lamellar ichthyosis. The hair is often

fractured, with varied microscopic findings and characteristic banding when viewed with polarized light; cystine and proline content are reduced. Additional findings include psychomotor and mental retardation and unusual sociability. Photosensitivity with abnormal DNA excision repair and retarded sexual development with decreased fertility are variable findings. HISTOPATHOLOGY Microscopic sections of skin show moderate hyperorthokeratosis and thinning of the granular layer.1 The spinous layer is moderately acanthotic and mildly papillomatous. Slight perivascular lymphocytic inflammation is present within the papillary dermis. DIFFERENTIAL DIAGNOSIS The histopathologic findings are nonspecific and similar to those of autosomal dominant ichthyosis vulgaris and related conditions. Although the differential diagnosis may not be resolvable by the cutaneous histopathology, microscopic examination of the hair shows trichoschisis (transverse breaks), and polarized light reveals alternating (tigertail) light and dark bands.19

X-linked Dominant Ichthyosis with Chondrodysplasia Punctata (Conradi-Hunermann Syndrome) This uncommon disorder is inherited as an X-linked dominant trait that is presumed to be lethal in male embryos and largely restricted in its expression to females. Maternal gonadal mosaicism is postulated in rare reports of seemingly sporadic cases.20 The disease has been linked with deficiency of 3 beta-hydroxysteroiddelta8-delta7-isomerase (emopamil binding protein), which catalyzes a step in the conversion of lanosterol to cholesterol.21,22 CLINICAL FEATURES The disorder may present with generalized ichthyosiform erythroderma and linear areas of thickened hyperkeratosis. The erythema resolves within weeks to months, leaving atrophic follicular involvement, ichthyosis, and hyperpigmentation following the lines of Blaschko. Patchy areas of cicatricial alopecia with nonspecific microscopic hair shaft abnormalities, sparse eyebrows and eyelashes, and nail dystrophy are also seen. Cataracts, short stature, and skeletal defects (chondrodysplasia punctata) are additional components of Conradi-Hunermann syndrome. HISTOPATHOLOGY In this disorder, moderate hyperorthokeratosis is associated with a thinned granular layer and slight

acanthosis.23 A mild perivascular lymphocytic infiltrate may be present in the papillary dermis. Prominent follicular hyperkeratosis associated with dyskeratotic cells occurs in young patients, with late follicular atrophoderma in adults. Some reports have suggested the presence of a variable neutrophilic reaction in the epidermis. DIFFERENTIAL DIAGNOSIS The findings are those of disorders sharing the histologic phenotype of autosomal dominant ichthyosis vulgaris. The differential diagnosis in suspected cases can be resolved by identification of the other components of the syndrome, particularly chondrodysplasia punctata supplemented by von Kossa stain to demonstrate the deposition of calcium salts within lesional epidermis. A reduced density of epidermal Langerhans cells may also be shown by immunostaining with CD1a. A vacuolated granular layer may also occur, along with spicules by electron microscopic examination. All of these findings, however, are seen early in the course of the disease and may resolve over time, leaving the residual, linear areas of pigmentary change, follicular atrophoderma, and cicatricial alopecia with no characteristic histologic features.

Harlequin Ichthyosis Harlequin ichthyosis is a rare, severe keratinizing disorder thought to be inherited as an autosomal recessive trait or a new dominant mutation.24 The disorder is phenotypically heterogeneous.25 Abnormal or absent lamellar granules within keratinocytes are observed by electron microscopy in all forms. Lamellar granules function in lipid transport. A member of the ATP-binding cassette transporter family designated ABCA12 ultrastructurally localizes to lamellar granules and functions in lipid secretion in and out of the cells via these granules.26 Mutational analyses of ABCA12 as a candidate gene for Harlequin ichthyosis and complementary single nucleotide polymorphism mapping strategies have shown that missense and nonsense mutations in highly conserved regions of the gene are etiologic for the condition; the phenotype is thus mediated by deleterious effects on skin barrier function resulting from defective lipid transport.26,27 CLINICAL FEATURES The condition is the most severe of the congenital ichthyoses. Newborns are incarcerated in a massively thick, platelike scale affecting the entire integument, which produces

ectropion and eclabium; restricts respiration and feeding; and alters development of the ears, nose, eyes, and mouth. The cuirass cracks soon after birth, resulting in deep fissures in geometric patterns. Death usually ensues. If the affected infant survives beyond the newborn period, the phenotype evolves into that of a severe nonbullous congenital erythroderma.

DISORDERS WITH HYPERORTHOKERATOSIS AND PROMINENT STRATUM GRANULOSUM A separate pathway of differential diagnosis is suggested when histologic examination indicates a normal to expanded stratum granulosum (Fig. 14-1). The prototypes for these disorders are X-linked recessive ichthyosis and the lamellar ichthyoses. These and most of the other entities included here look alike histologically. In addition, a number of multisystem syndromes enter the

differential diagnosis in which the specific diagnosis is made by the corresponding clinical context.

X-Linked Recessive Ichthyosis X-linked recessive ichthyosis is the second “common” ichthyosis (ichthyosis vulgaris is the other). Distinction between the two was clarified by Wells and Kerr2 on the basis of inheritance, clinical findings, and histology. However, definitive diagnosis is dependent on steroid sulfatase determination because the two disorders may be confused clinically in 10% to 15% of cases. The disorder occurs in between 1 in 4152 and 1 in 9500 individuals. Mutations (most commonly complete gene deletions) in the steroid sulfatase gene, a locus that maps to the telomeric short arm of the X chromosome (Xp22.3), are responsible for the defect.28 The resulting accumulation of cholesterol sulfate in keratinocytes (as well as in other tissues such as leukocytes) is thought to result in retention hyperkeratosis and scaling, and the increased cholesterol sulfate in combination with decreased cholesterol within the stratum corneum contributes to a deficiency in barrier function.29 Due to presumptive contiguous gene defects, some cases are associated with Kallmann syndrome, mental retardation, chondrodysplasia punctata, and short stature.30 CLINICAL FEATURES Affected individuals present at birth or soon thereafter (Table 14-3). A collodion membrane is seen infrequently, but affected infants more commonly manifest fine, relatively mild scaling at birth. The scaling worsens or generalizes in the first two to six months as larger, pigmented scales appear on the trunk, extremities, axillae, sides of the

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

HISTOPATHOLOGY The histologic pattern in Harlequin ichthyosis varies between reports.24,25 Across all categories, however, there is massive compact hyperorthokeratosis, creating a stratum corneum that is much thicker than the spinous layer (Fig. 14-3). Changes in the granular layer are variable. This zone is usually thinned, with keratohyalin granules either reduced in density or totally absent, but it may be normal. The follicles are dilated and hyperkeratotic. Inconstant and less striking changes include mild acanthosis and papillomatosis. Pronounced parakeratosis may be observed in patients who completely lack keratohyalin granules. A superficial perivascular lymphocytic infiltrate is an inconstant feature.

DIFFERENTIAL DIAGNOSIS The massive hyperorthokeratosis is distinctive and not simulated as a rule by any of the other ichthyoses. In questionable cases, electron microscopy may be used to establish reduced or absent lamellar granules or genetic testing can now be used. Clinical correlation usually resolves most of the differential diagnostic ambiguities, if any, because of the distinctive clinical phenotype.

Table 14-3 X-linked Recessive Ichthyosis

 FIGURE 14-3 Harlequin ichthyosis. Massive orthokeratotic thickening of the stratum corneum is seen in association with a thinned stratum granulosum and a spinous layer that is mildly acanthotic and papillomatous. The follicular ostia are dilated and plugged with keratin.

Clinical Features Present at birth or shortly thereafter Generalized fine scaling, especially at flexural sites Progresses over the first 6 months to large, pigmented, platelike scales Histopathologic Features Marked hyperorthokeratosis with occasional parakeratotic foci Granular layer usually thickened Variable acanthosis and papillomatosis Differential Diagnosis Ichthyosis vulgaris Autosomal recessive lamellar ichthyosis

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neck, and the popliteal and antecubital fossae, although the volar epidermis is spared. The brownish scales tend to be large polygonal plates that are adherent. Associated findings may include cryptorchidism and asymptomatic corneal opacities. Obstetric complications, such as a late-for-dates pregnancy, weak labor, and prolonged delivery, occur in as many as 30% of affected pregnancies because of blocked placental estrogen synthesis. HISTOPATHOLOGY Patients have marked hyperorthokeratosis with occasional foci of parakeratosis. The granular layer is usually thickened (Fig. 14-4), although this can vary, and it may be thinned in some sections. The spinous layer is variably acanthotic and papillomatous. Perivascular lymphoid infiltrates within the papillary dermis range from mild to marked. Follicular dilatation and plugging are usually absent but may occasionally be observed. DIFFERENTIAL DIAGNOSIS Although in contrast to autosomal dominant ichthyosis vulgaris, the granular layer is thickened, every patient does not have this feature, and in patients with a reduced stratum granulosum, distinction from ichthyosis vulgaris may not be possible from histologic criteria alone. Cases with thickening of the granular layer resemble autosomal recessive lamellar ichthyosis. Biochemical analysis for steroid sulfatase activity may be necessary to resolve the differential diagnosis.31

Lamellar Ichthyosis CLINICAL FEATURES Lamellar ichthyosis is a genetically heterogeneous disease. Most cases are transmitted as an autosomal recessive trait, but cases with dominant transmission have also been described.1 The recessively inherited form is a severe and often generalized dermatosis, usually presenting at birth and accounting for the majority of cases of collodion baby syndrome (Table 14-4). There are erythrodermic and nonerythrodermic clinical variants. Patients with the most severe phenotype show large, brown, platelike scales and pronounced ectropion. Those with milder phenotypes may have involvement of only the flexural sites and the palms and soles. Mutations in keratinocyte (type I) transglutaminase on chromosome 14qll, which cross-links the cornified envelopes of terminally differentiating keratinocytes, are associated with many cases of lamellar ichthyosis, with other cases mapping to a region on chromosome 2 and linked to mutations in the ABCA12 gene that is the major gene for Harlequin ichthyosis.26,32,33 Defective transglutaminase activity results in incomplete cross-linking of substrates such as loricrin and involucrin, disrupted assembly of cornified envelopes, and defective barrier function.34 HISTOPATHOLOGY The histologic patterns are indistinguishable across all erythrodermic and nonerythrodermic clinical variants of lamellar ichthyosis of autosomal

Table 14-4 Autosomal Recessive Lamellar Ichthyosis

Clinical Features Present at birth with generalized involvement, often with a collodion membrane Erythrodermic and nonerythrodermic variants Large platelike scales, ectropion Histopathology Mild to marked compact hyperorthokeratosis Normal to widened stratum granulosum Often acanthosis and papillomatosis Differential Diagnosis X-linked recessive ichthyosis

recessive type, as well as cases with autosomal dominant transmission. Mild to marked compact hyperorthokeratosis and a normal to increased stratum granulosum are observed in these patients (Fig. 14-5). Often acanthosis and occasionally papillomatosis are seen. Parakeratotic foci associated with a focally thinned granular layer are less commonly observed, but parakeratosis with a thickened granular layer is seen in the autosomal dominant variant. The papillary dermis may contain a perivascular lymphocytic infiltrate of variable intensity. DIFFERENTIAL DIAGNOSIS The histopathology is nonspecific, mimicking that of X-linked recessive ichthyosis, but serves to exclude clinical look-alikes, especially disorders with epidermolytic hyperkeratosis (bullous ichthyosiform erythrodermas). Distinction from the Comèl-Netherton syndrome, which clinically resembles erythrodermic autosomal recessive lamellar ichthyosis, is resolved by the presence of marked inflammation, with spongiosis, lymphocytic exocytosis, parakeratosis, and a thinned to absent granular cell layer.

Neutral Lipid Storage Disease with Ichthyotic (Ichthyosiform) Erythroderma (Dorfman Syndrome and Dorfman-Chanarin Syndrome)

318

 FIGURE 14-4 X-linked recessive ichthyosis. A continuous granular layer of normal to slightly increased thickness separates the densely compact orthokeratotic corneum from the histologically unremarkable stratum spinosum.

CLINICAL FEATURES Neutral lipid storage disease has been reported in fewer than 20 cases, primarily in individuals of Arabic background. The disorder is inherited as an autosomal recessive trait and results in the accumulation of neutral lipids in different tissues. Increased cellular triacylglycerol is thought to result from defective recycling of triacylglycerolderived diacylglycerol to phospholipids.35

HISTOPATHOLOGY Microscopic examination shows nonspecific findings of hyperorthokeratosis and acanthosis, although the hyperkeratosis may be marked. The granular layer is generally thickened. Prominent follicular plugging may also be present.7

 FIGURE 14-5 Lamellar ichthyosis. The compact and mildly thickened orthokeratotic corneum is separated from the slightly acanthotic stratum spinosum by a continuous granular layer of normal thickness.

Mutations in the gene for adipose triglyceride lipase (PNPLA2) are etiologic in some cases.36 Neutral lipid storage disease presents in the skin as diffuse nonbullous ichthyosiform erythroderma, which is indistinguishable from other ichthyoses of that phenotype. Hepatomegaly with abnormal liver function test results, myopathy, cataracts, and lipid vacuolization of leukocytes (Jordan anomaly) and keratinocytes are other components of the syndrome. HISTOPATHOLOGY The routine histologic findings are nonspecific, with acanthosis and hyperorthokeratosis present. Variable parakeratotic foci are also present. The stratum granulosum may be thickened or thinned. A slight perivascular infiltrate may be observed in the papillary dermis. The most distinctive feature is the presence of foamy cytoplasm (vacuoles containing lipid) within keratinocytes of the basal and granular layers; by histochemical staining, this is shown to be lipid accumulation. Lipid droplets may also be observed in fibroblasts, Schwann cells, smooth muscle, and eccrine gland epithelium.37 DIFFERENTIAL DIAGNOSIS The microscopic features are indistinguishable from other nonbullous congenital ichthyoses, but the observation of lipid droplets in the keratinocytes by microscopic examination of H&E-stained permanent sections or frozen sections if necessary with confirmation by histochemical lipid staining may allow discrimination from lamellar ichthyosis.

The Ichthyosis and Deafness Syndromes Although similar in name, the two ectodermal dysplasias are distinct clinically and histologically. Cases of HID (hystrix-like ichthyosis with deafness) have appeared to be sporadic. Although X-linked recessive inheritance has been excluded, autosomal dominant or recessive transmission is possible. Most cases of KID (keratitis, ichthyosis-like hyperkeratosis, and deafness) have also appeared to be sporadic, but some evidence supports an autosomal dominant inheritance. The underlying defects are largely unknown, although evidence indicates that both KID and HID may be caused by specific mutations in connexin 26.38 CLINICAL FEATURES Patients with HID present with patches of erythema soon after birth that progress to generalized, dark gray, scaly skin resembling ichthyosis hystrix. The palms and soles may be mildly affected, and alopecia and nail dystrophy may be seen. In patients with KID, erythroderma at birth disappears within a few days; erythematous, sharply marginated, keratotic plaques develop at about age 1 year and increase until puberty. The face, elbows and knees, palms and soles are involved, but the trunk is spared. In both syndromes, sensorineural hearing loss, frequent bacterial and fungal infections, and scarring alopecia are seen.39 Severe palmar–plantar involvement and vascularizing keratopathy are observed in KID; in HID, palmar–plantar involvement is mild, and only punctate keratitis is seen.

Sjögren-Larsson Syndrome CLINICAL FEATURES Sjögren-Larsson syndrome is a severe, autosomal recessive, neurocutaneous disease consisting of mental retardation, spasticity, and ichthyosis. The disorder is genetically homogeneous, with affected individuals exhibiting an enzymatic deficiency in fatty aldehyde dehydrogenase due to a wide range of deletions and point mutations in the encoding gene ALDH3A2.40,41 The generalized, yellow-brown, lichenified ichthyosis associated with SjögrenLarsson syndrome is of early onset and not specifically distinguishable from other widespread ichthyoses of the lamellar type. Erythema is mild and fades with age. HISTOPATHOLOGY Histologic sections exhibit acanthosis and some papillomatosis. Moderate compact hyperorthokeratosis characterizes the stratum corneum, but scattered foci of parakeratosis may be present. The granular layer is retained and may be thickened. Follicular hyperkeratosis is variably observed.1,7

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

DIFFERENTIAL DIAGNOSIS The diagnosis is made by the clinical recognition of the other components of the syndrome. In some reports of HID syndrome, vacuolated keratinocytes occur in the granular layer, with the nucleus surrounded by an empty halo and ringed by keratohyalin granules; that finding, along with the characteristic differences in clinical presentation, is helpful in distinguishing between the two disorders.

DIFFERENTIAL DIAGNOSIS Sjögren-Larsson syndrome cannot be discriminated histologically from autosomal recessive lamellar ichthyosis. The diagnosis is made by identification of the other components of the syndrome.

Palmoplantar Keratoderma As the isolated phenotype or an associated component of a syndrome, the palmoplantar keratodermas comprise a heterogeneous group of inherited diseases sharing the common feature of aberrant volar keratinization, occasionally in the setting of other ectodermal dysplasias.42

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The common forms are dominantly inherited; some less prevalent cases represent recessive transmission. The autosomal dominant palmoplantar keratoderma of Unna-Thost syndrome is considered the most common form of this group, but the nomenclature has been clouded by the discovery that the family originally described by Thost in the past century exhibits epidermolytic hyperkeratosis on microscopic examination, indicating overlap with the phenotype of palmoplantar keratoderma type Voerner.43 Palmoplantar keratodermas of the Meleda type and of the Papillon-Lefevre syndrome, which are often the most severe phenotypes, are recessive traits. Mutation in the cathepsin C gene is etiologic in Papillon-Lefevre syndrome. Some affected kindreds with nonepidermolytic palmoplantar keratoderma link genetically to the type I or II keratin gene clusters on chromosomes 17q and 12q.44 Most instances of epidermolytic palmoplantar keratoderma are caused by mutations in the gene for the palmand sole-specific keratin 9.45 In some instances, palmoplantar keratoderma is an acquired condition associated with underlying systemic disorders that predispose to its expression.46 Examples include lymphomas such as mycosis fungoides, myeloma and other internal cancers, acanthosis nigricans, and myxedema. Exposure to toxins such as dioxin and arsenic or to chemotherapeutic agents (eg, fluorouracil) may sometimes be etiologic. Keratoderma climactericum is the designation for the association with the postmenopausal or post-oophorectomy state. CLINICAL FEATURES Patients exhibit localized or diffuse and often marked hyperkeratosis of the palms and soles.47 The epidermolytic and nonepidermolytic variants are clinically indistinguishable. The onset may occur from birth to the fourth decade of life, although early onset is more common. The callouslike lesions are often well demarcated. The borders of the hyperkeratotic plaques may be erythematous. Spread onto the extensor surfaces may occur, especially in those with the Meleda type, and there may be hyperhidrosis, constricting bands with gangrene and autoamputation (as seen in Vohwinkel syndrome), thickening of the nails, and psoriatic-like lesions on other parts of the body. Keratoderma in patients with PapillonLefevre syndrome is associated with periodontosis, resulting in shedding of the permanent dentition. Maceration

due to hyperhidrosis is a feature of mal de Meleda. The Howel-Evans syndrome of palmoplantar keratoderma, which is genetically linked to 17q, is associated with squamous cell carcinoma of the esophagus later in life. Sclerodactyly, nail dystrophy, and squamous cell carcinoma of the affected skin are attributes of the autosomal dominant Huriez syndrome. Punctate keratoderma is a limited variant of varying age of onset characterized by firm, well-demarcated plugs of keratotic material located on normal volar skin, sometimes with a predilection for the skin creases. Rare associations of palmoplantar keratoderma include oculocutaneous tyrosinosis (corneal ulcers, painful volar punctate or more diffuse keratotic lesions, mental retardation), acrokeratoelastoidosis of Costa (with punctate lesions), hidrotic ectodermal dysplasia, and pachyonychia congenita. HISTOPATHOLOGY In all clinical varieties of palmoplantar keratodermas, marked hyperorthokeratosis of the corneum is present in association with thickening of the stratum granulosum. Additionally, acanthosis and some papillomatous changes are seen. Mild perivascular chronic inflammation occurs in the papillary dermis. Some patients display epidermolytic hyperkeratosis of the upper spinous and granular cell layers and scattered dyskeratotic cells (as found in, but apparently not limited to, Voerner syndrome). A pluglike compact column of parakeratosis within the stratum corneum is observed in the subtype of keratosis palmoplantaris punctata. A surface pit may overly the columnar focus. DIFFERENTIAL DIAGNOSIS Whereas the histologic pattern of nonepidermolytic cases is similar to that of the nonbullous lamellar ichthyoses, epidermolytic hyperkeratosis can be distinguished from the bullous ichthyosiform erythrodermas by correlation with the clinical features. Distinction from pityriasis rubra pilaris rests with the associated clinical findings.

Erythrokeratoderma Variabilis and Progressive Symmetric Erythrokeratoderma Erythrokeratoderma variabilis and progressive symmetric erythrokeratoderma are probably closely related variants of the same malady.48 Erythrokeratoderma variabilis is a rare, usually autosomal dominant disease that presents from birth

to early adulthood. The disorder is linked to mutations in the connexin genes.48 CLINICAL FEATURES Erythrokeratoderma variabilis manifests transient, polycyclic or circinate, bright patches of erythema that change in size, shape, and distribution over hours to days. The areas are bounded by a trailing scale and may be ringed by a thin, white line. They are commonly found on the extremities and buttocks, but the trunk and abdomen may also be involved. Affected areas are exacerbated by temperature extremes and stress. More stable, fixed, erythematous, hyperkeratotic plaques develop on the extensor surface of the extremities. Mild palmoplantar keratoderma may be seen in up to 50% of cases, and central nervous system abnormalities have been reported in some families. The lesions of progressive symmetric erythrokeratoderma resemble those of erythrokeratoderma variabilis, but their distribution is strikingly symmetric and limited to the extremities and buttocks, and they remain fixed after they appear. Although the two disorders are usually distinct, the occurrence of both—one each in sisters— suggests that they represent variants of the same process. HISTOPATHOLOGY Erythrokeratoderma variabilis is characterized by a normal granular cell layer underlying a hyperorthokeratotic stratum corneum. The epidermis is acanthotic and shows papillomatosis. The suprapapillary zones of the stratum spinosum may be thinned. The papillary dermis contains a perivascular lymphocytic dermatitis of variable intensity. Progressive symmetric erythrokeratoderma histologically shows hyperkeratosis with focal parakeratosis. The granular cell layer is normal to thickened. Perinuclear granular cell vacuolization may be seen. The spinous layer is acanthotic. DIFFERENTIAL DIAGNOSIS The histologic patterns of erythrokeratoderma variabilis and progressive symmetric erythrokeratoderma are nonspecific, resembling many of the nonbullous ichthyoses. The diagnosis rests with the clinicopathologic correlation.

Acanthosis Nigricans A relatively prevalent mucocutaneous disorder, acanthosis nigricans occurs in several clinically defined types, but most often it is found in association with obesity and insulin resistance and less commonly in an exuberant, paraneoplastic

form.49 The eruption is probably caused in most instances by circulating insulin and insulinlike growth factors acting on keratinocytes and other cutaneous cells that express the cognate growth factor receptor(s).

HISTOPATHOLOGY Despite the impression created by its name, there is usually little acanthosis; the epidermis is more often somewhat thinned and rather moderately to markedly papillomatous (Fig. 14-6). The papillomatosis has a blunted hill-anddale silhouette. The hyperkeratotic stratum corneum often retains the normal basket-weave architecture. Little, if any, perivascular lymphocytic infiltration of the papillary dermis is seen. DIFFERENTIAL DIAGNOSIS Distinction from seborrheic keratosis and hamartomatous epidermal nevi may occasionally be

Ichthyosis Follicularis (Follicular Ichthyosis) with Atrichia and Photophobia Syndrome CLINICAL FEATURES The essential phenotypic components of this syndrome are follicular ichthyosis often accentuated over the head and neck, generalized congenital nonscarring alopecia, and photophobia. Other common findings include mild generalized scaling with erythema, psychomotor and growth retardation, susceptibility to pyodermas, dentition abnormalities, and nail dystrophy.50 The strong gender predilection for males suggests an X-linked recessive inheritance. The expression of a contiguous gene defect may underlie the clinical variability of the disorder. HISTOPATHOLOGY Microscopic examination discloses moderate hyperorthokeratosis with follicular dilatation and plugging. The granular layer is preserved and

 FIGURE 14-6 Acanthosis nigricans. Pronounced hyperorthokeratosis in a basket-weave pattern overlies the papillomatous epidermis, but little acanthosis is seen.

may be thickened. Specimens of scalp skin reveal atrophy of the folliculosebaceous units and thinning of the dermis. DIFFERENTIAL DIAGNOSIS The retention of the granular layer allows distinction from autosomal dominant ichthyosis vulgaris and related disorders. The absence of epidermolytic hyperkeratosis excludes bullous ichthyosiform erythrodermas. Clinical features allow distinction from the keratosis pilaris syndromes.

Inherited Pityriasis Rubra Pilaris CLINICAL FEATURES Whereas most instances of the uncommon disease pityriasis rubra pilaris are sporadic, an inherited form exists and is observed most often juveniles.51 Inheritance is autosomal dominant. The underlying defect is unknown. The clinical lesions of pityriasis rubra pilaris are thick, erythematous, salmoncolored plaques that are localized to sites of predilection, such as the scalp, volar surfaces, and elbows and knees, or more generalized, eventuating into an exfoliative erythroderma. HISTOPATHOLOGY The epidermis is acanthotic and papillomatous, with elongation of the rete ridges that may create a psoriasiform pattern of hyperplasia.52 There may be widening of the intercellular spaces within the spinous layer. The stratum corneum is remarkable for marked hyperkeratosis, which in some foci exhibits horizontally alternating zones of ortho- and parakeratosis. The stratum granulosum is usually hypergranular. Dilatation and keratotic plugging of the follicular infundibulae are often reliably prominent features of pityriasis rubra pilaris and should be sought in additional recuts if the diagnosis is unclear from the original sections. The stratum corneum adjacent to the follicular ostia may show parakeratosis (shoulder parakeratosis). A slight perivascular lymphocytic infiltrate is observed in the papillary dermis. DIFFERENTIAL DIAGNOSIS The psoriasiform hyperplasia of pityriasis rubra pilaris may make distinction from psoriasis difficult or in some instances not possible, especially considering that alternating parakeratotic foci and variably thickened or absent stratum granulosum may be observed in the latter. However, the presence of neutrophilic foci within the corneum (Munro abscesses) and dermal papillae with lymphocytic infiltrates and dilated capillaries favor the interpretation of psoriasis, and there should be few, if any, dilated and keratotic follicular

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

CLINICAL FEATURES Although acanthosis nigricans may occur anywhere on the skin, the characteristic velvety hyperpigmented plaques of this disorder exhibit a predilection for the flexural sites of the axillae, nape, groin, and popliteal and antecubital fossae. Associated palmoplantar keratoderma (tylosis) may rarely occur in cases induced by internal malignancy. Occasionally, papillomatous epithelial hyperplasia may affect the conjunctiva and the stratified squamous mucosae of the oropharynx and anal canal.

necessary when the papillomatosis is pronounced; the usual absence of significant acanthosis helps rule out these considerations. Confluent and reticulate papillomatosis of Gougerot and Carteaud is generally not distinguishable histologically, but the flexural distribution of lesions of acanthosis nigricans compared with the more generalized distribution of confluent and reticulate papillomatosis permits clinical distinction of the two.

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infundibulae in the latter. Follicular plugging, although not an invariable feature, is helpful in resolving the differential diagnosis of other papulosquamous diseases when present. Discrimination from cases of nonbullous ichthyosiform erythrodermas may not be possible on histologic grounds alone.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

DISORDERS WITH HYPERPARAKERATOSIS There are few entities in which prominent parakeratosis is a clue to the diagnosis. More often, parakeratosis is found as a transient or inconstant feature in a disorder with hyperkeratosis developing in an orthokeratotic fashion. Among these are some cases of autosomal dominant ichthyosis vulgaris, lamellar ichthyoses, and Harlequin ichthyosis. Those entities are discussed under the sections reflecting their more constant histopathologic patterns.

Granular Parakeratosis Synonyms: Granular axillary parakeratosis Granular parakeratosis is a rare acquired condition thought to be a disorder of keratinization.53 Although an irritant contact reaction appears operative, other forms of mechanical irritation may also figure into the pathogenesis of these lesions. Recent studies on this entity suggest a basic defect in the processing of profilaggrin to filaggrin, resulting in a failure to degrade keratohyalin granules and to aggregate keratin filaments during cornification. Associated abnormalities of the cell surface structures and dysregulation of cornified envelope components may account for the retention hyperkeratosis.54 CLINICAL FEATURES Individuals of all ages ranging from younger than 1 year of age to the elderly present with intertriginous (most commonly axillary), erythematous, brown or red, scaly or keratotic papules and plaques that are often pruritic. Other sites, including the face, trunk, and buttocks, may also be involved. HISTOPATHOLOGY Characteristic histologic features include a conspicuously thickened stratum corneum with compact parakeratosis, slight epidermal hyperplasia (psoriasiform, papillomatous, or both), and a sparse perivascular lymphohistiocytic infiltrate (Fig. 14-7). Keratohyalin granules are diffusely present within the parakeratotic stratum corneum, and the retained granular layer manifests focal vacuolization.

322

 FIGURE 14-7 Granular parakeratosis. The stratum corneum is dramatically thickened with compact parakeratosis, psoriasiform epidermal hyperplasias, slight papillomatosis, and a perivascular lymphocytic infiltrate. Keratohyalin granules are diffusely present within the parakeratotic stratum corneum, and the retained granular layer manifests focal vacuolization.

DIFFERENTIAL DIAGNOSIS Granular parakeratosis must be distinguished from a number of inflammatory and noninflammatory conditions. Various psoriasiform dermatitides to be considered are psoriasis, pityriasis rubra pilaris, seborrheic dermatitis, allergic or irritant contact dermatitis, atopic dermatitis, nummular dermatitis, dyshidrotic eczema, nodules secondary to infestation, and dermatophyte and candidal infection. Psoriasis usually demonstrates a diminished granular layer and fairly regular psoriasiform hyperplasia. Pityriasis rubra pilaris shows alternating ortho- and parakeratosis. Seborrheic dermatitis frequently displays spongiosis and parafollicular parakeratosis. The various other dermatitides usually exhibit a spongiotic reaction pattern. The fungal infections are easily ruled out by stains for fungi. Noninflammatory processes, such as acanthosis nigricans, confluent and reticulated papillomatosis, seborrheic keratoses, and epidermal nevi, are excluded by the absence of basophilic granules within the parakeratotic layer.

Congenital Hemidysplasia, Ichthyosiform Erythroderma, Limb Defects Syndrome CLINICAL FEATURES This rare, congenital dermatosis, also known as CHILD

syndrome, is defined by unilateral nevoid skin lesions with features of ichthyosiform erythroderma and ipsilateral limb underdevelopment. The nevoid lesions, which may occur in the absence of the other components of the syndrome,55 may develop later in childhood and manifest as linear or diffuse erythematous plaques with waxy yellowbrown scales. The lesions may expand or resolve spontaneously. Because nearly all affected individuals are girls, inheritance is hypothesized to be X-linked dominant and lethal in hemizygous boys.56 Point mutations in NADPH (nicotinamide adenine dinucleotide phosphate) steroid dehyrogenase-like protein are etiologic in some cases.57 HISTOPATHOLOGY Histologic sections show epidermal acanthosis associated with papillomatous hyperplasia. Prominent foci of parakeratosis are found within a compact, hyperkeratotic stratum corneum.58 The granular layer is normal to thinned. Foamy histiocytes may be found in the dermal papillae, simulating verruciform xanthoma. DIFFERENTIAL DIAGNOSIS The histopathologic features are nonspecific. Pityriasis rubra pilaris, epidermal nevi, and erythrodermic psoriasis require consideration. Whereas the presence of alternating

zones of para- and orthokeratosis within the stratum corneum and follicular plugging and minimal inflammatory infiltrates permit the diagnosis of pityriasis rubra pilaris, Munro abscesses within the corneum and inflammatory infiltrates and capillary ectasia within the dermal papillae suggest a diagnosis of psoriasis.

Comèl-Netherton Syndrome with Ichthyosis Linearis Circumflexa or Congenital Ichthyosiform Erythroderma

HISTOPATHOLOGY The microscopic findings in skin specimens are similar across the variable clinical phenotype of either ichthyosis linearis circumflexa (most often) or ichthyotic (ichthyosiform) erythroderma.1 Accumulation of eosinophilic periodic acid Schiff (PAS)–positive material within the stratum corneum is the most characteristic criterion. Parakeratotic hyperkeratosis is marked, and the corneal layer often contains masses of pyknotic neutrophils. Although disputed in some reports, the granular layer is usually thinned and may be focally absent. A subcorneal cleft created by separation of much of the stratum corneum is frequently observed. The spinous layer is acanthotic, and papillomatosis is well developed (Fig. 14-8).7 The papillary dermis contains a marked perivascular lymphocytic infiltrate, which may be associated with spongiosis of the overlying epidermis and lymphocytic exocytosis. Electron microscopy reveals cytoplasmic inclusion bodies, probably lysosomes, in spinous and granular cells that are not seen in other ichthyoses. DIFFERENTIAL DIAGNOSIS The psoriasiform epidermal hyperplasia of ichthyosis

 FIGURE 14-8 Comèl-Netherton syndrome. A moderately thickened stratum corneum with parakeratotic foci is associated with a hyperplastic epidermis and a brisk superficial perivascular lymphocytic infiltrate.

linearis circumflexa may resemble psoriasis. The PAS-positive stratum granulosum, irregular elongation of the rete ridges, subcorneal clefting, when present, and lack of moundlike parakeratosis serve to distinguish between the two disorders. Nodose swelling of hair shafts due to trichorrhexis invaginata taken in context with the combined clinicopathologic phenotype of ichthyosis linearis circumflexa or ichthyotic erythroderma should permit reliable diagnosis in questionable cases.

Porokeratosis CLINICAL FEATURES Whereas the clinical spectrum of porokeratosis is diverse, the defining feature of all types, except for punctate porokeratosis, is the distinctive fine, threadlike rings corresponding to the histologic cornoid lamella at the perimeter of the clinical lesions, which are often gyrate or annular but may also be linear. These rings are numerous or sparse (even solitary) and may be situated at glabrous, volar, genital, and mucocutaneous sites. The clinically recognized varieties consist of the isolated, plaque-type lesions with central atrophy in porokeratosis of Mibelli (Fig. 14-9A); the common disseminated superficial porokeratosis consisting of small annular lesions sited on sunexposed extremities and determined to be linked to a susceptibility locus on chromosome 12q (Fig. 14-9 B); linear porokeratosis; porokeratosis plantaris,

palmaris, et disseminata; and a punctate form restricted to the palms and soles. Point mutations in the SART3 gene on chromosome 12q have been identified in kindreds affected with disseminated superficial actinic porokeratosis (DSAP).62 It has been suggested that the cornoid lamella is formed by atypical keratinocytes that are hyperproliferative and defective in keratinization, resulting in aberrant desquamation.63 Porokeratosis is associated with immunosuppression, and malignancies such as Bowen disease arise within these lesions, but the relative risk of malignant degeneration is unknown.64 Porokeratosis is also found incidentally as a nonspecific reaction pattern in a broad spectrum of other neoplastic and inflammatory disorders.

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

CLINICAL FEATURES A rare autosomal recessive disorder of unknown etiology, Comèl-Netherton syndrome presents clinically with a distinctive hair abnormality designated trichorrhexis invaginata (“bamboo hair”) and cutaneous signs of exfoliative ichthyosiform erythroderma, ichthyosis linearis circumflexa, or both, which consists of migratory or evanescent, erythematous patches fringed by a double-edged scale. The other clinical manifestations are variable but often include an associated atopic diathesis, recurrent infections, failure to thrive in infancy, enteropathy, and mild palmoplantar keratoderma.59 Mutations in the serine protease inhibitor SPINK5 are found in affected families.60,61

HISTOPATHOLOGY The histologic hallmark of all clinical varieties of porokeratosis is the cornoid lamella, which is sometimes distributed to both sides of a biopsy sample, delimiting a central zone of either acanthokeratosis or atrophy. It consists of a thin, layered column within the corneum created by parakeratotic corneocytes. This tier of cells is often obliquely oriented to the epidermal surface and appears to arise from a dell in the upper viable layers of the epidermis in association with a focal absence of the stratum granulosum (Fig. 14-9). Dyskeratotic cells are frequently observed in the subjacent upper spinous layer. Edema and patchy, bandlike infiltrates with scattered apoptotic

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A

B

C  FIGURE 14-9 Porokeratosis. (A) Porokeratosis of Mibelli. Coalescent erythematous papules and plaques with distinctive raised, fine, threadlike annulus at the periphery of each lesion corresponding to histologic cornoid lamella. (B) Disseminated actinic porokeratosis. Scattered small individual macules and papules are present, each with a subtle threadlike annulus on the chronically sun-exposed skin of an extremity. (C) The obliquely oriented cornoid lamella containing parakeratotic corneocytes has arisen from a superficial dell, the base of which contains several dyskeratotic cells.

bodies may be a feature within the papillary dermis subjacent to the inner zone of a porokeratotic lesion, particularly in the DSAP variant, in which the pattern may be lichenoid in quality.

324

DIFFERENTIAL DIAGNOSIS The cornoid lamella is a distinctive structure that is not usually confused with other processes, although its presence in tissue sections may be subtle and easily overlooked. Although it is the characteristic finding in porokeratosis, it is not completely specific to the diagnosis. A cornoid lamella may occasionally be found in variety of other

conditions, such as warts, solar keratosis, seborrheic keratosis, squamous cell carcinoma, and basal cell carcinoma. Clinicopathologic correlations or observation of other pathologic processes in the tissues are necessary to resolve the differential diagnosis in instances associated with incidental cornoid lamellae.

EPIDERMOLYTIC DISORDERS The unifying feature in the disorders assembled under this section is epidermal separation due to shearing through various levels of the basement membrane

zone or to vesiculation resulting from cytolysis or acantholysis of epidermal keratinocytes. The basal or suprabasal spinous cells are most often affected in the cytolytic and acantholytic diseases. These usually genetic disorders range from bullous variants of certain ichthyoses to the mechanobullous diseases associated with mutations in genes for keratins and other structural proteins. The diagnostic algorithm (Fig. 14-10) principally exploits the level of the separation within the epidermal layers and, secondarily, associated histologic changes of defective keratinization, if any. Table 14-5 summarizes

Level of separation

Basal cell/sub-basal lysis

Spinous layer separation

Epidermolysis bullosa simplex Dowling-Meara Koebner Weber-Cockayne Epidermolysis bullosa, junctional Epidermolysis bullosa dystrophica

Mode of separation

Cytolysis

Acantholysis

Yes

No

BCIE BCIE-Siemens Ichthyosis Hystrix Palmoplantar keratoderma (Voerner) Pachyonychia congenita (some) Peeling skin syndrome (some)

EBS-W/C

Yes

No

Darier disease Grover disease Hailey-Hailey (most)

Hailey-Hailey (some)

 FIGURE 14-10 Diagnostic algorithm for the epidermolytic disorders. The hierarchy for differential diagnosis follows primarily from the level of separation within the epidermis or basement membrane zone and secondarily from the mode of separation, whether cytolysis or acantholysis. BCIE = bullous congenital ichthyosiform erythroderma; EBS = epidermolysis bullosa simplex; W/C = Weber Cockayne.

Table 14-5 Differential Diagnosis of Epidermolytic Disorders HISTOLOGIC FEATURE DISORDER

LEVEL OF SEPARATION

MECHANISM OF SEPARATION

HYPERKERATOSIS

STATUS OF GRANULAR LAYER

ACANTHOSIS

OTHER

Epidermolysis bullosa simplex Epidermolysis bullosa junctional Epidermolysis bullosa dystrophica Bullous ichthyosiform erythroderma

Basal or spinous layer (or both) Basement membrane zone Beneath basement membrane Spinous and granular layers

Cytolysis

+ (occasional)

Normal to +

0

Focal dyskeratotic cells

Shearing through lamina lucida Shearing through anchoring fibril zone Epidermolytic hyperkeratosis

0

Normal

0

0

Normal

0

++ to +++

+ to ++

+ to ++

Palmoplantar keratoderma (Voerner type) Pachyonychia congenita Darier disease

Spinous and granular layers

Epidermolytic hyperkeratosis

++

+

+

Upper spinous layer

Cytolysis

++ to +++

++

+ to ++

Suprabasal layer

Acantholysis

+ to ++

+ to ++

+

Hailey-Hailey disease

Spinous layers

Acantholysis

0 to +

Normal to +

+-+

Grover disease Peeling skin syndrome

Suprabasal layer Subcorneal

Acantholysis Inter- or intracellular cleavage

+ +

+ Normal or thinned

0 to + + to ++

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

Hyperkeratosis?

Perivascular lymphocytic infiltrates Perivascular lymphocytic infiltrates Follicular plugging in some cases Corp ronds and grains “Dilapidated brick wall” appearance Perivascular lymphocytic infiltrates

325

the salient histologic features that may be used to facilitate the differential diagnosis of the epidermolytic diseases.

DISORDERS WITH BASAL LAYER OR BASEMENT MEMBRANE ZONE LYSIS

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

The entities described here are limited to the clinicopathologic varieties of epidermolysis bullosa, which are mechanobullous diseases that have in common heritable lesions in genes coding for structural proteins of basal keratinocytes or for components of the basement membrane zone.

Epidermolysis Bullosa Simplex The genetically heterogeneous diseases grouped under epidermolysis bullosa simplex share an autosomal dominant inheritance, pathophysiologic changes of minor trauma–induced cytolysis within the basal or suprabasal keratinocytes, and the tendency for lesions to heal without scarring. Tonofilament clumps within basal and suprabasal keratinocytes are observed by electron microscopy in the Dowling-Meara variant; these structures contain the keratin pair 5 and 14 by immunolabeling. Point mutations occur in either gene (K5 or K14) in all clinical variants of epidermolysis bullosa simplex.65 The clinical severity is evidently determined in each affected kindred by the extent to which the specific mutation disrupts the functional properties of the gene product.66 Unusual variants of the disorder may result from mutations in other structural genes, such as the cell-linker protein plectin.67

A

326

CLINICAL FEATURES The phenotypes include the generalized Koebner variant; the Dowling-Meara variant, which is characterized by herpetiform clustering of blisters; and the localized (usually acral) Weber-Cockayne variant.68 The Weber-Cockayne variant may represent a mild variant of the Koebner variant. Whereas the Dowling-Meara and Koebner variants usually present early in infancy with blisters and erosions induced by minor trauma, the onset of the Weber-Cockayne variant is often delayed. Mucosal lesions, minor scarring, nail shedding, and widespread erosions with a risk of secondary pyogenic infection occur in severely affected patients. Spontaneous improvement is sometimes seen in later childhood and adulthood. HISTOPATHOLOGY In all variants of epidermolysis bullosa simplex, vesicles form by cytolysis within the basal or lower spinous cell layers (Fig. 14-11).69 Histologic sections thus show focal dissolution of the basal or spinous keratinocytes, resulting in epidermal separation through that layer. Dyskeratotic changes may manifest histologically within the cells, especially in the DowlingMeara variant. On occasion, the DowlingMeara and Koebner variants have been associated with palmoplantar keratoderma in which the histologic sections exhibit compact hyperorthokeratosis and a variably thickened granular layer in addition to the cytolytic changes within the keratinocytes. DIFFERENTIAL DIAGNOSIS In the DowlingMeara subtype, the separation may occur deep in the basal layer such that by

light microscopy it appears that the entire epidermis has formed the roof of the blister; this may simulate the findings in junctional epidermolysis bullosa and may require electron microscopy or immunomapping of basement membrane components for resolution of the level of the separation. The DowlingMeara variant is distinguished from the other two varieties by herpetiform clustering of the clinical lesions and by keratin filament clumping on electron microscopy of lesional skin samples.

Epidermolysis Bullosa, Junctional (Letalis) Junctional epidermolysis bullosa includes several genetically heterogeneous diseases70 that, although phenotypically variable, share autosomal recessive transmission and subepidermal separation through the lamina lucida of the basement membrane zone due to reduced numbers of hemidesmosomes.71 Mutations in the peptide subunits of laminin 5 (epiligrin) and, occasionally, the 180-kDa bullous pemphigoid antigen, both of which are lamina lucida components, are etiologic in most cases.72 More severe phenotypes are linked to premature termination codon mutations in both alleles of one of the three laminin 5 subunit genes, LAMB3, but the less severe variants are associated with slice junction or missense mutations of one allele in trans to a premature termination codon mutation of the other.73 CLINICAL FEATURES The most severe clinical presentation occurs in the Herlitz syndrome (epidermolysis bullosa letalis), which exhibits widespread cutaneous and

B

 FIGURE 14-11 Epidermolysis bullosa, Dowling-Meara variant. (A) Basal and suprabasal keratinocytes display prominent cytolytic degeneration. (B) The more superficial epidermal layers appear normal.

mucosal blisters and erosions soon after birth, usually proving fatal within the first one to two years of life. Less severe (nonHerlitz) forms of junctional epidermolysis bullosa exhibit qualitatively similar changes but differ in the extent of the cutaneous and mucosal blisters and erosions, allowing a normal lifespan, albeit with lifelong blistering. Many of the latter forms display abnormal dental enamel development, which imparts a cobblestone appearance to the teeth.

DIFFERENTIAL DIAGNOSIS By light microscopy, junctional epidermolysis bullosa may be simulated by dystrophic variants of that disease spectrum or by subepidermal autoimmune vesiculobullous disorders such as bullous pemphigoid. The clinical context will direct the histopathologic interpretations along the appropriate pathways. Resolution of the differential diagnosis for the mechanobullous disorders is usually obtained by immunolabeling for markers of basement membrane components, such as type IV collagen and laminin, to localize the plane of separation or by electron microscopy. The autoimmune disorders are confirmed

Epidermolysis Bullosa Dystrophica Epidermolysis bullosa dystrophica is genetically heterogeneous, with either autosomal dominant or recessive inheritance. Cases of dystrophic epidermolysis bullosa have long been known to demonstrate morphologic abnormalities of the anchoring fibrils, which are structures distributed below the basal lamina.74 Type VII collagen was an early candidate for the etiologic molecular defect because it is a major collagenous component of the anchoring fibrils. Immunolabeling for type VII collagen demonstrates either reduced content or disarrayed organization of this component. Genetic studies confirmed linkage between markers for the collagen VII locus on chromosome 3 and both the dominantly and recessively inherited clinical phenotype; mutational analyses subsequently confirmed mutations in the COL7A1 gene.75,76 CLINICAL FEATURES As a reflection of genetic heterogeneity, the clinical severity of epidermolysis bullosa dystrophica varies widely. On one hand, the recessive form (Hallopeau-Siemens syndrome) presents in infancy with extensive blistering and scarring of the entire cutaneous and squamous mucosal surfaces of the oropharynx, anus, and esophagus, eventuating in mutilating deformities, shedding

 FIGURE 14-12 Epidermolysis bullosa, junctional. Separation has occurred beneath the basal keratinocyte layer but superficial to the eosinophilic basement membrane.

of nails, joint contractures, pseudosyndactylies, enteric strictures, and increased risk of squamous cell carcinoma, which may be clinically aggressive.75,77 The phenotype of the dominant form, although also exhibiting mechanically induced blisters and secondary scarring, is much less severe. HISTOPATHOLOGY Due to molecular defects in the subepidermal anchoring fibrils, histologic sections show separation of the entire epidermis from the dermis, with the PAS-positive basement membrane segregating to the epidermal roof of the blister cavity. DIFFERENTIAL DIAGNOSIS Ambiguities in the differential diagnosis are resolved by immunostaining for type IV collagen or electron microscopy to localize the plane of separation below the lamina densa, confirming that the basal lamina remains attached to the epidermis. Immunostaining also demonstrates reduced labeling for collagen type VII in the anchoring fibril zone.

DISORDERS WITH SPINOUS LAYER VESICULATION DUE TO CYTOLYSIS OR ACANTHOLYSIS The entities grouped under this category range from hereditary ichthyoses featuring the distinctive histologic change of epidermolytic hyperkeratosis to vesiculobullous disorders displaying the common feature of spinous layer acantholysis (eg, acantholytic dyskeratosis). Epidermolytic hyperkeratosis is a morphologic manifestation of congenital or acquired disorders of keratinocytic maturation that may be focal or diffuse. It is defined by hyperkeratosis and suprabasilar vacuolar and reticular degeneration (cytolysis) of the strata spinosum and granulosum. Epidermolytic hyperkeratosis is the hallmark feature of generalized ichthyosis known as bullous congenital ichthyosiform erythroderma and of related but more anatomically restricted disorders of either the glabrous or volar skin, such as ichthyosis bullosa of Siemens, ichthyosis hystrix of Curth and Macklin, some epidermal nevi (hamartomas), and palmoplantar keratosis of Voerner. Epidermolytic hyperkeratosis is also found rather commonly as a focal histologic phenomenon in unrelated lesions, including melanocytic nevi, seborrheic keratoses, actinic keratoses, acrochordons, and inflammatory dermatoses, or in morphologically normal skin. A solitary lesion of epidermolytic

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

HISTOPATHOLOGY Separation occurs beneath the basal cell layer but above the lamina densa (Fig. 14-12) due to dissolution of the lamina lucida, as shown by electron microscopy. Histologic sections reveal a plane of separation formed between the epidermis and the basement membrane zone. By PAS staining, the basement membrane remains on the dermal side of the split.

diagnostically by the characteristic patterns of autoantibody deposition as shown by direct immunofluorescence methods.

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS 328

hyperkeratosis presenting as a wartlike papule is designated epidermolytic acanthoma. The histologic pattern of suprabasilar vesiculation accompanied by acantholysis and dyskeratotic cells defines acantholytic dyskeratosis. The blistering is usually apparent only at the histologic, not clinical, level. The clinical phenotype of acantholytic dyskeratosis ranges broadly from the focal and incidental acantholytic dyskeratoma on the skin or squamous mucosa and warty dyskeratoma to an uncommon linear form in zosteriform epidermal nevi and to more generalized entities that are acquired and often transient (Grover disease) or are of genetic etiology and persistent (Darier disease). The more generalized entities manifesting acantholytic dyskeratosis are described after descriptions of the epidermolytic, hyperkeratotic disorders. The uncommon, localized disorders that are incidental clinical curiosities (eg, acantholytic dyskeratoma, warty dyskeratoma) are not discussed further in this chapter except as differential diagnostic considerations.

Bullous Congenital Ichthyosiform Erythroderma (Epidermolytic Hyperkeratosis and Bullous Ichthyosis) This dominantly inherited, uncommon dermatosis presents with generalized erythroderma, severe scaling, and blistering. Cornrowlike scaling accumulates in the antecubital fossae, axillae, and over the knees and dorsal ankles. Original ultrastructural studies of ichthyosiform erythroderma indicated clumping and aggregation of suprabasal keratin filaments (tonofilaments) at the cell periphery,78 suggesting molecular defects in keratin genes. Genetic linkage studies demonstrated cosegregation of the trait and markers for the type I and II keratin loci on chromosomes 17q and 12q, and mutational analyses showed that point mutations in the critical rod domains of both suprabasal keratins 1 and 10 associated with the phenotype.79 The etiologic role of the keratin mutations has been established experimentally by expression of mutant keratin alleles in transgenic mice that reproduce the phenotype.80 In some families, somatic mutations with associated epidermal nevi exhibiting the histologic changes of epidermolytic hyperkeratosis have resulted in generalized bullous congenital ichthyosiform erythroderma in subsequent generations as a result of gonadal mosaicism.

Table 14-6 Bullous Congenital Ichthyosiform Erythroderma

Clinical Features Onset at birth or early childhood Erythema, blistering, and verrucous plaques, usually widespread Flexural accentuation Abatement of blistering with age Histopathologic Features Massive hyperorthokeratosis Thickened granular layer with coarse keratohyalin granules Acanthotic spinous layer with epidermolytic changes Differential Diagnosis Ichthyosis bullosa of Siemens Palmoplantar keratoderma, Voerner type Incidental finding in hyperproliferative epidermal disorders

CLINICAL FEATURES Epidermolytic hyperkeratosis is clinically heterogeneous, but the phenotype is relatively uniform within affected kindreds81,82 (Table 14-6). In most cases, widespread erythema, blistering, and hyperkeratotic verrucous plaques are noted at birth or during childhood, frequently with accentuation in the flexures. Clinical blistering often abates after the first few years of life. The presence or absence of palmoplantar keratoderma distinguishes some pedigrees.

HISTOPATHOLOGY Microscopically, all cases exhibit massive hyperorthokeratosis, in either a compact, or more often, a basketweave pattern.1,7 The granular layer is thickened and contains coarse keratohyalin granules. The acanthotic epidermis is distinctive for cytoplasmic edema and perinuclear vacuolization affecting the keratinocytes of the granular and spinous cell layers. The basal and, occasionally, the suprabasal keratinocytes appear normal. The hydropic changes create indistinct boundaries between the epidermolytic cells and a reticular pattern of degeneration, referred to as epidermolytic hyperkeratosis or acanthokeratolysis (Fig. 14-13). When fully evolved in the pattern of epidermolytic hyperkeratosis, vesiculation occurs through the upper spinous to granular layers, the roof of which is formed by thickened stratum corneum and the floor by edematous keratinocytes. A slight to moderate perivascular lymphoid infiltrate is contained in the superficial dermis. DIFFERENTIAL DIAGNOSIS Bullous congenital ichthyosiform erythroderma is distinguished from ichthyosis bullosa of Siemens by clinical differences and by involvement of the entire suprabasal epidermal compartment; the cytolytic changes in the latter disorder are restricted to the upper spinous and granular layers. Epidermolytic hyperkeratosis is not specific to these bullous ichthyoses because it is commonly observed as an incidental

 FIGURE 14-13 Bullous ichthyosiform erythroderma. The markedly acanthotic and hyperkeratotic epidermis exhibits prominent epidermolysis at the levels of the mid- to upper spinous and granular cell layers. The widened stratum granulosum contains coarsely clumped keratohyalin granules.

finding contiguous to melanocytic nevi and hyperproliferative disorders of the epidermis, including linear epidermal nevus, verrucae, actinic keratosis, squamous cell carcinoma, seborrheic keratosis, solitary epidermolytic acanthoma, sundry inflammatory conditions, and some (Voerner-type) palmoplantar keratodermas. Diagnosis in those situations is contingent on recognition of the associated findings that are distinctive for each disorder. The epidermolytic palmoplantar keratodermas are diagnosed from the corresponding clinical presentation.

Ichthyosis Bullosa of Siemens

CLINICAL FEATURES Dark gray, hyperkeratotic lesions are restricted to certain sites of predilection, which include the shins, para-articular (flexural) areas, and periumbilical areas. Characteristic superficial blistering with subsequent shedding of the affected skin (“molting”) and erosions may occur after mild trauma and with sweating.86 HISTOPATHOLOGY The principal histologic change is that of epidermolytic hyperkeratosis, which is limited to the upper strata of the epidermis and is generally less well developed and less extensive than in bullous congenital ichthyosiform erythroderma.87 Tonofilaments forming perinuclear aggregates are seen on electron microscopy. Mild acanthosis may also be a feature. DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis is similar to that for bullous congenital ichthyosiform erythroderma. Ichthyosis bullosa of Siemens is discriminated clinically from the former by the absence of erythroderma, by the more limited distribution of the keratotic lesions, and by the characteristic formation of superficial blisters.

This rare ichthyotic disease is inherited as an autosomal dominant trait. Ultrastructurally, the hyperkeratotic lesions show disruption of the keratin filament network of the suprabasal keratinocytes. Immunolabeling studies for keratin expression have shown that both normal-appearing and lesional skin persistently express fetal keratins.87 Frameshift mutations in the variable tail domain of keratin gene KRT1 underlie the disorder.88 CLINICAL FEATURES The clinical onset of ichthyosis hystrix is usually in childhood. The hyperkeratotic and papillomatous, coalescent papules and verrucous, linear plaques may be localized or distributed extensively and bilaterally in whorled or arborizing arrays of thickened, darkened (hystrixlike) scales anywhere on the skin surface. A palmoplantar involvement is variable. HISTOPATHOLOGY The distinctive pattern of epidermolytic hyperkeratosis is found against the backdrop of mild hyperorthokeratosis, acanthosis, papillomatosis, and elongation of the rete ridges. In the epidermolytic areas, perinuclear vacuolization occurs within the granular and upper spinous layer keratinocytes, with irregularity of cell borders progressing to reticular degeneration. Hypertrophy of the granular layer, which contains coarse keratohyalin granules, is seen. A slight to moderate perivascular lymphoid infiltrate is present in the superficial dermis.

which the designation Voerner is eponymously assigned. The condition has been linked to mutations in the 1A domain of the keratin 9 gene, the expression of which is restricted to the suprabasal zone of the palms and soles.45,78,89,90 Some kindreds with mild epidermolytic palmoplantar keratodermas harbor mutations in keratin 1.91 CLINICAL FEATURES The clinical presentation of diffuse palmoplantar keratoderma does not allow distinction of the epidermolytic variant of Voerner from the ostensibly nonepidermolytic variety described by Unna and Thost. The volar lesions typically are sharply demarcated with erythematous borders. The lesions may be associated with knuckle-pad– like changes and nail clubbing.92 HISTOPATHOLOGY Changes of epidermolytic hyperkeratosis in the upper spinous and granular cell layers are associated with mild orthohyperkeratosis, acanthosis, and papillomatosis.93 A slight to moderate perivascular lymphoid infiltrate is present in the superficial dermis. Clumping of suprabasal keratins is found by electron microscopy. DIFFERENTIAL DIAGNOSIS The differential diagnosis is that discussed under bullous congenital ichthyosiform erythroderma. The clinical presentation, however, appropriately focuses the diagnostic considerations to the palmoplantar keratodermas.

Pachyonychia Congenita

Palmoplantar Keratoderma of Voerner (Epidermolytic Palmoplantar Keratoderma)

Heterogeneous dyskeratotic and dysplastic alterations of ectodermal tissues are characteristic of pachyonychia congenita, a rare, genetically heterogeneous trait that is transmitted in an autosomal dominant manner with variable expressivity.94 Genetic linkage analyses have established that the loci for the more common Jadassohn-Lewandowsky variant and the rarer Jackson-Lawler subtype map to chromosome 17q in close proximity to the type I keratin gene cluster; mutations in keratin 6a account for some cases of the former variant,95 and defective alleles for keratins 16 and 17 are etiologic for the latter subtype.96,97 The seemingly pleiotropic phenotypes reflect the tissue-specific distributions of the variously defective keratin gene products.98

Some kindreds with the autosomal dominant form of diffuse palmoplantar keratoderma show epidermolytic hyperkeratosis on biopsy of the affected skin, to

CLINICAL FEATURES Onset of pachyonychia congenita is usually in early infancy, but tardive presentation into the teenage

DIFFERENTIAL DIAGNOSIS Ichthyosis hystrix (Curth-Macklin type) is distinguished by a discrete dark shell around the nuclei of spinous cells and by the presence of binucleate cells.1 By electron microscopy, a continuous shell of intermediate filaments is seen separating the perinuclear compartment, which often contains vacuoles, from an outer, cytoplasmic compartment. Otherwise, the differential diagnosis is that discussed under bullous ichthyosiform erythroderma.

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

This mechanobullous condition is an autosomal dominant disease characterized by a mild, nonerythrodermic clinical phenotype with microscopic changes of epidermolytic hyperkeratosis limited to the granular layer and upper stratum corneum in lesional skin.83 There is clinical and histologic overlap with bullous congenital ichthyosiform erythroderma. Ichthyosis bullosa links genetically to the type II keratin gene cluster on chromosome 12q,83 and most cases are caused by point mutations in the differentiation specific keratin, 2e, which is expressed in the upper spinous and granular layers.84,85

Ichthyosis Hystrix of Curth and Macklin

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years may occur. In the hallmark manifestation of the disorder, symmetrically thickened nails are present in all patients, but the other components of the clinical syndrome are variable.99 The nail involvement, termed pachyonychia, consists of subungual hyperkeratosis in which keratinous material sequentially lifts the nail plate from the bed in a proximal to distal gradient, resembling a ski jump in profile. The more common JadassohnLewandowsky variant exhibits pachyonychia; palmoplantar keratoderma with tender blisters; pedal callosities; hyperhidrosis; and erosions, follicular hyperkeratosis, and leukokeratotic changes of the oral mucosa (resembling white sponge nevus). Multiple epidermoid inclusion cysts, natal teeth, and hair abnormalities (including alopecia) characterize the rarer Jackson-Lawler subtype. HISTOPATHOLOGY The principal histologic changes of involved, thickened skin are marked hyperorthokeratosis, papillomatosis, acanthosis, and moderate hypergranulosis; focal parakeratosis and follicular plugging may also be present. Sections may display an upper spinous layer vesicle created by prominent intracellular edema. The papillary dermis contains a sparse perivascular lymphocytic infiltrate. DIFFERENTIAL DIAGNOSIS In cases without intraspinous vesiculation, the histologic pattern may be indistinguishable from lamellar and X-linked recessive ichthyoses. However, the clinical presentation, especially the pachyonychia, is distinctive.

established as the locus for Darier disease.101 Spontaneous mutations account for some cases. CLINICAL FEATURES The clinical onset of Darier disease ranges from childhood to the early adult years. The lesions are hyperkeratotic, crusted, erythematous papules coalescing as plaques, often with a follicular localization, that are predisposed to seborrheic areas, especially the presternal skin; however, flexural, volar, and oral mucosal lesions also occur occasionally.102 Clinical variants include hypertrophic, vesicular, and linear lesions. Distinctive nail changes are present in most patients and are often associated with palmar pits and keratoses.103 Neuropsychiatric disorders, including mental retardation, cosegregate in some families. Darier disease confers an infection-prone diathesis to a range of fungal, bacterial, and viral pathogens, which in turn exacerbate the clinical condition. The disorder typically has an unremitting course. HISTOPATHOLOGY The characteristic pattern of acantholytic dyskeratosis in Darier disease occurs in association with epidermal papillomatosis, acanthosis, and hyperkeratosis. Acantholytic changes giving rise to microscopic lacunae and dyskeratosis develop in the immediate suprabasal zone (Fig. 14-14). Villus structures lined by single cell layers of basal keratinocytes are created by the apparent

upward proliferation of the dermal papillae into these lacunae. Lying free within the lacunae are dyskeratotic spinous keratinocytes, which have lost their intercellular bridges and may have prematurely keratinized. In the upper epidermis, the acantholytic cells take the morphologic forms of corp ronds and grains. Corp ronds reside in the upper spinous and granular layers and consist of acantholytic cells with homogeneously pyknotic nuclei; a clear pericellular halo; and refractile, eosinophilic cytoplasms. Grains are smaller counterparts within the stratum granulosum or higher, displaying pericellular halos and sparse cytoplasms and resembling (but more plump than) parakeratotic corneocytes. The folliculosebaceous elements may have infundibular dilatation and plugging. A perivascular mixed lymphocytic infiltrate occurs in the superficial dermis. Variants of Darier disease include vesiculobullous lesions, created by large lacunae, and hypertrophic lesions, with accentuation of downward proliferation by the rete. DIFFERENTIAL DIAGNOSIS The pattern of acantholytic dyskeratosis is not specific to Darier disease because it is often found in warty dyskeratoma, Grover disease, and focal acantholytic dyskeratoma and may reside as an incidental finding in diverse lesions, such as verrucae, basal cell carcinoma, keratoacanthoma, psoriasis, and angiomata. Although also

Darier Disease (Darier-White Disease and Keratosis Follicularis)

330

An uncommon dominantly inherited dermatosis, Darier disease manifests as focal keratinocyte defects in intercellular adhesions that are restricted to the sites of the clinical lesions. Fine structure studies have suggested that the initial event in the lesions is separation of the paired desmosomal plaques, followed by retraction of the tonofilaments from their attachment sites in the plaques and redistribution to a perinuclear pattern; dyskeratosis occurs after the initiating acantholytic event. The mutant genetic locus responsible for Darier disease is highly penetrant100 and has been mapped to chromosome 12q, but genes for keratins and other known epidermal proteins were excluded as candidate loci. The gene ATP2A2, which encodes the endosarcoplasmic reticulum calcium ATPase isoform 2, is now

 FIGURE 14-14 Darier disease. Prominent suprabasal acantholysis is present in association with dyskeratotic cells (corp ronds and grains), hypergranulosis, and hyperkeratosis.

evident on occasion in Hailey-Hailey disease, the latter disorder usually exhibits few corp ronds or grains and more widespread acantholysis; this differential diagnosis is further discussed under Hailey-Hailey disease.

Hailey-Hailey Disease

CLINICAL FEATURES The disease often presents in the second to fourth decades of life with vesicles, bullae, and chronic erosive plaques on the neck and in flexural sites, especially the axillae, inframammary folds, and groin, that are well demarcated, often arcuate, and spread centrifugally. They are subject to exacerbation by perspiration, secondary infection, friction, and heat105 (Table 14-7) and confer a burning sensation or mild itch. Uncommon morphologic variants include dermatitic, verrucoid, and papular lesions. Although the condition is chronic, remissions occur, and spontaneous improvement may occur later in

HISTOPATHOLOGY The most typical finding in patients with Hailey-Hailey disease is widespread acantholysis of the spinous layer, which characteristically involves at least half the thickness of the epidermis. Acanthosis is usually present. Whereas numerous completely acantholytic cells may be situated free within the resulting intraspinous vesicles, other regions of contiguously affected cells are not completely separated but rather remain partially tethered to each other (Fig. 14-15). When fully developed, this suprabasal change gives an appearance that has been aptly likened to a “dilapidated brick wall.” As in Darier disease, villus projections of elongated papillae lined by a single row of basal cells often project into the lacunae and bullae. The acantholytic cells generally retain an otherwise normal appearance without morphologically apparent dyskeratosis, but focally, the latter may develop and may resemble the corp ronds and grains of Darier disease. DIFFERENTIAL DIAGNOSIS Hailey-Hailey and Darier diseases share common features of suprabasal acantholysis and formation of villus structures that protrude into separations created by acantholytic

keratinocytes. In Darier disease, however, the separations take the form of small lacunae, contrasted with larger vesicles and bullae resulting from more widespread acantholysis in HaileyHailey disease. Moreover, dyskeratosis is typically a feature of Darier disease and is associated with the development of corp ronds and grains. The discrimination of Hailey-Hailey disease from pemphigus vulgaris may be difficult because the initial pathologic process in each disorder is suprabasal acantholysis. In pemphigus, however, less acantholysis is present overall, and the separations are often strikingly restricted to the cell layer immediately superficial to the basal keratinocytes, lacking the “dilapidated brick wall” effect of Hailey-Hailey disease. When present, the finding of intralesional eosinophils supports the diagnosis of pemphigus vulgaris. Definitive resolution of the differential diagnosis requires direct immunofluorescence assay for display of the characteristic intercellular autoantibody deposition in pemphigus but not in Hailey-Hailey disease.

Grover Disease (Transient Acantholytic Dermatosis) A common, acquired abnormality, Grover disease is a non–immune-mediated acantholytic disorder of the epidermis that affects middle-aged or elderly men most often.106,107 The onset is often acute, and the duration may be transient or persistent

Table 14-7 Hailey-Hailey Disease

Clinical Features Onset in the second to fourth decades of life Bullae and erosions at flexural sites that are exacerbated by friction and heat Dermatitic, verrucoid, and papular variants Histopathologic Features Widespread acantholysis affecting more than half of the spinous layer “Dilapidated brick wall” appearance Infrequent dyskeratotic cells Villi projecting into lacunae Acanthosis Differential Diagnosis Grover disease Darier disease Pemphigus vulgaris

 FIGURE 14-15 Hailey-Hailey disease. Acantholysis affects the suprabasal to mid-spinous layers in an incomplete fashion that has resulted in keratinocytes remaining partially tethered to one another, giving the impression of a “dilapidated brick wall.”

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

Hailey-Hailey disease represents a widespread subclinical abnormality of cell adhesion mediated by dissolution of desmosomal plaques.103 Its clinical manifestations, however, are usually restricted to intertriginous anatomic regions that are subject to friction, maceration, and opportunistic infection. This uncommon disorder is genetic, segregating as an autosomal dominant trait linked to chromosome 3q21, and the responsible locus is ATP2C1, which encodes a calcium transport ATPase; regulation of cytoplasmic calcium is defective in cultured keratinocytes from patients with the disease.104

the adult years. With rare exceptions, the mucous membranes are unaffected. The erosions are often secondarily infected. Longitudinal white bands may be found in the nail beds.

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for several years. Structural alterations and dysfunction of keratinocyte adhesion molecules are characteristic of the lesions. Fine structure studies have described dissolution of the components of the desmosomal attachment plaque.103 Although resembling Darier disease, Grover disease does not share an abnormality in the ATP2A2 gene.108 CLINICAL FEATURES Intensely pruritic papules, and occasionally papulovesicles, occur predominantly on the trunk and less often on the buttocks and thighs. A history of fever, excessive perspiration, or occlusion of the affected skin (such as from enforced bed rest) are variable features. Other inflammatory dermatoses, such as eczemas, psoriasis, and Sweet syndrome, may coexist, and some cases are apparently initiated by ultraviolet radiation or chemotherapeutic pharmaceuticals. HISTOPATHOLOGY The principal microscopic finding consists of small foci of spinous layer acantholysis (Fig. 14-16). The spectrum of acantholysis in Grover disease includes both superficial and deep variants, which respectively mimic pemphigus foliaceus and vulgaris. Most often, however, the acantholytic change takes the form of that found in either pemphigus vulgaris or Darier disease, with acantholytic dyskeratosis. On occasion, the histologic image of Hailey-Hailey disease is simulated, or uncommonly, the predominant feature is spongiosis but with

little acantholysis. In some individuals, the histologic pattern may be mixed. The acantholytic focus is usually subtended by a mixed lymphoid reaction arrayed about the vessels of the superficial plexus, with a variable eosinophil component, which, when present, assists with the diagnostic exclusion of Darier disease. DIFFERENTIAL DIAGNOSIS The histopathologic pattern found in Grover disease differs from that of each disease it simulates by the multifocal presentation of small microscopic foci of acantholysis. In dubious instances, the differential diagnosis may be resolved by reference to the clinical presentation, which is generally distinctive for each of the entities simulated histologically by Grover disease.

Peeling Skin Syndrome Several rare syndromes have been described that share the cardinal feature of peeling of the skin.1,109,110 Two distinct phenotypes, A and B, have been described. In type A, no associated abnormalities are described; in type B, variable findings include decreased plasma tryptophan levels, elevated serum copper and iron levels, aminoaciduria, and elevated serum IgE levels. The presentation is frequently congenital, and inheritance patterns have suggested autosomal recessive transmission, often with a history of parental consanguinity. Autoreactive antibodies do not mediate the disorders. A missense mutation in the transglutaminase gene TGM5 is

etiologic in the localized acral variant of the syndrome but apparently not in the more generalized condition.111 The protein product of TGM5 localizes to the stratum granulosum, where it cross-links structural proteins, forming the cornified envelope in the terminal differentiation of the epidermis; defective function of the transglutaminase compromises cell–cell adhesion in the outermost strata of the epidermis. CLINICAL FEATURES Patients with type A peeling skin syndrome display generalized, asymptomatic, noninflammatory skin peeling. In contrast, patients with type B present clinically with generalized patches of peeling skin in association with inflammation and pruritus. A localized, acral variant affecting the dorsal surfaces has also been defined.112 The palms and soles may exhibit keratoderma, and dystrophic nail changes and easily plucked hair are commonly associations. HISTOPATHOLOGY The stratum corneum is hyperkeratotic. The upper epidermis characteristically separates, with the histologic split forming between the stratum corneum and stratum granulosum or in the lower stratum corneum. One report documents splitting within keratinocytes in a patient with type A, but the split appears to be intercellular in patients with type B. In patients with type B, psoriasiform epidermal hyperplasia with both hyperkeratosis and parakeratosis may be present. The granular layer may be either retained or lacking, the keratohyalin granules may appear abnormal, and considerable acanthosis with elongated rete ridges and an underlying chronic perivascular lymphocytic dermatitis in the papillary dermis may be present. DIFFERENTIAL DIAGNOSIS In histologic sections not displaying the subcorneal separation, the differential diagnosis for disorders histologically resembling autosomal dominant ichthyosis vulgaris requires resolution. Epidermal separation at or near that found in peeling skin syndrome may be observed in staphylococcal-scalded skin syndrome and pemphigus foliaceus, but acantholytic cells occur focally in the latter disorders.

THE PERFORATING DERMATOSES

332

 FIGURE 14-16 Grover disease. This microscopic lacuna, which has been created by acantholysis restricted to the suprabasal keratinocytes, contains dyskeratotic cells and is lined at the base by cells anchored to the basement membrane. Corp ronds and grains are situated in the upper epidermal strata.

Four primary perforating dermatoses— Kyrle disease, perforating folliculitis, reactive perforating collagenosis, and elastosis perforans serpiginosa—have traditionally been defined among the conditions

tance patterns in some kindreds diagnosed with reactive perforating collagenosis have raised the possibility of a genetic diathesis in those instances.121 CLINICAL FEATURES The florid (Kyrle disease–like) presentation is rare, but the milder phenotype is rather common in the setting of chronic renal failure, diabetes, or (less commonly) liver disease (Table 14-8).119,120,122 At clinical presentation, which may occur at any age, there may be few to many lesions, which are often localized to the legs, or the onset may be more generalized to all extremities and the torso, with a predilection for the extensor surfaces. The mucous membranes and volar surfaces are spared. The condition is characteristically pruritic but not invariably so. The early lesions are pinhead-sized follicular and extrafollicular papules that resemble keratosis pilaris.115 With progression, the lesions evolve into larger, red-brown or purplish papules and nodules or occasionally plaques and tend to remain nonconfluent. Mature lesions display a central cuplike depression containing a conical, keratinaceous plug. An isomorphic (Koebner) response is frequent. It is uncommon for the condition to remit spontaneously, but improvement may occur after renal transplantation.

Table 14-8 Acquired Perforating Dermatosis

Clinical Features Onset at any age, with few to many lesions and a predilection for the extensor surfaces Commonly associated with chronic renal failure and diabetes mellitus Koebnerization Pruritic, nonconfluent follicular or extrafollicular papules Central, conical keratinaceous plug Histopathologic Features Keratotic plug within epidermal invagination over focus of the perforation Bordered by acanthotic, hyperkeratotic epidermis Inflammatory debris in the channel, with basophilic collagen or eosinophilic elastin Granulomatous reaction at the base Differential Diagnosis Elastosis perforans serpiginosa Acneiform eruptions Keratosis pilaris

neutrophils in the subjacent dermis, and (variably) tinctorial changes in the connective tissue fibers. Some foci are clearly follicular (Fig. 14-17), and others are perifollicular (Fig. 14-18).120 The central cuplike keratotic plug within the epidermal invagination overlies the locus of epithelial perforation, with its apex oriented downward.123 Some reports describe vacuolar changes in the keratinocytes at the

Acquired Perforating Dermatosis

HISTOPATHOLOGY Early lesions are associated with variable acanthosis, follicular and perifollicular hyperkeratosis,

Acquired perforating dermatosis (including Kyrle disease, perforating folliculitis, and reactive perforating collagenosis) is commonly associated with chronic renal failure, hemodialysis, and diabetes mellitus.117-119 Its pathogenesis is poorly understood and has been the subject of wide-ranging conjecture, which includes theories of alterations in vitamin A metabolism, accumulation of nondialyzable metabolic products recognized as foreign by the skin, disordered keratinocyte maturation (eg, keratinization occurring at the expense of proliferation), and an unusual effect of humoral and cell-mediated immunity. The pathophysiologic mechanism may not be the same for all cases of acquired perforating dermatosis; rather, the mechanism may represent a common response pathway to a variety of epidermal and dermal alterations acting alone or in combination. The common association with uremia during the early phases of hemodialysis120 tends to support the theory of dermal deposition of a nondialyzable toxic metabolite. Autosomal recessive inheri-

 FIGURE 14-17 Acquired perforating dermatosis. The perforation in this follicular lesion has occurred through the infundibulum. Brightly eosinophilic elastin fibers are seen within the basophilic collagenous debris filling the transepithelial channel. The adjacent stroma contains a sparse, mixed mononuclear infiltrate.

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

displaying transepidermal elimination of stromal elements.113,114 In addition, numerous reports have discussed secondary transepidermal elimination in association with a clearly identifiable primary cutaneous process.113 The prototype for the primary perforating diseases is Kyrle disease, as described early in the early 1900s.115 With further studies, however, it became evident that there are more clinicopathologic similarities than there are differences between Kyrle disease and the other entities, which has obscured the criteria that were originally advanced for their recognition.116 Kyrle disease itself may not be a distinct entity but rather the extreme phenotype of a more common pathophysiologic process.113,117 Perforating folliculitis and reactive perforating collagenosis, according to the current trend for unification, may be phenotypic variants of a disease spectrum or merely different stages in lesional development. Given these considerations and in view of their common clinical association with renal disease and diabetes mellitus, Kyrle disease, reactive perforating collagenosis, and perforating folliculitis have been incorporated for the present purposes under the general designation acquired perforating dermatosis, as recommended by others.117,118 Elastosis perforans serpiginosa is, however, segregated on the basis of its association with disorders of connective tissues and its rather distinctive clinical presentation.

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pattern of inheritance, indicating a genetic substrate.127 The frequent association in approximately 25% of patients with either Down syndrome or an inborn disorder of connective tissue metabolism, such as Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, or Marfan syndrome,126 suggests that the pathophysiology is based on a molecular defect in the connective tissues. Some cases have been coincident with penicillamine therapy. From these associations, hyperplastic connective tissue fibers may act as local irritants, provoking epidermal hyperplasia that envelops the altered material, which is then carried upward by the process of keratinocyte differentiation for transepidermal elimination.126

 FIGURE 14-18 Acquired perforating dermatosis. The perforation is situated at an extrafollicular site.

base of the plug and breaks in the basement membrane before channelization. The basophilic material undergoing transepidermal elimination is composed of a mixture of inflammatory cells and leukocytic debris, a parakeratotic column of keratinaceous material, and fragments of basophilic collagen or eosinophilic elastin.117,123,124 At the base may be a foreign-body granulomatous reaction, with or without a suppurative component, occurring after the epithelium has been breached.125 The walls of the channels are bordered by flattened, anucleate, and variably glycogenated keratinocytes, which suggests premature keratinization; these altered keratinocytes follow the outflow of material through the epidermis.115 Extracellular lysosomal enzymes derived from the neutrophils may play an initiating role by altering elastin and collagen (with its basophilic degeneration) and possibly opening up the channel125; under this model, however, the mechanism initiating the chemoattraction of the neutrophils is undefined.

tion may occur in each. The locus of the elimination may be follicular, extrafollicular, or both. Moreover, each condition may be associated with chronic renal failure or diabetes mellitus. Observation of an infundibular locus with hair material destined for transepidermal elimination, as defined for perforating folliculitis,122 may depend on the stage of disease or the extent of the histologic sampling of the biopsy specimen.117 For these reasons, it seems arbitrary to separate them. Elastosis perforans serpiginosa also exhibits histologic similarities, but this condition is distinctive clinically, and it exhibits microscopically a definite increase in the number and thickness of the papillary dermal elastic fibers on elastin stains.126 A cuplike invagination plugged with keratinaceous material is a feature of keratosis pilaris, but there should be no epithelial breach nor elimination of degenerated collagen or elastin in the condition.

DIFFERENTIAL DIAGNOSIS No absolute criteria discriminate the classic perforating dermatoses of Kyrle disease, perforating folliculitis, and reactive perforating collagenosis because transepidermal elimination of altered collagen, elastin, or both via a central, cuplike invagina-

An uncommon but clinically distinctive disorder recognized since the early 1950s, elastosis perforans serpiginosa has as its hallmark the transepidermal elimination of altered elastic fibers. Its pathogenesis remains unclear, but some cases are familial, with an autosomal dominant

Elastosis Perforans Serpiginosa

CLINICAL FEATURES The lesions of elastosis perforans serpiginosa, which are often asymptomatic, occur in arcuate to annular arrays that are characteristically localized to one region of the body, most often the nape but on occasion the face or upper extremities (Table 14-9). The lesions are coalescent flesh-colored or erythematous, keratotic papules with central invaginations. There may be clinical resemblance to granuloma annulare or porokeratosis of Mibelli. Spontaneous remissions occur. HISTOPATHOLOGY The lesions, which may be either follicular or extrafollicular, are associated with hyperplasia and hyperkeratosis of the contiguous epidermis. Transepidermal elimination of altered elastin occurs through a central, narrow channel with a funnel-like or corkscrew

Table 14-9 Elastosis Perforans Serpiginosa

Clinical Features Typically solitary or few lesions, with a predilection for the nape Common association with Down syndrome and disorders of connective tissue Arcuate lesions formed by coalescence of keratotic papules with central plugs Histopathologic Features Increased number and sizes of elastin fibers at the base Narrow transepithelial channel delimited by acanthotic, hyperkeratotic epidermis Brightly eosinophilic elastin among basophilic debris in the channel Granulomatous reaction at the base Differential Diagnosis Acquired perorating dermatosis

configuration, which is delimited by a collarette formed from the acanthotic epidermis. Within the channel there is basophilic necrotic material composed of parakeratotic keratin, degenerated keratinocytes, inflammatory cells, and (most distinctively) brightly eosinophilic elastic fibers126 (Fig. 14-19). At the base of the perforation is a chronic inflammatory infiltrate containing multinucleate macrophages. With specific elastin stains of early and fully evolved lesions, increased numbers and sizes of elastic fibers are situated in the subjacent dermis, from which a stream of fibers enters the perforating channel, losing their normal staining quality as they do so. DIFFERENTIAL DIAGNOSIS The differential diagnosis of the primary perforating dermatoses is most reliably resolved by the differences in their clinical presentations and disease associations because the elimination of altered, eosinophilic elastic fibers via a central keratotic channel may be observed in patients with any of the four classic perforating diseases. The finding of increased numbers and sizes of elastic fibers in the subjacent papillary dermis in elastosis perforans serpiginosa by special staining, however, may offer a criterion for its histologic discrimination.119 The clinical differential diagnosis of elastosis perforans serpiginosa versus granuloma annulare and porokeratosis of Mibelli is discriminated histologically by the absence of transepidermal elimination

and by the presence of necrobiotic dermal changes and the cornoid lamella, respectively, in the latter two diseases.

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 FIGURE 14-19 Elastosis perforans serpiginosa. A channel breaches the acanthotic, hyperkeratotic epidermis and is covered by a wedge-shaped, parakeratotic plug containing aggregates of leukocytic debris. The stroma subjacent to the perforation contains a neutrophil-rich inflammatory infiltrate, within which are several eosinophilic elastic fibers.

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drogenase deficiency. Mol Genet Metab. 2007;90:1-9. Lucker GP, Van de Kerkhof PC, Steijlen PM: The hereditary palmoplantar keratoses: an updated review and classification. Br J Dermatol. 1994;131:1-14. Kuster W, Becker A: Indication for the identity of palmoplantar keratoderma type Unna-Thost with type Vorner. Thost’s family revisited 110 years later. Acta Derm Venereol. 1992;72:120-122. Kelsell DP, Stevens HP, Ratnavel R, et al: Genetic linkage studies in non-epidermolytic palmoplantar keratoderma: evidence for heterogeneity. Hum Mol Genet. 1995;4:1021-1025. Rugg EL, Common JE, Wilgoss A, et al: Diagnosis and confirmation of epidermolytic palmoplantar keratoderma by the identification of mutations in keratin 9 using denaturing high-performance liquid chromatography. Br J Dermatol. 2002;146:952-957. Patel S, Zirwas M, English JC 3rd: Acquired palmoplantar keratoderma. Am J Clin Dermatol. 2007;8:1-11. Itin PH, Lautenschlager S: Palmoplantar keratoderma and associated syndromes. Semin Dermatol. 1995;14:152-161. Common JE, O’Toole EA, Leigh IM, et al: Clinical and genetic heterogeneity of erythrokeratoderma variabilis. J Invest Dermatol. 2005;125:920-927. Torley D, Bellus GA, Munro CS: Genes, growth factors and acanthosis nigricans. Br J Dermatol. 2002;147:1096-1101. Hamm H, Meinecke P, Traupe H: Further delineation of the ichthyosis follicularis, atrichia, and photophobia syndrome. Eur J Pediatr. 1991;150: 627-629. Chan H, Liu FT, Naguwa S: A review of pityriasis rubra pilaris and rheumatologic associations. Clin Dev Immunol. 2004;11:57-60. Vanderhooft SL, Francis JS, Holbrook KA, et al: Familial pityriasis rubra pilaris. Arch Dermatol. 1995;131:448-453. Scheinfeld NS, Mones J. Granular parakeratosis: pathologic and clinical correlation of 18 cases of granular parakeratosis. J Am Acad Dermatol. 2005;52(5): 863-867. Metze D, Rutten A. Granular parakeratosis: a unique acquired disorder of keratinization. J Cutan Pathol. 1999;26: 339-352. Happle R, Mittag H, Kuster W: The CHILD nevus: a distinct skin disorder. Dermatology. 1995;191:210-216. Bittar M, Happle R, Grzeschik KH, et al: CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions. Arch Dermatol. 2006;142:348-351. Konig A, Happle R, Fink-Puches R, et al: A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. J Am Acad Dermatol. 2002;46:594-596. Hashimoto K, Topper S, Sharata H, et al: CHILD syndrome: analysis of abnormal keratinization and ultrastructure. Pediatr Dermatol. 1995;12:116-129. Judge MR, Morgan G, Harper JI: A clinical and immunological study of Netherton’s syndrome. Br J Dermatol. 1994;131:615-621. Chavanas S, Bodemer C, Rochat A, et al: Mutations in SPINK5, encoding a serine

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protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25:141-142. Komatsu N, Saijoh K, Jayakumar A, et al: Correlation between SPINK5 gene mutations and clinical manifestations in Netherton syndrome patients. J Invest Dermatol. 2007;128(5):1148-1159. Zhang ZH, Niu ZM, Yuan WT, et al: A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis. Br J Dermatol. 2005;152:658-663. Ito M, Fujiwara H, Maruyama T, et al: Morphogenesis of the cornoid lamella: histochemical, immunohistochemical, and ultrastructural study of porokeratosis. J Cutan Pathol. 1991;18:247-256. Schamroth JM, Zlotogorski A, Gilead L: Porokeratosis of Mibelli. Overview and review of the literature. Acta Derm Venereol. 1997;77:207-213. Fuchs E, Coulombe P, Cheng J, et al: Genetic bases of epidermolysis bullosa simplex and epidermolytic hyperkeratosis. J Invest Dermatol. 1994;103(suppl): 25S-30S. Rugg EL, Horn HM, Smith FJ, et al: Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations. J Invest Dermatol. 2007;127: 574-580. Koss-Harnes D, Hoyheim B, AntonLamprecht I, et al: A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol. 2002;118:87-93. Horn HM, Tidman MJ: The clinical spectrum of epidermolysis bullosa simplex. Br J Dermatol. 2000;142:468-472. Smith LT: Ultrastructural findings in epidermolysis bullosa. Arch Dermatol. 1993;129:1578-1584. Varki R, Sadowski S, Pfendner E, et al: Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. J Med Genet 2006;43:641-652. Brown TA, Gil SG, Sybert VP, et al: Defective integrin alpha 6 beta 4 expression in the skin of patients with junctional epidermolysis bullosa and pyloric atresia. J Invest Dermatol. 1996;107:384-391. Vidal F, Baudoin C, Miquel C, et al: Cloning of the laminin alpha 3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics. 1995;30:273-280. Nakano A, Chao SC, Pulkkinen L, et al: Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. Hum Genet. 2002;110:41-51. Varki R, Sadowski S, Uitto J, et al: Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J Med Genet. 2007;44:181-192. Jarvikallio A, Pulkkinen L, Uitto J: Molecular basis of dystrophic epidermolysis bullosa: mutations in the type VII collagen gene (COL7A1). Hum Mutat. 1997;10:338-347. Christiano AM, Suga Y, Greenspan DS, et al: Premature termination codons on both alleles of the type VII collagen gene (COL7A1) in three brothers with recessive dystrophic epidermolysis bullosa. J Clin Invest. 1995;95:1328-1334.

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1 underlies mild epidermolytic palmoplantar keratoderma in three kindreds. J Invest Dermatol. 2001;116:606-609. Kuster W, Zehender D, Mensing H, et al: [Vorner keratosis palmoplantaris diffusa. Clinical, formal genetic and molecular biology studies of 22 families]. Hautarzt. 1995;46:705-710. Requena L, Schoendorff C, Sanchez Yus E: Hereditary epidermolytic palmoplantar keratoderma (Vorner type)— report of a family and review of the literature. Clin Exp Dermatol. 1991;16: 383-388. Dahl PR, Daoud MS, Su WP: JadassohnLewandowski syndrome (pachyonychia congenita). Semin Dermatol. 1995; 14:129-134. Bowden PE, Haley JL, Kansky A, et al: Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet. 1995;10:363-365. McLean WH, Rugg EL, Lunny DP, et al: Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet. 1995;9:273-278. Smith FJ, Liao H, Cassidy AJ, et al: The genetic basis of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10:21-30. McLean WH, Smith FJ, Cassidy AJ: Insights into genotype-phenotype correlation in pachyonychia congenita from the human intermediate filament mutation database. J Investig Dermatol Symp Proc. 2005;10:31-36. Leachman SA, Kaspar RL, Fleckman P, et al: Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10:3-17. Munro CS: The phenotype of Darier’s disease: penetrance and expressivity in adults and children. Br J Dermatol. 1992; 127:126-130. Sakuntabhai A, Dhitavat J, Burge S, et al: Mosaicism for ATP2A2 mutations causes segmental Darier’s disease. J Invest Dermatol. 2000;115:1144-1147. Burge SM, Wilkinson JD: Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27:40-50. Hashimoto K, Fujiwara K, Harada M, et al: Junctional proteins of keratinocytes in Grover’s disease, Hailey-Hailey’s disease and Darier’s disease. J Dermatol. 1995;22:159-170. Hu Z, Bonifas JM, Beech J, et al: Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24:61-65. Burge SM: Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126: 275-282. Grover RW: Transient acantholytic dermatosis. Arch Dermatol. 1970;101:426-434. Quirk CJ, Heenan PJ: Grover’s disease: 34 years on. Australas J Dermatol. 2004; 45:83-86; quiz 87-88. Powell J, Sakuntabhai A, James M, et al: Grover’s disease, despite histological similarity to Darier’s disease, does not share an abnormality in the ATP2A2 gene. Br J Dermatol. 2000;143:658.

109. Levy SB, Goldsmith LA: The peeling skin syndrome. J Am Acad Dermatol. 1982;7:606-613. 110. Al-Ghamdi F, Al-Raddadi A, Satti M: Peeling skin syndrome: 11 cases from Saudi Arabia. Ann Saudi Med. 2006;26: 352-357. 111. Cassidy AJ, van Steensel MA, Steijlen PM, et al: A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome. Am J Hum Genet. 2005;77:909-917. 112. Hashimoto K, Hamzavi I, Tanaka K, et al: Acral peeling skin syndrome. J Am Acad Dermatol. 2000;43:1112-1119. 113. Mehregan AH: Perforating dermatoses: a clinicopathologic review. Int J Dermatol. 1977;16:19-27. 114. Sehgal VN, Jain S, Thappa DM, et al: Perforating dermatoses: a review and report of four cases. J Dermatol. 1993;20: 329-340. 115. Kyrle J: Hykeratosis follicularis et parafollicularis in cutem penetrans. Arch Dermatol Syphilol (Berlin) 1916;123:466-493. 116. Saray Y, Seckin D, Bilezikci B: Acquired perforating dermatosis: clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol. 2006;20:679-688. 117. Rapini RP, Herbert AA, Drucker CR: Acquired perforating dermatosis. Evidence for combined transepidermal elimination of both collagen and elastic fibers. Arch Dermatol. 1989;125:10741078. 118. Patterson JW, Brown PC: Ultrastructural changes in acquired perforating dermatosis. Int J Dermatol. 1992;31:201-205. 119. Hood AF, Hardegen GL, Zarate AR, et al: Kyrle’s disease in patients with chronic renal failure. Arch Dermatol. 1982;118:85-88. 120. Garcia-Bravo B, Rodriguez-Pichardo A, Camacho F: Uraemic follicular hyperkeratosis. Clin Exp Dermatol. 1985;10: 448-454. 121. Ramesh V, Sood N, Kubba A, et al: Familial reactive perforating collagenosis: a clinical, histopathological study of 10 cases. J Eur Acad Dermatol Venereol 2007;21:766-770. 122. Mehregan AH, Coskey RJ: Perforating folliculitis. Arch Dermatol. 1968;97:394-399. 123. Constantine VS, Carter VH: Kyrle’s disease. II. Histopathologic findings in five cases and review of the literature. Arch Dermatol. 1968;97:633-639. 124. Mehregan AH, Schwartz OD, Livingood CS: Reactive perforating collagenosis. Arch Dermatol. 1967;96:277-282. 125. Zelger B, Hintner H, Aubock J, et al: Acquired perforating dermatosis. Transepidermal elimination of DNA material and possible role of leukocytes in pathogenesis. Arch Dermatol. 1991;127: 695-700. 126. Mehregan AH: Elastosis perforans serpiginosa: a review of the literature and report of 11 cases. Arch Dermatol. 1968;97: 381-393. 127. Langeveld-Wildschut EG, Toonstra J, van Vloten WA, et al: Familial elastosis perforans serpiginosa. Arch Dermatol. 1993;129:205-207.

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

77. Horn HM, Tidman MJ: The clinical spectrum of dystrophic epidermolysis bullosa. Br J Dermatol. 2002;146:267-274. 78. Anton-Lamprecht I: Ultrastructural identification of basic abnormalities as clues to genetic disorders of the epidermis. J Invest Dermatol. 1994;103(suppl): 6S-12S. 79. Rothnagel JA, Dominey AM, Dempsey LD, et al: Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science. 1992;257:1128-1130. 80. Fuchs E, Esteves RA, Coulombe PA: Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis. Proc Natl Acad Sci U S A. 1992;89:69066910. 81. DiGiovanna JJ, Bale SJ: Clinical heterogeneity in epidermolytic hyperkeratosis. Arch Dermatol. 1994;130:1026-1035. 82. Nomura K, Umeki K, Hatayama I, et al: Phenotypic heterogeneity in bullous congenital ichthyosiform erythroderma: possible somatic mosaicism for keratin gene mutation in the mildly affected mother of the proband. Arch Dermatol. 2001;137:1192-1195. 83. Steijlen PM, Kremer H, Vakilzadeh F, et al: Genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of Siemens and with autosomal dominant ichthyosis exfoliativa. J Invest Dermatol. 1994;103:282-285. 84. Rothnagel JA, Traupe H, Wojcik S, et al: Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nat Genet. 1994;7:485-490. 85. Smith FJ, Maingi C, Covello SP, et al: Genomic organization and fine mapping of the keratin 2e gene (KRT2E): K2e V1 domain polymorphism and novel mutations in ichthyosis bullosa of Siemens. J Invest Dermatol. 1998;111: 817-821. 86. Steijlen PM, Perret CM, Schuurmans Stekhoven JH, et al: Ichthyosis bullosa of Siemens: further delineation of the phenotype. Arch Dermatol Res. 1990; 282:1-5. 87. Niemi KM, Virtanen I, Kanerva L, et al: Altered keratin expression in ichthyosis hystrix Curth-Macklin. A light and electron microscopic study. Arch Dermatol Res. 1990;282:227-233. 88. Sprecher E, Yosipovitch G, Bergman R, et al: Epidermolytic hyperkeratosis and epidermolysis bullosa simplex caused by frameshift mutations altering the v2 tail domains of keratin 1 and keratin 5. J Invest Dermatol. 2003;120:623-626. 89. Navsaria HA, Swensson O, Ratnavel RC, et al: Ultrastructural changes resulting from keratin-9 gene mutations in two families with epidermolytic palmoplantar keratoderma. J Invest Dermatol. 1995;104:425-429. 90. Terrinoni A, Cocuroccia B, Gubinelli E, et al: Identification of the keratin K9 R162W mutation in patients of Italian origin with epidermolytic palmoplantar keratoderma. Eur J Dermatol. 2004;14: 375-378. 91. Hatsell SJ, Eady RA, Wennerstrand L, et al: Novel splice site mutation in keratin

337

CHAPTER 15 Disorders of Pigmentation

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

A. Neil Crowson Sarah Zeller Raymond L. Barnhill

338

The source of pigment that causes hyperpigmentation of the skin ranges from endogenous products such as melanin and hemosiderin to exogenous agents such as dyes for tattoos, ingested metals, and drugs. In some instances, these agents are combined to produce hyperpigmentation. For example, in argyria- and chlorpromazine-related hyperpigmentation, silver particles plus melanin and drug metabolites plus melanin, respectively, contribute to dyschromasia. Ultraviolet (UV) rays often enhance these pigmentations, so sun-exposed skin shows more intense discoloration. When the epidermis is heavily melanized, pigment incontinence may result in upper dermal melanization as well. Disorders of hypopigmentation and depigmentation are caused mainly by damage to and dysfunction of epidermal melanocytes (Figs. 15-1 and 15-2). In some congenital diseases (eg, piebaldism), melanocytes are absent. The circulation of blood through the superficial capillary plexus may influence the skin color, as evidenced by nevus anemicus. Both hyper- and hypopigmentations may be congenital or hereditary, postinflammatory, or induced by chemicals and foreign materials. Melanocytes from all sites (skin, hair bulb, eyes) produce melanosomes that in the normal process mature into electrondense stage IV melanosomes in darkskinned individuals. The maturation is arrested at stage I or II in fair-skinned whites (Fig. 15-3). In leukodermic conditions, various dysfunctions of tyrosinase or damage to melanocytes produce fewer pigmented melanosomes or a decrease in their number (Figs. 15-4 and 15-5), changes that are more visible in dark skin. Hyperactivity of melanocytes results in various hyperpigmented conditions, and in such disorders, lesions are again more striking in dark than in light skin. In some conditions, the transfer of melanosomes from normal melanocytes to the surrounding basal keratinocytes is disturbed, causing an uneven light color of the lesion

Disorders of pigmentation

Hypomelanosis

Markedly reduced or absent epidermal melanocytes and melanin Established vitiligo Piebaldism Physical leukoderma Chemical exposure Traumatic injury Burns Radiation Onchocerciasis Pinta Scleroderma Halo nevus Melanoma-associated leukoderma

Hyperpigmentation

Normal numbers or slightly reduced numbers of epidermal melanocytes; markedly reduced epidermal melanin Albinism Postinflammatory hypomelanosis Trichrome or evolving vitiligo Pityriasis alba Tinea versicolor Tuberous sclerosis Hypomelanosis of Ito Nevus depigmentosus Malnutrition

 FIGURE 15-1 Disorders of pigmentation.

(eg, nevus depigmentosus) or hyperpigmentation in some instances (eg, PeutzJeghers syndrome). In many hyperpigmented conditions (eg, lentigo simplex and senilis), the rete ridges are elongated, and an aggregation of melanocytes and pigment occurs (Fig. 15-6). The DOPA stain has long been the standard method to demonstrate melaninsynthesizing melanocytes (Table 15-1). Silver stains such as the Fontana-Masson stain have been used to demonstrate melanin granules (aggregated melanosomes) (see Fig. 15-4). It is now much more convenient to use melanocytespecific monoclonal antibodies such as MEL-5, Melan-A, or HMB-45, which are applicable to formalin-fixed, paraffinembedded tissues through immunoperoxidase methodologies.

HYPOPIGMENTATION DISORDERS In these disorders, the histopathology is mostly nonspecific (see Fig. 15-1 and Table 15-2). Epidermal melanocytes are either absent or inactive; accordingly, the epidermis is hypomelanized or totally depigmented.

Piebaldism (Patterned Leukoderma) CLINICAL FEATURES Piebaldism manifests congenital patches of depigmentation (leukoderma), a white forelock, or poliosis (white hairs) in 85% of patients.1-3 Both mice and humans with a null

mutation at either the endothelin 3 or the endothelin receptor b locus show major deficiencies in both melanocytes and enteric ganglion cells, resulting in congenital white spotting and aganglionic megacolon.4 Hyperpigmented macules may occur in the depigmented lesions or in normal skin. The disease has an autosomal dominant inheritance pattern. Unlike vitiligo, the leukoderma is mostly permanent because melanocytes are largely absent in the lesion. Occasionally, repigmentation may occur at the periphery of a lesion or within the depigmented macule. In a similar disorder of mice, socalled “dominant white spotting,” a mutation or deletion of c-kit (a gene encoding a cell surface receptor tyrosine kinase) has been detected. The c-kit protooncogene, originally found in HZ4feline sarcoma virus (hence the name kit), is important for the production of cell surface receptors for embryonic growth factors (eg, stem cell factor, mast cell growth factor) and seems to promote development, migration, and survival of melanocytes. The human piebaldism gene locus has been mapped to chromosome 4q12, a site near the human KIT gene locus. Multiple KIT point mutations, including missense, nonsense, and splice-site nucleoside substitutions, may result in the piebald phenotype.5,6 A novel C-KIT mutation (Val62OAla) has been detected in a family with piebaldism that resulted in progressive depigmentation.7 Some humans and mice with the piebald

Disorders of hyperpigmentation

Predominantly increased epidermal melanin (some pigment incontinence)

Both epidermal and dermal melanin increased Postinflammatory hypermelanosis Melasma

Patterned or circumscribed hypermelanosis Freckle CALM Melanotic macule of Albright Lentigo Melasma (epidermal) Becker’s melanosis

Increased melanin, epidermal and/or dermal, and other pigments Tattoo Hemochromatosis Argyria Chrysiasis Mercury Arsenic Lead Bismuth Minocycline Antimalarials Amiodarone Chlofazamine Phenothiazine

 FIGURE 15-2 Disorders of hyperpigmentation. CALM = café-au-lait macule.

phenotype who lack apparent C-KIT mutations have been found to harbor deletions in the zinc-finger neural crest transcription, although the function of

SLUG in the development of melanocytes remains unclear.8 Other diseases that have been noted to be associated with piebaldism are congen-

ital dyserythropoietic anemia type II (HEMPAS),9 neurofibromatosis type 1 (NF1),10 Grover disease,11 and sensorineural deafness. The occurrence of sensorineural deafness in a patient with genotypically confirmed piebaldism extends the phenotypic range of piebaldism due to C-KIT gene mutation in humans and strengthens the clinical similarity between piebaldism and the various forms of Waardenburg syndrome.12 In Klein-Waardenburg syndrome,13 which is also dominantly inherited, a white forelock is present in 50% of affected individuals, and congenital patches of leukoderma are associated with hypertelorism and heterochromia of the irides as well as deafness.

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

Diffuse hypermelanosis Addison disease Myxedema Grave disease Malnutrition Hemochromatosis, early Chemotherapeutic agents

Predominantly increased dermal melanin (pigment incontinence) Postinflammatory hypermelanosis Melasma (dermal) Incontinentia pigmenti Prurigo pigmentosa

HISTOPATHOLOGIC FEATURES By DOPA reaction and immunohistochemistry, melanocytes are absent in the leukoderma and white hair of the forelock, and electron microscopy reveals no melanocytes with melanosomes. In contrast, the hyperpigmented macules contain normal numbers of melanocytes.

 FIGURE 15-3 An epidermal melanocyte is actively synthesizing melanosomes. Stage 1 melanosome contains amorphous, nebulous material. In stage 2, cristae are formed, and melanin begins to deposit on them. In stage 3, melanin polymers become denser, and in stage 4, the increased density masks the underlying structure of cristae.

DIFFERENTIAL DIAGNOSIS Without clinical information, the depigmented macules in patients with piebaldism cannot be distinguished histologically from established lesions of vitiligo and leukodermas resulting from chemicals, trauma, or burns that show loss of all epidermal melanocytes. Most other leukodermas are distinguished from piebaldism by the presence of melanocytes.

339

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

A

 FIGURE 15-4 Vitiligo. (A) Depigmentation involving the neck in a characteristic periorificial distribution. (B) A Melan-A immunostain at the edge of a vitiligo lesion. Depigmented skin shows progressive loss of melanocyte density.

Vitiligo and Vogt-Koyanagi-Harada Syndrome

 FIGURE 15-5 Oculocutaneous albinism.

340

B

Vitiligo is an acquired patchy pigment loss of the skin and rarely the hairs that may develop at any age; rarely, it may be congenital (Table 15-3). Up to 30% of cases have a familial basis. Individuals with vitiligo may present with focal lesions, that is, one or more isolated macules; segmental lesions, which are unilateral and often show a dermatomal pattern; generalized symmetric lesions that are commonly periorificial; or universal involvement (Fig. 15-4A). Individual macules of established vitiligo often measure several millimeters in diameter; are completely depigmented with a milk white color; and have well-defined, often scalloped borders. Trichrome vitiligo refers to three types of lesions: white (established vitiligo), light tan (transitional areas that will become depigmented), and normal brown areas. When serum IgG from vitiligo patients is injected into nude mice to which normal human skin has been grafted, melanocytes of the grafted skin are damaged and significantly decreased, suggesting an autoimmune mechanism in the etiology.14 A similar occurrence has

gastritis, autoimmune thyroid disease,23 ankylosing spondyloarthritis,24 idiopathic CD44 +ve T-cell lymphocytopenia,25 and lepromatous leprosy.26 These associations strengthen the hypothesis of a role for autoimmunity in vitiligo.

been seen in humans after bone marrow transplantation, as in the case of a patient who developed generalized vitiligo 3 months after receiving an allogeneic bone marrow transplant from an HLA-matched sister with vitiligo.15,16

Table 15-1 Evaluation of Disorders of Pigmentation 1. Hematoxylin and eosin–stained sections of lesional and uninvolved skin for basilar melanocytes, melanin, and other changes such as inflammation, granulomas 2. Silver stains such as Fontana-Masson for melanin, dendritic melanocytes 3. Other stains, such as PAS, acid-fast bacillus, Fite-Faraco for infectious organisms; Prussian blue for iron, hemosiderin 4. DOPA reaction to demonstrate melanocytes (specific for tyrosinase), not practical since special fixation and development required 5. Antibodies to tyrosinase pathway–related or melanosomal matrix–related antibodies (e.g., Melan-A, Mel-5, Mitf or HMB-45) to demonstrate melanocytes by immunohistochemistry 6. Electron microscopy to demonstrate quantitative and qualitative aspects of melanosomes 7. Clinical information, such as congenital or acquired onset, diffuse or circumscribed nature of process, distribution of disorder, history of trauma, chemical exposure, other dermatosis, infectious disease

Autoantibodies are formed against the melanocyte or melanosome and destroy them via antibody-mediated cytotoxicity and complement-mediated cytolysis, either as a primary pathogenic mechanism or as a secondary response to the damage caused by autoreactive T lymphocytes.17 Target antigens demonstrated in the sera of vitiligo patients include those against the tyrosinase antigen gp 100/pmel17 and tyrosinase-related proteins trp-1 and trp-2, 18 Pmel17, the transcription factor SOX10, and the melanin-concentrating hormone receptor 1 (MCHR1).19 The titers of autoantibody, as well as the frequency of A103specific CD8 +ve T cells among the total T-cell pool,20 seem to correlate with disease activity. There is also evidence of modification of epidermal cytokine expression in patients with vitiligo. Granulocyte-macrophage colony-stimulating factor, fibroblast growth factor β, and stem cell factor are decreased, and interleukin-6 and tumor necrosis factor (TNF)–α are increased in vitiliginous skin compared with perilesional, nonlesional, and healthy skin.21 In Vogt-Koyanagi-Harada syndrome, the skin and other melanocyte-bearing tissues, such as the leptomeninges, uveal tract, and stria vascularis of the ear, are attacked by autoantibodies to produce meningitis, uveitis, and dysacousia, respectively.22 Vitiligo is polygenic in nature and has been associated with various other autoimmune diseases. These diseases include diabetes mellitus, atrophic

DIFFERENTIAL DIAGNOSIS The clinical differential diagnosis of vitiligo depends on the distribution and extent of hypopigmentation, as well as on other factors, and includes leukoderma from chemicals, trauma, and burns; halo nevi and melanoma; piebaldism; and Waardenburg syndrome, all of which may show an absence of epidermal melanocytes and melanin and thus be histologically indistinguishable from established vitiligo. Other entities that may be confused clinically with vitiligo include lupus erythematosus, hypochromic mycosis fungoides, postinflammatory hypopigmention, tuberous sclerosis (TS), pityriasis alba, tinea versicolor, leprosy, idiopathic guttate hypomelanosis, and nevus depigmentosus. In general, the latter processes show basilar melanocytes, diminished epidermal melanin, and distinctive features in some patients. The presence of some basilar melanocytes and epidermal melanin does not necessarily rule out vitiligo because they may be seen in the skin adjacent to vitiligo, in trichrome vitiligo, and in repigmenting vitiligo.

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

 FIGURE 15-6 Lentigo simplex. A heavy melanization of rete ridges, particularly around the tip, is seen.

HISTOPATHOLOGIC FEATURES In wellestablished lesions, neither melanocytes nor melanin can be detected in the epidermis with hematoxylin and eosin (H&E) or immunohistochemical stains or electron microscopy. At the periphery of the lesion, large melanocytes with long dendritic processes and many melanosomes are present (see Fig. 15-4B), as if they are trying to cover the depigmented areas. Lymphocytic infiltration and basal cell vacuolization may be seen at the advancing border of vitiligo. The light-tan areas in patients with trichrome vitiligo show both basilar melanocytes and melanin.

Oculocutaneous Albinism CLINICAL FEATURES Oculocutaneous albinism manifests as total loss of pigment from the skin and hair with associated blue irides and red fundi of the eyes27 (Fig. 15-5A). It is congenital and inherited recessively. The two subtypes are tyrosinase positive and tyrosinase negative. In the former, a plucked hair bulb becomes dark after incubation in

341

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Table 15-2 Disorders of Hypopigmentation: Principal Histopathologic Features

342

DISORDER

BASILAR MELANOCYTES

MELANIN IN BASAL LAYER

Established vitiligo Vitiligo margin

Absent Present, enlarged

Absent Present, reduced

Trichrome vitiligo (light tan skin) Piebaldism, Waardenberg syndrome, Woolf syndrome Albinism

Present Absent

Present Absent Greatly reduced or absent

Chédiak-Higashi syndrome

Normal number, morphology Present

Greatly reduced or absent

Tuberous sclerosis (ash-leaf macules)

Present

Reduced

Hypomelanosis of Ito

Normal or decreased in number Normal numbers

Decreased

Postinflammatory hypomelanosis

Normal or slightly reduced numbers

Decreased

Pityriasis alba

Reduced

Decreased

Tinea versicolor

Normal

Decreased

Idiopathic guttate hypomelanosis

Slightly decreased

Decreased

Physical, chemical depigmentation

Absent

Absent

Nevus depigmentosus

DOPA solution. These patients may develop freckles and pigmented nevi. In the latter, the hair bulb does not become dark after incubation in DOPA solution, and patients never become pigmented. However, the degree of skin pigmentation, such as the ability to tan, is variable among both types depending on the mutant alleles. Due to a lack of melanin pigment in the developing eye,28 optical findings, such as foveal hypoplasia, misrouting of optic nerve to the brain, and reduced visual acuity, are universal for all types of albinism. The tyrosinase-negative type is now further subclassified into OCA-1A, in which there is no tyrosinase activity; OCA-lB (yellow OCA) and OCA-1MP (minimal pigment OCA), in which some tyrosinase activity is present; and OCA2TS, which is temperature sensitive. Various mutations of the tyrosinase gene on chromosome 11q14-21 are responsible for these different clinical phenotypes. The tyrosinase-positive subtypes are OCA2, caused by a mutation in the OCA2 gene (formerly P-gene)

Decreased

responsible for melanosome biogenesis and transport of tyrosinase; OCA3, in which mutated tyrosinase-related protein (TYRP 1) leads to early degradation of tyrosinase; and OCA4, which is characterized by mutations of the membraneassociated transporter protein gene (MATP, also known as SLC45A2).29,30 Albinism is one of the symptoms of Vici syndrome,31 which consists of delayed development, agenesis of the corpus callosum, hypotonia, cardiomyopathy, cataracts, and recurrent infections and has been seen as well in a patient with primary melanoma of the lung.32 HISTOPATHOLOGIC FEATURES In all disease subtypes, basal melanocytes are observed, but the epidermal melanin content is greatly diminished or absent. Electron microscopy proves the presence of normal melanocytes. In the tyrosinasepositive type, some melanosomes mature to stages III and IV, but in the tyrosinase-negative type, the melanosomes are not pigmented even after incubation with DOPA.

OTHER FINDINGS Basal layer vacuolization, lymphocytic infiltrates

Large pigment granules (giant melanosomes) Reduced number, size, and melanization of melanosomes Underdeveloped dendrites Poorly developed dendrites, decreased melanosomes Block in transfer of melanosomes to keratinocytes Fewer and smaller melanosomes Defective melanosome maturation and transfer block Atrophic epidermis, melanocytes with stubby dendrites; immature melanosomes, stages I and II Possible scarring

Hermansky-Pudlak Syndrome CLINICAL FEATURES Hermansky-Pudlak syndrome (HPS) includes a group of genetically distinct disorders characterized by tyrosinase-positive oculocutaneous albinism, a platelet storage pool deficiency that results in a bleeding diathesis, and impaired formation or trafficking of intracellular vesicles. It is an autosomal recessive disorder that affects mainly persons of Puerto Rican origin, although there have been several reported cases in Turkish, Pakistani, and Ashkenazi Jewish kindreds.33,34 There are eight human HPS subtypes, each associated with specific defects in protein trafficking that lead to dysfunction of intracellular lysosome-related organelles.35 The disease complex is subclassified as HPS1 (HPS1 gene abnormality), HPS2 (ADTB3A gene abnormality), and HPS3 (HPS3 gene abnormality). A mutation in the AP3 complex results in abnormal intracellular vesicle formation.36 HISTOPATHOLOGIC FEATURES Melanocytes manifest shortened dendritic processes,

Table 15-3 Vitiligo

Table 15-4 Albinism

Clinical Features Abnormalities of optic system Nystagmus, photophobia, decreased visual acuity Blue and translucent iris (blue eyes) Hair white to yellow White skin Often greatly increased risk for skin cancer Autosomal recessive: Numerous variants Histopathologic Features Melanocytes normal in number and structure Greatly reduced or absent epidermal melanin Differential Diagnosis Rare genetic disorders with hypopigmentation Universal vitiligo

Chédiak-Higashi syndrome CLINICAL FEATURES Chédiak-Higashi syndrome is an autosomal recessive disorder that resembles oculocutaneous albinism because of the fair color of the skin, hair, and irides; nystagmus; and photophobia.37,38 The skin is creamy white, but the degree of depigmentation is not very striking. The hair is light blond to brown and has a silver-green sheen. In addition to reduced pigmentation, affected individuals also have severe immunologic defects (eg, impaired chemotaxis and abnormal natural killer cell function), bleeding tendencies, and progressive neurologic dysfunction.39 Patients rarely survive beyond childhood because of an increased susceptibility to bacterial infection. They may also succumb to an “accelerated phase” during which a nonmalignant lymphohistiocytic infiltration of multiple organs resembling lymphoma occurs. The current treatment is a bone marrow transplant, which aborts the accelerated phase and the immune problems but does not prevent the neurologic disorders, which continue to develop with age.40,41 Although the function of the large protein which the LYST gene encodes is unknown, Chédiak-Higashi syndrome appears to be a disorder of vesicle trafficking.42 This protein may insert itself between other proteins that mediate intracellular fusion or fission reactions.43-45 HISTOPATHOLOGIC FEATURES As with oculocutaneous albinism, basilar melanocytes are present, but epidermal melanin is diminished. Silver stains detect large melanin granules throughout the epidermis and in melanophages in the upper dermis; ultrastructurally, these granules are localized to membrane-bound giant melanosomes in skin and hair. The classic diagnostic feature of Chédiak-Higashi syndrome is the presence of huge cytoplasmic granules and lysosomes within cells.46 Giemsa stains of peripheral blood smears show numerous large granules in leukocytes. These granules are formed by the fusion of abnormal phagosomes incapable of normal bacterial killing.

Ash Leaf Spots of Tuberous Sclerosis Tuberous sclerosis (TS) is an autosomal dominant disease in which find ash leaf–shaped hypopigmented spots (ie, ash

leaf spots) are seen in 50% to 98% of patients.47 Hypopigmented macules are the most frequent skin finding in patients with TS and are considered a tertiary diagnostic feature.48 These spots are scattered over the trunk and extremities from birth or early childhood and thus are a significant early sign of the disease, similar to the axillary freckling of neurofibromatosis. Poliosis and depigmented spots on the iris and retina are also seen. Multiple organ systems may have hamartomatous involvement, including the central nervous system (CNS) (with epilepsy being the most common feature), kidneys, heart, and other viscera. When there is pulmonary involvement, the condition is known as pulmonary lymphangioleiomyomatosis (LAM).49 The skin, kidney, and brain lesions of individuals with TS express CD31 and vascular endothelial growth factor (VEGF).50 The combination of congenital hypopigmented lesions with seizures and mental retardation strongly suggests a diagnosis of TS. The gene for TS has been mapped to chromosomes 9q(33-) 34.3 (tuberous sclerosis-1 or TS1) and l6p13.3 (TS2). The gene product is hamartin for TS1 and is tuberin for TS2; hamartin and tuberin bind together to form a tumor suppressor heterodimer. This complex inhibits the mammalian target of rapamycin (mTOR)51, which results in abnormal cell differentiation and proliferation.49 Mutations in TS2 are seen in the majority of de novo cases and 50% of familial cases and usually portend a more severe clinical phenotype.52,53

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

Clinical Features Onset any age, especially in adolescents, young adults Patterns: Generalized—periorificial, bony prominences, extensor surfaces. Segmental—dermatomal Localized Milk-white macular lesions, well-defined, scalloped borders Trichrome lesions, light-tan Associations: Thyroid disease, diabetes mellitus, Addison disease, pernicious anemia Histopathologic Features Established (depigmented) lesions: Absence of epidermal melanocytes and melanin Marginal (normal) skin Epidermal melanocytes and melanin present Basal layer vacuolization often Sparse lymphocytic infiltrates Trichrome vitiligo: Epidermal melanocytes and melanin present but usually reduced Differential Diagnosis Piebaldism Chemical, physical depigmentation Post-inflammatory hypopigmentation Lupus erythematosus Pityriasis alba Tinea versicolor Tuberous sclerosis Leprosy Melanoma-associated leukoderma Idiopathic guttate hypomelanosis Nevus depigmentosus

and there is a reduced number of melanosomes in both melanocytes and keratinocytes; these melanosomes mature only to stages I to III.37

HISTOPATHOLOGIC FEATURES A normal to reduced density of melanocytes is present, but the DOPA reaction is weak compared with the surrounding normal skin. By electron microscopy, the size of melanosomes and degree of melanization are less than the normal counterparts, and their dendrites are less well developed. DIFFERENTIAL DIAGNOSIS The principal entities to be considered are piebaldism, vitiligo, nevus depigmentosus, hypomelanosis of Ito, and postinflammatory hypopigmentation. The ash leaf macules are discriminated from piebaldism and vitiligo by the presence of melanocytes in the former. Nevus depigmentosus may be difficult to distinguish from ash leaf macules because both lesions are usually congenital and show basilar melanocytes in hypopigmented skin. However, the clinical findings of seizures and mental retardation are indicative of TS. The lesions of postinflammatory hypopigmentation are acquired and more variable clinically.

343

Idiopathic Guttate Hypomelanosis

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Relatively common among older (>50 years) African American men and women (Table 15-5), idiopathic guttate hypomelanosis may be equally frequent in whites but is not as noticeable. Numerous well-demarcated depigmented and hypopigmented (porcelain white) macules 2 to 10 mm in diameter are seen on the shins and, less frequently, on the extensor aspects of the arms. The pathogenesis is uncertain, but given the distribution, a link to chronic UV exposure has been proposed.54-56 HISTOPATHOLOGIC FEATURES The epidermis is atrophic with flattened rete ridges and shows decreased melanin content; biopsies taken at the interface between normal and hypopigmented skin show an abrupt loss of basal layer melanization (Fig. 15-7). Basilar melanocytes are observed but are reduced in number, as confirmed by immunoperoxidase studies using monoclonal antibodies against the KIT receptor and melanocyte differentiation antigens (Tyrp-1, tyrosinase, and gp100/pmel17).56 Ultrastructurally, most melanosomes are immature (stages I and II), and their dendrites are underdeveloped; normal melanocytes may be intermingled with these less active ones. DIFFERENTIAL DIAGNOSIS Vitiligo, chemical and traumatic depigmentation, postinflammatory hypopigmentation, tuberous sclerosis, and tinea versicolor enter into the differential diagnosis.

Table 15-5 Idiopathic Guttate Hypomelanosis

344

Clinical Features Older individual (especially >50 years) Sun-exposed surfaces of the extremities Discrete, usually round, white macules ~5 mm in diameter, multiple, often numerous Histopathologic Features Hyperkeratosis Effacement of epidermis Reduction in number of melanocytes Poorly developed dendrites Significant reduction in epidermal melanin Electron microscopy: Stage I and II melanosomes Differential Diagnosis Vitiligo Physical leukoderma Post-inflammatory hypopigmentation Tinea versicolor

 FIGURE 15-7 Idiopathic guttate hypomelanosis. An abrupt loss of basal layer melanization is seen in this biopsy taken at the interface between normal and hypopigmented skin.

Idiopathic guttate hypomelanosis differs from vitiligo and chemical and traumatic depigmentation by the presence of melanocytes and is discriminated from other leukodermas by its distinctive clinical features and distribution.

Hypomelanosis of Ito or Incontinentia Pigmenti Achromians Hypopigmented bands or streaks following Blaschko lines on the trunk at birth or during the first year of life characterize hypomelanosis of Ito. Repigmentation may occur in some cases. Structural hair shaft abnormalities are often associated.57 Mental retardation or seizure disorders may be present in addition to various other congenital anomalies. Karyotyping of blood lymphocytes, skin fibroblasts, or keratinocytes reveals nonuniform chromosomal abnormalities, including mosaicism for tetrasomy l2p and for trisomy 18, suggesting that somatic cell line mosaicism is responsible for the hypopigmentation. Diploidy/triploidy 45, X/46, X, r(X) or 45, X/46, X_1_mar and chimerism of 46, XX/46, and XY are also relatively frequent. Single-gene inheritance has not been proven in this disease. Due to the nonspecific manifestation of different chromosomal mosaicisms, it has been suggested that the term hypomelanosis of Ito be discarded for more pathogenically or clinically descriptive terminology such as pigmentary dysplasia, pigmentary mosaicism of the Ito type, pigmentary mosaicism, or hypopigmentation along the lines of Blaschko.58-60

HISTOPATHOLOGIC FEATURES The hypopigmented area has fewer and smaller melanocytes than the normal skin; electron microscopy demonstrates decreased numbers of melanosomes in the melanocytes and basal keratinocytes,61 with some melanocytes showing degenerative changes and containing no melanosomes. DIFFERENTIAL DIAGNOSIS The major conditions to be considered are nevus depigmentosus and postinflammatory hypopigmentation. The clinical findings of symmetric swirled lesions in patients with seizures, mental retardation, and other developmental abnormalities should facilitate this discrimination because the histology may be similar.

Nevus Depigmentosus Nevus depigmentosus manifests as a solitary congenital patch of hypopigmentation on the trunk, neck, and other locations.62 Such a lesion may be localized, segmental, or less often systematized. Lesions may be circumscribed, irregular, oval or round, or a unilateral band or streak that may be arranged along one or more lines of Blaschko. When systematized, the lesion is indistinguishable from hypomelanosis of Ito.63 In contrast to vitiligo or piebaldism, depigmentation is not complete, and the contour is usually not smooth as in vitiligo but is rather ragged. Nevus depigmentosus may be associated with

either ispilateral or contralateral segmental lentiginosis or with the acquired onset of multiple pigmented nevi within the hypopigmented region.64-66

vitiligo, and leprosy. In general, the clinical features and identification of microorganisms should allow discrimination of pityriasis alba from other leukodermas.

HISTOPATHOLOGIC FEATURES The number of basilar melanocytes is normal or decreased,67 and the amount of epidermal melanin is decreased in special stains; electron microscopy reveals poorly developed, less dendritic melanocytes with a greatly reduced number of otherwise normal melanosomes. In addition, some membrane bound aggregated melanosomes may be seen in keratinocytes.68

Postinflammatory Leukoderma or Hypomelanosis

Pityriasis Alba Pityriasis alba causes hypopigmented patchy macules around the nose, cheeks, and eyebrow areas of children, particularly in blacks, and is often misdiagnosed as tinea faciae because fine scales may cover the lesion.69 The condition may be as common but is less noticeable in white children and is probably a variant of seborrheic dermatitis or atopic dermatitis, with Pityrosporum infection a contributing factor.70-72 The prevalence of pityriasis alba in patients with atopic dermatitis of Middle Eastern or Asian origin ranges from 12% to 25%.71 HISTOPATHOLOGIC FEATURES The main findings are hyperkeratosis with patchy parakeratosis, slight acanthosis with spongiosis, and a superficial perivascular lymphocytic infiltrate. The lack of pigmentation is due to decreased basal layer melanin; the number of basilar melanocytes is normal or decreased, and these cells produce fewer and smaller melanosomes. Transfer of melanosomes to the keratinocytes is normal. The clinical depigmentation may reflect postinflammatory alterations, but it is possible that Pityrosporum species are involved in the etiology because the tyrosinase inhibitor azelaic acid is produced by these lipophilic yeasts. DIFFERENTIAL DIAGNOSIS The major conditions to be considered are postinflammatory hypopigmentation, tinea versicolor,

HISTOPATHOLOGIC FEATURES In general, reversible forms of leukoderma show basilar melanocytes often in normal

Table 15-6 Postinflammatory Hypopigmentation

Clinical Features Widespread or localized Usually follows dermatitis, such as eczematous dermatitis, psoriasis, pityriasis lichenoides, lichen planus, lupus erythematosus, seborrheic dermatitis, mycosis fungoides Off-white (not fully depigmented) macular lesions with ill-defined margins Repigmentation occurs Histopathologic Features Basilar melanocytes present Reduced melanin in epidermis (blocked transfer to keratinocytes often) Evidence of antecedent inflammatory process may be present in early lesions Differential Diagnosis Vitiligo Chemical, physical depigmentation Tinea versicolor Pityriasis alba Leprosy

Clinical Features Physical injury Thermal injury Radiation Chemical exposure Phenols Catechols Sulfhydryl compounds Depigmented macular lesions of sites of exposure/injury Histopathologic Features Absence of melanocytes and melanin Reparative changes (depending on agent) Differential Diagnosis Vitiligo Scleroderma Onchocercosis Pinta Melanoma-associated leukoderma

numbers but in some instances reduced in number or damaged in concert with reduced epidermal melanin. Some pigment incontinence may be present as well as features of the antecedent dermatitis, such as, for example, lupus erythematosus. The melanocytes may or may not be detected with special stains depending on the degree of melanocyte damage. Permanent forms of leukoderma are characterized by an absence of intraepidermal melanocytes and melanin. In old scars, the melanocytes may have recovered, but fibrosis and the relative paucity of blood vessels contribute to the white color; examples include atrophie blanche, lichen sclerosis et atrophicus, and nevus anemicus.

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

DIFFERENTIAL DIAGNOSIS Conditions to be excluded include piebaldism, segmental vitiligo, tuberous sclerosis, postinflammatory hypopigmentation, and hypomelanosis of Ito. Nevus depigmentosus is congenital and differs from the first two disorders histologically by virtue of having normal numbers of intraepidermal melanocytes and from the latter three entities based mainly on clinical features because the histology may be quite similar.

Hypomelanotic macular lesions may follow a diverse group of inflammatory dermatitides such as eczematous dermatitis, seborrheic dermatitis, psoriasis, drug eruptions, pityriasis lichenoides chronica, lupus erythematosus, lichen planus, alopecia mucinosa, sarcoidosis, and mycosis fungoides (Table 15-6). The clinical lesions are usually off-white (not fully depigmented), often have indistinct margins, and show gradual repigmentation. Melanocytes may also be severely damaged by various physical, chemical, thermal, and other pathologic injuries (Table 15-7). Hypopigmentation may be temporary or permanent. Repigmentation may occur rapidly on sun-exposed sites and in less severely damaged areas. The repigmentation is irregular and often shows a mottled pattern. Total destruction of melanocytes in burns, exposure to certain chemicals, infectious diseases such as pinta or onchocerciasis, discoid lupus erythematosus, scleroderma, halo nevi, and so on may leave a permanent leukoderma.

Table 15-7 Physical Leukoderma (Depigmentation)

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes conditions with detectable basilar melanocytes and those with absence of epidermal melanocytes. The former include early or trichrome vitiligo, tuberous sclerosis, hypomelanosis of Ito, nevus depigmentosis, leukoderma secondary to infectious processes (tinea versicolor, leprosy, syphilis), and pityriasis alba. The latter include established vitiligo, piebaldism, and other forms of secondary depigmentation. Diagnosis is predicated on confirming a relationship to an antecedent dermatosis, chemical exposure, or trauma; exclusion of an infectious agent; and clinical features.

Nevus Anemicus Nevus anemicus is characterized by a congenital white patch with an irregular

345

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

border and is found most commonly on the trunk, particularly the chest.72,73 Familial cases have been reported.74 Rubbing the border makes the normal skin erythematous while the lesion remains white. It is a vascular malformation in which the abnormality of the involved vessels is functional rather than anatomic.75 The abnormality seems to be a focal hypersensitivity of blood vessels to catecholamines, possibly mediated by an abnormality in endothelial adhesion molecule induction (E selectin expression),76 resulting in vasoconstriction. The intralesional injection of an α-adrenergic blocker, unlike the intralesional injection of vasodilators such as histamine and acetylcholine,76 may induce erythema. Nevus anemicus may be linked with certain genodermatoses, including neurofibromatosis and phakomatosis pigmentovascularis.77 HISTOPATHOLOGIC FEATURES Epidermal melanocytes and dermal blood vessels are normal in number and size. Other dermal components are likewise normal.

HYPERPIGMENTATION DISORDERS In this group of diseases, the epidermal melanocytes manifest an increase in function, in number, or both; accordingly, the epidermis is hypermelanized, and excess pigment is present in the upper dermis either in an extracellular locale or, after phagocytosis, in the cytoplasms of macrophages (melanophages). Vacuolar degeneration of basal cells releases melanin granules into the upper dermis to cause hyperpigmentation, particularly in darkskinned individuals (Fig. 15-8). Disorders of hyperpigmentation thus may be classified histologically according to the predominant pattern as epidermal, dermal (pigment incontinence), or mixed epidermal and dermal. The predominant location of the excess melanin correlates with the color of the hyperpigmentation: brown (epidermal), blue-gray (dermal), and brown-gray (mixed epidermal and dermal). Attempting to classify these disorders is often of limited use because many patients have varying degrees of both epidermal and dermal hyperpigmentation. These disorders are also classified by clinical distribution as generalized or diffuse and patterned or circumscribed.

Generalized or Diffuse Hyperpigmentations 346

Although the patient is diffusely hyperpigmented in the following conditions,

 FIGURE 15-8 Lupus erythematosus. Vacuolization of the basal cells and incontinence of the released melanin into upper dermis are seen. These melanin granules are tattooed in the dermis semipermanently. A thin epidermis makes these pigment granules more readily visible.

disease-specific, preferential areas of hyperpigmentation may be seen (see Fig. 15-2). Sun-exposed areas are affected more frequently in many of these conditions.

Addison Disease Addison disease is a primary disorder of adrenocortical insufficiency and is recognized in the modern era to be predominantly of autoimmune etiology.78 Patients present with hyperpigmentation that is most pronounced in the sun-exposed areas that normally exhibit dark skin such as the axillae, nipples, genitalia and other skin folds, and oral mucosa (including the tongue). Also present are fatigue; nausea; loss of appetite and weight; low blood sugar and sodium; low blood pressure; and decreased levels of plasma cortisol, adrenocorticotropic hormone (ACTH), urinary 17-hydroxy-corticosteroids (OHCS), and 17-ketosteroids (KS). Formerly, blunted or absent responses of plasma cortisol levels to ACTH stimulation were a mainstay of diagnosis, but autoantibodies targeting steroid 21-hydroxylase causing adrenocortical atrophy or hypofunction79 are now detectable clinically and enable the accurate diagnosis of Addison disease of autoimmune type.80 The infrequent nonautoimmune causes reflect metastatic tumors; bilateral adrenal hemorrhage due to anticoagulant therapy; adrenal gland infarction due to coagulation defects such as seen

in the setting of antiphospholipid antibody syndrome81 or factor V Leiden82 infections such as histoplasmosis, tuberculosis, or cytomegalovirus infections83; and infiltrative disorders such as sarcoidosis or amyloidosis.84 The mechanism of hyperpigmentation is thought to be related to the elevated ACTH secretion, which is accompanied by the byproducts α- and β-melanocyte-stimulating hormone (MSH), which stimulate melanin synthesis.85,86 HISTOPATHOLOGIC FEATURES The number of melanocytes is normal, but their activity is increased, resulting in heavily melanized cells in the basal layer and stratum spinosum, often associated with pigment incontinence. DIFFERENTIAL DIAGNOSIS This pattern of increased epidermal melanin with some degree of pigment incontinence is entirely nonspecific and may be associated with a wide variety of etiologies. Some examples include Graves disease, malnutrition, hemochromatosis (especially early), argyria, arsenic ingestion, use of drugs with photosensitizing characteristics such as amiodarone and minocyclin, and use of psychotropic and chemotherapeutic agents.87

Nelson Syndrome CLINICAL FEATURES Nelson syndrome reflects an ACTH-producing pituitary

without incontinence of melanin to the upper dermis is responsible for the pigmentation: porphyria cutanea tarda, dermatomyositis, progressive systemic sclerosis, Whipple intestinal lipodystrophy, primary biliary cirrhosis, vitamin B12 deficiency, and folate deficiency.

HISTOPATHOLOGIC FEATURES Increased melanin production by a normal population of basal melanocytes is observed.

1. Dyschromatosis symmetrica (DohiKoyama), acropigmentatio symmetrica (Dohi), leucopathia punctaa ta et reticularis symmetrica (Matsumoto).100 The dorsal hands, feet, and extensor surfaces of the forearms and lower legs manifest punctate or reticulated hyper- and hypopigmentation. Distal lesions are more prominent than proximal ones, and the face is freckled. Because some patients manifest photosensitivity, some authors believe that these are forme frustes of xeroderma pigmentosum. Inheritance is autosomal dominant. Dyschromatosis symmetrica is characterized by mutations of either the double-stranded RNA-specific adenosine deaminase gene (ADAR1 or DSRAD) on chromosome 1q21.3 or an as yet uncharacterized locus on chromosome 6.101

POEMS or Crow-Fukase Syndrome CLINICAL FEATURES POEMS is an acronym for polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. In this syndrome, an M protein–producing plasma cell dyscrasia is present. The clinical picture is more broad and more pleomorphic than the acronym suggests.93 For example, patients may manifest sclerotic bone lesions, Castleman disease, papilledema,94 or high-output cardiac failure, perhaps related to high levels of VEGF in the serum.95,96 The skin manifests pigmentation that is diffuse or more prominent on the extensor surfaces of the arms, neck, and back. The hyperpigmentation may be the result of the deposition of neoplastic plasma cell products in the skin; findings of a superficial and deep lymphoplasmacytic perivascular infiltrate without demonstrable kappa or lambda light chain restriction have been reported.94 Also seen are vasculitis,97 scleroderma-like fibrosing dermopathy,98 plethora, leukonychia94 and Raynaud phenomenon.98,99 In addition to the pigmentary anomaly and scleroderma-like skin thickening, hypertrichosis and glomeruloid or cherry-type angiomas are nearly constant, albeit not pathognomonic, findings.91,98,99 Treatment of the plasmacytoma may decrease the hyperpigmentation.

OTHER CONDITIONS Generalized or diffuse hypermelanosis may occur in individuals with the disorders listed below and in those with other conditions. In the following disorders, hypermelanosis of the epidermis with or

Acromelanosis A number of different names are applied to similar dyschromic conditions that are rare or variable in their presentations and are characterized by a hyper- or hypopigmented epidermis showing increased or decreased melanocyte activity with variable basal layer melanization and pigment incontinence.105

universalis 2. Dyschromatosis hereditaria (Toyama-IchikawaHiraga). 100,102,103 In this variant, the lesions are generalized. Sharply demarcated brown macules occur on hypopigmented skin. It has been suggested that this entity is clinically and genetically distinct from dyschromatosis symmetrica. In contrast to dyschromatosis symmetrica, dyschromatosis universalis hereditaria demonstrates normal numbers of activated melanocytes containing decreased amounts of fully melanized melanosomes and may be autosomally recessively inherited.104 3. Diffuse acromelanosis.100,102,103 Diffuse and not reticular pigmentation of the fingers is seen in children from deeply pigmented ethnic groups. Pigmentation may extend proximally as the patient ages. 4. ANOTHER syndrome. This acronym designates alopecia, nail dystrophy,

ophthalmic complications, thyroid dysfunction, hypohidrosis, ephelides and enteropathy, and respiratory tract infection.106,107 Reticulated hyperpigmentation appears during infancy, often on the trunk and the hands and feet, including the palms and soles. Mild basal cell hyperpigmentation and pigment incontinence in the upper dermis are seen.

Circumscribed or Patterned Hypermelanosis In this group of hyperpigmentation disorders, patterned or special regional increases in skin pigmentation occur (Table 15-8). The pigmentation is often reticulated, punctate, or spotty. 1. Zosteriform hyperpigmentation. Lentiginous, cribriform, or macular hyperpigmented lesions are present at birth or develop in the second to fourth decades of life. The pattern of pigmentation is dermatomal or zosteriform on various parts of the body. Histopathologic features range from increased basal layer pigmentation with absent melanocytic hyperplasia to a morphology in which variable keratinocytic pigmentation is accompanied by collections of nevus cells at the tips of rete ridges. Dermal melanophages may be present.108-110 Recently, it has been suggested that zosteriform hyperpigmentation exists on the same spectrum of disease as linear and whorled nevoid hypermelanosis.111

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

adenoma, as is seen in 10% to 47% of patients with Cushing syndrome who have undergone adrenalectomies.88,89 By the same feedback inhibition mechanism as the one that is in play in Addison disease, β-MSH and ACTH are increased concomitant to pituitary hyperplasia or the development of an adenoma. Because the pituitary neoplasm may be slow growing and because tumor volume and plasma ACTH levels correlate, it may take decades for symptoms to occur after adrenalectomy.90,91 Hyperpigmentation is similar to that in Addison disease and consists of generalized darkening of the skin and hair. In addition, multiple lentigines and pigmented bands involving the nails may be seen.92

2. Inherited patterned lentiginosis. Multiple small, pigmented spots are scattered mainly on sun-exposed areas such as the face and outer arms but also on the buttocks and sometimes the palmoplantar surfaces of persons of African origin.112 The onset is in infancy or early childhood, and transmission is in an autosomal dominant fashion. Lightcolored siblings tend to develop this anomaly. Prominent hyperpigmentation of the lower epidermis, particularly the basal layer, and effaced rete ridges are observed. 3. LEOPARD, Moynahan’s, or multiple lentigines syndrome. This is an autosomal dominant disease typified by multiple lentigines affecting any part of the body from the scalp to the feet. Most cases are associated with mutations of protein-tyrosine phosphatase, nonreceptor type 11 (PTPN11).113-115 In addition to

347

Table 15-8 Circumscribed Hypermelanosis

Sunlight responsive, 1–3-mm macules Light to medium brown

Normal

Reduced, normal, increased

Persistent 1–5-mm macule. Light to dark brown Sun-exposed skin, 5–15-mm macules Medium to brown 2–5-cm oval macule, uniform tan to dark brown

Elongated, club-shaped epidermal rete ridges Elongated, club-shaped rete ridges, often anastomosing Normal

Increased

Patterned macular pigmentation on face Macular or raised lesion, a few to several cm Tan to dark brown, often hairy

Normal

Freckle

Lentigo

Café-au-lait macule

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

BASILAR MELANOCYTES

CLINICAL FEATURES

Solar lentigo

348

EPIDERMAL CONFIGURATION

DISORDER

Melasma Becker melanosis

lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation, and deafness are present; because of these associated abnormalities, the disorder is also called LEOPARD syndrome.116,117 Elongation of rete ridges, increased melanocytes, and increased melanization of the epidermis are noted. On electron microscopy, giant melanosomes and complex melanosomes are seen. 4. Peutz-Jeghers syndrome. In this autosomal dominant disorder associated with mutations of the serine threonine kinase gene STK11/ LKB1,118,119 patients have small, irregularly contoured macules localized to the oral mucosa, lips, perioral skin, and dorsal skin of the fingers.120-122 In the majority of cases, multiple polyps develop in the small intestines that may become malignant in 2% to 3% of patients. The basal cells are heavily pigmented, but there is no increase in the number of melanocytes with special stains. There may be some disturbance of pigment transfer to basal keratinocytes. 5. Dowling-Degos disease or reticulate pigmented dermatosis of the flexures. This is a dominantly inherited condition that manifests slowly spreading areas of reticular hyperpigmentation involving flexural or frictional surfaces such as the axillae;

Elongated rete ridges to papillomatous

OTHER FEATURES Melanocytes larger with increased development of dendrites

Normal or increased

Normal or slightly increased Normal or slightly increased Normal or slightly increased

neck; groin; and in women, inframammary folds.123,124 Rare generalized forms have been reported.125 Perioral comedo-like follicular keratosis and pitted scars may be present. The distribution of hyperpigmentation is similar to that in acanthosis nigricans, but the lesions manifest a velvety texture. The age of onset is usually in the third and fourth decades of life. Haber syndrome consists of rosacea-like facial erythema and telangiectasia associated with black keratotic papules of the axillae, neck, and occasionally trunk; it may be the same as Dowling-Degos disease.126 Dowling-Degos disease and Haber syndrome both manifest elongated, tapered, heavily melanized retia with small horn cysts or follicular plugs (Fig. 15-9), generating an appearance similar to adenoid seborrheic keratosis. 6. Naegli-Franceschetti-Jadassohn syndrome. This is a rare autosomal dominant disease of childhood onset in which punctate pigmentation involves the axillae, neck, and trunk.100 Mutations of KRT14 may render keratinocytes more susceptible to TNF-α–induced apoptosis.127 Hypohidrosis, palmoplantar hyperkeratosis, and abnormalities of the teeth and nails may be present. Increased epidermal melanization and melanophages in the upper dermis may be detected.

Association with neurofibromatosis, melanin macroglobules Pigment incontinence may be prominent Smooth muscle hamartoma in dermis often

7. Dermatopathia pigmentosa reticularis. This is a heterogeneous autosomal dominant disease. A constant finding is reticulated pigmentation over the trunk and extremities. Loss of the fingernails and toenails; hypohidrosis; and atrophy of the skin of the elbows, knees, and extremities may occur.128 8. Cantu syndrome. This is an autosomal dominant disorder characterized by hypertrichosis, osteodysplasia, and cardiomegaly with onset in adolescence. Small punctate, hyperpigmented macules that often have a reticular pattern involve the face, forearms, and feet. Hyperkeratosis of the palms and soles may be associated with the disorder.129,130 neurodysraphic 9. Centrofacial lentiginosis. This is also an autosomal dominant disease characterized by centrofacial lentigines without mucous membrane involvement.131 No lentigines are present in areas other than the face. Associated abnormalities include seizures, mental retardation, psychiatric disorders, endocrine disorders, and bone abnormalities. Lentigines regress over time. 10. Carney syndrome. This is also called lentiginosis with cardiocutaneous myxomas or NAME (nevi, atrial myxoma, myxoid neuroma, and ephelides) syndrome. This autosomal dominant syndrome is caused by inactivating mutations in

 FIGURE 15-9 Dowling-Degos disease. Irregularly elongated, slender rete ridges are heavily pigmented. A few keratin cysts and keratin plugs are present.

the PRKAR1A gene coding for the cyclic AMP–dependent protein kinase A regulatory subunit type 1A.132,133 Mucous membrane lentiginosis and associated cardiac (classically with cardiac myxomas) and endocrine abnormalities may be present.134,135 11. Generalized lentiginosis. In this disorder, patients have many lentigines that appear at birth in a generalized dense distribution yet sparing mucous membranes and without associated abnormalities.136

Incontinentia Pigmenti (Bloch-Sulzberger Syndrome) Incontinentia pigmenti is a multisystem polydysplasia with prominent cutaneous findings accompanied by variable anomalies of dental, CNS, and eye development.137 This is mainly an X-linked dominant disorder that is usually lethal in hemizygous males. Survival of affected males has been attributed to the presence of hypomorphic alleles, postzygotic somatic mosaicism of the NEMO gene, or the 47 XXY karyotype (Klinefelter syndrome).138,139 Mutations in the NF-κB essential modulator (NEMO/IKKγ) gene mapped to chromosome Xq28 account for 85% of cases.140 Mutations of the NEMO gene are also responsible for an allelic X-linked disorder, hypohidrotic ectodermal dysplasia with severe immunodeficiency syndrome. 141,142 When

activated, NF-κB controls the expression of multiple genes, including a variety of cytokines, and protects against apoptosis.137 It is postulated that NF-κB stimulation in IKKγ-positive cells results in the elaboration of cytokines inclusive of RANTES and eotaxin that provoke tissue and peripheral blood eosinophilia. Recent studies have shown that the expression of eotaxin in the epidermis parallels the accumulation of eosinophils.143 The variable expressions and severity of disease are explained by X inactivation (Lyon hypothesis) in females. For example, if the affected allele is inactivated, amelioration of the disease may occur and produce subtle cutaneous and dental findings. The alternate extreme generates debilitating CNS and ophthalmologic anomalies.137 In consequence of mosaicism, some affected patients may manifest involvement of one or a few limbs only.137 There are four stages of cutaneous disease, each of which may overlap or be skipped: vesicular, verrucous, hyperpigmented, and atrophic. The vesicular stage is seen in 90% of patients and manifests between birth and 2 weeks of age as erythematous lesions that occur in groups, often distributed along Blaschko lines on the trunk and extremities in 65% of patients and on the extremities alone in 33% of patients.137 These lesions resolve in a few weeks and are followed at age 2 to 6 weeks in about 70% of patients by the second stage of verrucous lesions that

HISTOPATHOLOGIC FEATURES In vesicular lesions, intraepidermal eosinophilic spongiosis with vesicle formation, intraepidermal eosinophilic microabscesses, and dyskeratosis are seen. In the verrucous stage, skin biopsies show hyperkeratosis and acanthosis with papillomatosis and cytoid bodies. In the lesions of whorled or linear hyperpigmentation, the most prominent alterations are vacuolar basilar keratinocytic degeneration and pigment incontinence. The atrophic latestage lesions manifest epidermal atrophy with attenuation of the retiform pattern and atrophy of adnexal structures with loss of the eccrine straight ducts and secretory coil. Basilar melanocytes are functionally normal but markedly reduced in number. DIFFERENTIAL DIAGNOSIS Clinicopathologic correlation greatly augments the diagnosis of incontinentia pigmenti, with no other pathologic condition showing the classic constellation of lesions and their characteristic progression through the aforementioned recognizable stages. With respect to the early stage, immunobullous diseases such as bullous pemphigoid or dermatitis herpetiformis may generate eosinophilic spongiosis and dyskeratosis but are easily separable based on direct immunofluorescence findings. The hyperpigmented lesions show nonspecific pigment incontinence indistinguishable histologically from other forms of predominantly dermal postinflammatory hyperpigmentation. However, on occasion, the concomitant features of eosinophilic spongiosis or a whorled pattern of dyskeratosis may be observed. Linear and whorled nevoid hypermelanosis may be similar clinically but lacks

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

follow the previous vesicular lesions and particularly affect the extremities. These verrucous lesions subside in 80% of affected patients by 6 months of age, and as they subside, they yield whorled hyperpigmentation in areas that correspond to the previous verrucous lesions (ie, in Blaschko pattern). The late stage is seen in teens and young adults who exhibit atrophic lesions with hypo- or depigmentation on the extremities. These stages may coexist at any given time in any given patient or, alternatively, may not occur at all. Alopecia of the vertex, sometimes accompanied by agenesis of eyebrows and eyelashes, nail dystrophy (≤40% of patients), dental defects (≤80% of patients), eye findings (cataracts, blindness), and CNS abnormalities (seizures, mental retardation) are common disease manifestations.137

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pigment incontinence, the clinical hyperpigmentation reflecting basilar keratinocyte pigmentation.137

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Dyskeratosis Congenita Dyskeratosis congenita is a heredofamilial bone marrow failure syndrome associated with increased cancer susceptibility.144,145 Most often transmitted as an X-linked recessive trait affecting males, dyskeratosis congenita is caused by mutations of the DKC1 gene that maps to Xq28 and encodes for dyskerin, a protein held to play a role in ribosomal biogenesis. Cell lines with this mutation manifest markedly increased apoptosis with increasing cell division, thus explaining the worsening severity of disease expression after age 10 years.146 Other mutations associated with telomerase enzyme deficiency and progressive telomerase shortening have been described in TERC, TERT, NOP10, and TINF2 telomerase enzyme deficiency and progressive telomere shortening.147 Occasionally, an autosomal dominant mode of inheritance has been observed, with females also being affected. The clinical triad is pterygium-like nail dystrophy, leukoplakia of the oral and occasionally the anal mucosa, and extensive reticulated hyperpigmentation. Leukoplakia may degenerate into squamous cell carcinoma. The hair is thin and lusterless in approximately 50% of patients. The same genetic anomaly is implicated in some cases of idiopathic pulmonary fibrosis. HISTOPATHOLOGIC FEATURES Patients have increased basal layer melanization with slightly increased melanocytes and pigment incontinence. Oral leukoplakia may show in situ or invasive squamous cell carcinoma.

Melasma or Chloasma

350

Melasma is observed most commonly on the faces of dark-skinned women living in tropical or subtropical locations where UV irradiation is intense. Increased estrogen and progesterone levels seem to be causative in susceptible women; pregnancy, contraceptive use, estrogen replacement therapy, and ovarian tumors are often linked to the onset. The face is symmetrically involved in one of three patterns: a centrofacial pattern involving the forehead, nose, cheeks, upper lip, and chin; a malar pattern; and a mandibular pattern. The hyperpigmentation may be predominantly epidermal and consequently brown, dermal and therefore bluish, or both epidermal and dermal and thus both brown and blue.148

HISTOPATHOLOGIC FEATURES Epidermal melanocytes are usually slightly increased in number and activity. Corresponding to the clinical patterns, increased melanin may be localized primarily to the epidermis, upper dermis, or both. Immunostains highlight enlarged, intensely stained melanocytes with prominent dendritic processes. Melanocytes may demonstrate increased numbers of melanosomes on electron microscopy.149 DIFFERENTIAL DIAGNOSIS The major entities to be considered include postinflammatory hyperpigmentation, café-au-lait macules (CALMs), and lentigo. Melasma may be histologically indistinguishable from postinflammatory hyperpigmentation, but the clinical presentation should readily allow its discrimination.

Ephelides or Freckles Freckles, or ephelides, are light-brown macules that predominantly affect lightskinned individuals and occur on sunexposed areas, particularly the face, upper back, shoulders, and dorsa of the hands and forearms. Fair-skinned individuals are more often affected; in northern Sweden, the prevalence among children of ages 12 to 16 years is 18.4%.150 Only occasionally are freckles seen in persons with dark complexions. Lesions are typically less than 2 mm in diameter and almost always smaller than 4 mm in diameter. The borders may be irregular, but pigmentation is uniform, becoming more obvious after sun exposure and less conspicuous during the winter months.151 Lesions often first appear during childhood and tend to persist into adulthood. Freckles may manifest an autosomal dominant pattern of inheritance, appearing in sequential generations.152 Freckles may become clinically inapparent in elderly individuals but even then are be identifiable under Wood’s lamp examination.153 HISTOPATHOLOGIC FEATURES A freckle reflects increased melanization of the epidermis attributed to increased melanin production that manifests as hyperpigmentation of basal layer keratinocytes unaccompanied by elongated retia, adnexal involvement, or increased numbers of melanocytes. Indeed, melanocytes may even be decreased in number relative to uninvolved skin.152 With silver preparations, dendritic melanocytes may be identified, a finding associated with photoadaptive effects. Melanization of the basal layer occurs because of larger and more active melanocytes that produce stage IV

melanosomes, even in fair-skinned individuals. Melanophages may be present in the papillary dermis. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes café-au-lait spots, melanotic macules of Albright, lentigo simplex, and actinic lentigo. In contrast to freckles, the café-au-lait spots manifest giant melanosomes and a normal or slightly increased number of melanocytes. Melanotic macules of Albright and lesions of melasma may be indistinguishable from freckles.153 Lentigo simplex shows elongated retia with variable melanocytic hyperplasia. Other conditions may produce a histomorphology indistinguishable from that of freckles but are associated with a distinctly different clinical appearance, namely, reticulate pigmentation of the neck,154 reticulate pigmentary anomaly of the flexures (Dowling-Degos disease),155 and reticulate acropigmentation of Kitamura,156 with which it overlaps,157 and the Naegli-FranschettiJaddasohn syndrome, which combines reticulate pigmentation of the trunk and limbs with anomalies of eccrine and nail structures.154,158 Solar lentigo differs from freckles by also showing elongated and hypermelanotic club-shaped retia; melanocytes may be normal in number or may present in up to twice the density of non–sun-exposed skin.

Café-Au-Lait Spots and Axillary Freckling Café-au-lait macules (CALMs) are one of the hallmarks of NF1 or von Recklinghausen multiple neurofibromatosis, being seen in 90% of patients.159,160 NF1 is associated with mutation in the NF1 gene, resulting in abnormal expression of neurofibromin, an inhibitor of the Ras growth-promoting pathway.161 The light tan color of CALMs is only apparent in light skin; in individuals with dark complexions, the color is much darker. CALMs are not influenced by UV rays and are most common on the covered areas of the body. If an individual has six CALMs of 1.5 cm or larger, the development or presence of NFl is 100% certain. Axillary, inguinal, and inframammary freckles are not darkened by sun exposure and are different from facial freckles both clinically and histologically. Axillary or inguinal freckles are observed in 8l% of affected children younger than age 6 years and often precede the appearance of neurofibromas. HISTOPATHOLOGIC FEATURES The epidermis is of normal thickness and exhibits basal layer hyperpigmentation. Although the

number of basilar melanocytes appears normal, an increased number and activity of melanocytes can be demonstrated with special stains. By light or electron microscopy, giant melanosomes up to 5 μm in diameter are seen in these melanocytes but are said to be absent in the lesions of children and are also found in melanotic macules of McCuneAlbright syndrome, lentigo simplex, melanocytic nevi, multiple lentiginosis, Chediak-Higashi syndrome, and other conditions.

Macules of McCune-Albright Syndrome Albright syndrome manifests as polyostotic fibrous dysplasia, melanotic macules, and hyperfunctional endocrinopathies that typically eventuate in precocious puberty. It mainly occurs in females. The clinical expression of the syndrome is attributed to sporadic postzygotic mutations of the GNAS1 gene that encodes the α subunit of a signal-transducing guanine nucleotidebinding (G) protein and the mosaic distribution of cells that express the mutant allele.162-164 The G proteins couple hormone receptors to the enzyme adenylate cyclase, the distribution of which includes renal proximal tubules, to generate parathyroid hormone resistance. Mutations in the paternal allele are only rarely expressed clinically.165,166 Patients harbor a sporadic mutation that also results in activation of the tyrosinase gene that is the pathophysiologic basis of skin pigmentation.164 Due to mosaicism, the pigment distribution follows Blaschko lines,167,168 occasionally resulting in a pigmented rectangular pattern. Lesions are usually unilateral and typically involve the head and neck region, buttocks, sacrum, and nuchal area, manifesting irregular borders that have been compared with the coastline of Maine. In contrast, the CALMs of neurofibromatosis are more generalized and generally have smooth or rounded borders reminiscent of the coastline of California, although they too can have a “shaggy” contour, and in fact, this criterion is not reliable.169 Solitary or multiple CALMs are seen in roughly two-thirds of patients with Albright syndrome.169,170 The pigmentation in lesions of Albright syndrome is usually darker, and the lesions are

HISTOPATHOLOGIC FEATURES The basal layer of the epidermis is hyperpigmented. The melanocytes are not increased in number but contain giant or macromelanosomes. DIFFERENTIAL DIAGNOSIS The considerations are similar to those of CALMs.

Becker Pigmented Hairy Nevus or Melanosis CLINICAL FEATURES Becker nevus is an acquired lesion that appears in childhood or early adolescence and is believed by most authorities to be a cutaneous hamartoma.171-178 Becker nevus is also termed pigmented hairy epidermal nevus because the presence in some examples of epidermal hyperplasia can make distinction from an epidermal nevus problematic. The term Becker nevus syndrome is applied to the combination of a Becker nevus with developmental defects such as ipsilateral hypoplasia of the breast or limb or skeletal anomalies such as scoliosis, limb asymmetry, or spina bifida occulta.173,179 Becker nevus has a predilection for males and rarely may be familial, with a presumed autosomal dominant pattern of inheritance, although loss of heterozygosity resulting in mosaicim has also been proposed.173,179 Becker nevus

presents as an area of pigmentation up to 20 cm in diameter, sometimes with hypertrichosis that may be associated with a smooth muscle hamartoma; follicular papules, slight induration, and occasionally pain are then observed. A lymphangioma174 or a connective tissue nevus175 may rarely coexist. Because it is not a primary proliferative disorder of melanocytes,176 individuals with Becker nevus are not at increased risk for the development of melanoma. HISTOPATHOLOGIC FEATURES The epidermal changes vary from almost normal to showing acanthosis, papillomatosis, elongation of rete ridges, and hyperpigmentation of the basal layer. Melanocytes may be slightly increased in number in the epidermis. Becker pigmented hairy nevus therefore refers to the hamartomatous combination of hair follicles, increased melanocytes, and smooth muscle. Dermal melanophages are often present. Hair follicles are usually normal but on occasion may be increased in number and enlarged. Increased bundles of smooth muscle are usually present in the reticular dermis177 (Fig. 15-10). Sebaceous gland hyperplasia and thickening of dermal connective tissue may occur. DIFFERENTIAL DIAGNOSIS Becker nevus must be distinguished from an epidermal nevus; a large or congenital lentigo; and other papillomatous lesions, such as confluent and reticulated papillomatosis (of Gougerot-Carteaud) on occasion.

 FIGURE 15-10 Becker nevus. Hypermelanosis of the basal layer and an increased number of arrector pili muscles are seen. Often, as in this case, there is epidermal acanthosis with a papillomatous or mammilated surface cognate to an epidermal nevus.

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

DIFFERENTIAL DIAGNOSIS CALMs cannot be discriminated histologically from melanotic macules of Albright syndrome and may mimic freckles or melasmas. CALMs do not exhibit the elongated epidermal rete ridges and increased numbers of melanocytes observed in simple lentigo.

often larger.167 Distribution along Blaschko lines is not said to be a feature of neurofibromatosis.167

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The clinical finding of a unilateral hyperpigmented and often a hairy patch or plaque and of a smooth muscle hamartoma histologically should facilitate discrimination from the other entities.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Prurigo Pigmentosa Prurigo pigmentosa is a rare idiopathic dermatosis consisting of recurrent erythematous papules and reticulate hyperpigmentation most commonly seen in Japanese women in the second and third decades of life.180,181 Cases have been reported in Turkish, Iranian, and Sicilian women as well.182,183 The eruption begins acutely with erythematous papules that become confluent to form intensely pruritic linear or anastomosing elevated lesions; vesicular or exudative papular lesions are described in the initial acute stage. The upper back, shoulders, neck, and chest are common sites of involvement. A familial basis has been reported. Potential etiologic factors include diabetes mellitus, bacterial infection,184 friction with underwear, and contact with cosmetic and antiseptic agents.185 Treatment with minocycline has produced good results.186,187 HISTOPATHOLOGIC FEATURES The early inflammatory stage manifests an interface dermatitis with vacuolization of basal cells, cytoid body formation, exocytosis of lymphocytes, and spongiosis. Pigment incontinence is noted in the older pigmented lesions. DIFFERENTIAL DIAGNOSIS The histologic findings are nonspecific and indistinguishable from other forms of postinflammatory hyperpigmentation that follow an interface dermatitis.

Postinflammatory Hyperpigmentation

352

Damage to basal keratinocytes from multiple sources may result in pigment incontinence in the upper dermis. Interface injury may be a stimulus for melanocytes to produce melanin and to thus generate epidermal hypermelanization (Table 15-9). Another theoretical mechanism is the result of the epidermal inflammatory response producing proinflammatory mediators that stimulate melanosome transfer from their dendrites into dermal melanophages. 188 Melanin polymers may act as an antioxidant; it is possible that epidermal melanocytes may actively transfer melanosomes to the dermal foci of

Table 15-9 Postinflammatory Hypermelanosis

Clinical Features Usually follows inflammatory process Localized or widespread Common dermatoses include lichen planus, lupus erythematosus, eczematous dermatitis, psoriasis, phytophotodermatitis, drug eruptions Gradual loss of pigmentation but may be permanent Histopathologic Features Variable degrees of 1. Epidermal hypermelanosis 2. Pigment incontinence Differential Diagnosis Melasma Endocrine dysfunction Addison disease Malnutrition

inflammation. Dark-skinned individuals are prone to more florid changes because their melanocytes are easily stimulated to produce more melanin granules; the discoloration may be permanent. Causative dermatoses include lichen planus, lichenoid drug eruption, discoid lupus erythematosus (see Fig. 15-8), dermatomyositis, Riehl melanosis, notalgia paresthetica, and mycosis fungoides. In fixed drug eruption and erythema dyschromicum perstans (“ashy dermatosis”), repeated episodes of interface dermatitis eventuate in a gray-blue dyspigmentation as the incontinent melanin accumulates in large amounts in a deeper location in the dermis. Trauma or chronic irritation may also cause postinflammatory hyperpigmentation. HISTOPATHOLOGIC FEATURES Variable epidermal inflammatory changes, such as interface dermatitis, are often visible in early lesions together with melanin deposition in the upper dermis, either free or in melanophages. Epidermal melaninization may be increased. Long-standing lesions typically show pigment incontinence without active inflammation. DIFFERENTIAL DIAGNOSIS The pigmentary alteration alone is entirely nonspecific; an etiologic diagnosis depends on identification of the antecedent inciting injury. Clinical correlation should exclude other causes such as regression of a pigmented lesion.

Friction Melanosis (Nylon Towel Melanosis) Ill-defined, light-brown hyperpigmentation may occur over the bony prominences such as the clavicle, shoulder blades, frontal neck, Adam’s apple, and shins due to repeated rubbing by nylon towels or scrub brushes189,190 or from vigorous rubbing with nonsynthetic fabrics.191 Over the nonbony areas, pigmentation occurs in a rippled pattern similar to that of macular amyloidosis. Early reports described patients who used more durable nylon towels or brushes for a long time that replaced traditional cotton towels or plant-fiber brushes in postwar Japan; similar changes have been described subsequently in Italian patients using horse-hair brushes and cotton towels.190 It is believed that chronic frictional trauma of thin skin over the hard bony structures causes epidermal damage and subsequent pigment incontinence. The mechanism seems to be similar to that involved in lichen amyloidosis, in which tonofilaments of damaged keratinocytes are transformed into amyloid filaments.192,193 HISTOPATHOLOGIC FEATURES Skin biopsies show epidermal atrophy, pigment incontinence, and basal cell vacuolization leading to dermal–epidermal cleavage in severe cases. Amyloid deposits are rarely demonstrated.190,191

Generalized Melanosis in Metastatic Melanoma Widespread metastasis of melanoma may produce generalized melanosis and melaninuria; slate-blue diffuse discoloration of the skin, mucous membranes, and conjunctivae may occur.194 The exact pathogenesis of generalized melanosis remains unclear; tumor-derived factors seem to drive the hyperproliferation of normal melanocytes.195 Neutrophils and monocytes in the circulation may contain melanin, and the intima of arteries and many visceral organs are black. HISTOPATHOLOGIC FEATURES Perivascular melanophages contain melanin granules that are often DOPA positive, indicating that melanin synthesis is still active in the phagocytosed melanosomes, which most likely are derived from bloodborne melanoma cells carried to the skin. The dermal blood vessels may be occluded with DOPA-positive pigment granules. In some cases, only melanophages are present; in other cases, both melanoma cells and melanophages are admixed in the dermis.

Table 15-10 Metal Deposition and Dyspigmentation DISORDER

EPIDERMAL HYPERMELANOSIS

DERMAL ALTERATION

Hemochromatosis Argyria (silver deposition) Chrysiasis (gold deposition) Mercury

Present Present, sun-exposed skin May be present

Arsenic Lead Bismuth

Present

Hemosiderin Silver particles, basement membranes of sweat glands, elastic fibers Gold particles in macrophages and endothelium Brown-black mercury granules either free or in macrophages Arsenic particles Lead particles Bismuth granules in papillary and reticular dermis

May be present

Miscellaneous pigmented substances may deposit in the skin and produce various discolorations (Tables 15-10 and 15-11).

Ochronosis Endogenous ochronosis is an autosomal recessive disease of homogentisic acid oxidase deficiency.196-198 A slow accumulation of homogentisic acid, which is an intermediate product of metabolism of phenylalanine to tyrosine, causes pigmentation of cartilages and eventually the skin. An affected child’s urine, if

exposed to the air or an alkylizing agent for a few hours, turns pink to brown (alkaptonuria), and staining of the diaper is the first sign of the disease in 50% of cases.199-202 Cutaneous signs usually do not develop until 30 years of age.199 This is a rare disease in the United States (one in 250,000) but is more frequent in the Dominican and the Czech Republics (one in 25,000). Because the cartilage of the ear is covered with thin skin, a bluish gray to dark brown color is readily noticed. A butterfly pattern of pigmentation of the face, including the nose, may suggest photosensitivity. Axillary sweat may be variously colored from greenish blue to greenish yellow-

Refractile granules on dark-field examination Refractile granules on dark-field microscopy

brown. The sclera and teeth may also be pigmented. Alkaptonuria is diagnosed by gas chromatography–mass spectrometry analysis or a colorimetric assay of a 24-hour urine specimen.199 Exogenous ochronosis or pseudoochronosis is caused by the chronic topical use of high-concentration (6%–8%) hydroquinone, resorcinol, phenol, quinine injection, systemic antimalarial therapy, or exposure to benzene.198 In hydroquinone-induced ochronosis, blue-black pigmentation is seen most obviously on prominent parts of the face (ie, the cheeks, forehead, nose, and in some cases, the chin), suggesting photoinduction. The discoloration is usually permanent

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

Pigment Deposits Other Than Melanin

OTHER FINDINGS

Table 15-11 Drug-Related Dyspigmentation DRUG Minocycline 1. Facial, blue-black pigmentation 2. Extremities, bluegray pigmentation

EPIDERMAL HYPERMELANOSIS Usually not present Usually not present

3. Sun-exposed skin, brown pigmentation Antimalarials Chloroquine Quinacrine Amiodarone

Present

Chlofazamine Psychotropic drugs

Present Present

Chemotherapeutic drugs

Present

DERMAL ALTERATION

OTHER FINDINGS

Drug metabolite-protein complex in macrophages that stains for iron but not melanin Drug metabolite-protein complex that stains for iron and is positive by the Fontana reaction but fails to bleach (and thus is not melanin) Melanin, negative iron stain

Drug-melanin complex, hemosiderin Quinacrine Drug metabolite in endothelium, macrophages

Drug metabolite pigment granules in phagolysomes

Melanin, ceroid-like material Drug-metabolite melanin in macrophages, endothelial cells Melanin

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

despite discontinuation of hydroquinone. Annular lesions similar to actinic granuloma may occur.200 It has been proposed that the inhibition of the enzyme homogentisic oxidase is a pathogeneic mechanism shared by both endogenous and exogenous ochronosis.203

tattoos are clinically evident. The usual histologic appearance for the common carbon tattoo is that of a jet-black material rather than the granular brown character of melanin in dermal melanocytic lesions.

HISTOPATHOLOGIC FEATURES The pigment in the dermis is a yellow-brown or ochre color with the H&E stain, hence the designation ochronosis. A blue-gray-brown color is produced by scattering of light from deep-seated ochre-colored pigment (Tindall effect). The pigment is also observed in the endothelial cells of the blood vessels, basement membranes, secretory cells of eccrine glands, and dermal macrophages. However, the most diagnostic form of deposition is the banana-shaped dermal collagen fibers that become swollen, rigid, and fragmented with jagged ends. The same pigment is deposited on elastic fibers, which also degenerate. The epidermis is normally pigmented. Sarcoidal granulomata may occur, as may transepidermal elimination of degenerated collagen.200

Hereditary hemochromatosis is a spectrum of autosomal recessive diseases characterized by hyperabsorption of dietary iron.202,204-207 The five predominant designations are HFE-related or type 1 hemochromatosis, type 2 hemochromatosis (juvenile hemochromatosis), type 3 hemochromatosis (transferrin receptor 2 hemochromatosis), type 4 hemochromatosis (ferroportin disease), and hypoceruloplasminemia.208 The causative gene in type 1 hereditary hemochromatosis is designated HFE; most patients of European origin are homozygous for a cystein to tyrosine residue subsitution204 that likely renders the gene’s protein product incapable of binding to the transferrin receptor, dysregulating the threshold for iron absorption by enterocytes. Clinical penetration is seen in 4% to 25% of homozygotes.205,207 Skin pigmentation, liver cirrhosis, cardiac failure, and diabetes mellitus make up the clinical tetrad.202,204-207 In white skin, discoloration varies from bronze (bronze diabetes) to blue-gray; in pigmented skin, the discoloration is brown to black. Pigmentation is most pronounced in the sun-exposed areas, skin creases and folds, and nipples and often

Tattoos Tattoos may occur secondary to accidental introduction of pigments into the skin, such as the graphite of lead pencils or of carbon in coal miners, but are more commonly a reflection of the deliberate cosmetic injection of dye substances.201 Common dyes injected in professional tattoo parlors are cinnabar or mercuric sulfide (red), chromic oxide (green), cobaltous albuminate (light blue), cadmium sulfide (yellow), and iron oxide or ochre (brown).

Idiopathic Hemochromatosis

precedes other symptoms; this is an important sign because early treatment with phlebotomy and chelating agents improves the prognosis significantly as long as serum ferritin levels are kept at 100 ng/mL or lower. Systemic symptoms in patients with type 1 disease appear only after sufficient iron storage (20 to 60 g), usually between 35 and 60 years of age; in type 2 hemochromatosis, clinical signs of hypogonadism and cardiomyopathy develop before age 30 years.207 HISTOPATHOLOGIC FEATURES In early cases without systemic symptoms, epidermal atrophy and basilar hypermelanosis (but no deposition of hemosiderin) are observed. Hemosiderin deposition is seen later in the cytoplasm of eccrine secretory cells, periglandular connective tissue, and perivascular macrophages. DIFFERENTIAL DIAGNOSIS The golden refractile appearance of hemosiderin and a Prussian blue stain permit separation from melanin and other pigments.

Hemosiderin from Other Sources Any hemorrhage leaves erythrocytes in tissue, and their degradation causes temporary or long-term hemosiderosis. Yellow-brown discoloration follows chronic, repeated bleeding such as in stasis dermatitis, vasculitis, and pigmented purpuric dermatoses. Histopathology is related to the individual conditions. Hemosiderin is seen

HISTOPATHOLOGIC FEATURES After an acute inflammatory reaction, these inert pigments elicit little or no tissue reaction in most cases. Pigments are found scattered in the upper dermis, particularly around blood vessels. Late-stage reactions include dermal contact dermatitis, lichenoid dermatitis, foreign-body reaction with giant cells, and sarcoidal granulomatous reactions (Fig. 15-11). Several patients have developed hilar lymphadenopathy together with sarcoidal reactions at tattoo sites; patients with underlying sarcoidosis manifest exaggerated reactions to injected dyes. Lymphomatoid reactions may be seen with cinnabar tattoos.

354

DIFFERENTIAL DIAGNOSIS The major conditions to be considered include blue nevi and other dermal melanocytoses as well as iron and other metal depositions. Most

 FIGURE 15-11 Tattoo with graphite (pencil). Black pigment particles are scattered from the main body of accidentally inoculated graphite. A granulomatous reaction is seen.

most often in perivascular spaces and is demonstrable with iron stains.

Gold Deposition (Chrysiasis) or Chrysoderma

“Bronze Baby” Syndrome

Prolonged injection of gold salts induces slate-gray to blue discoloration of exposed skin. In such patients, laser treatment of skin conditions may elicit chrysiasis in normal-colored skin.215,216

HISTOPATHOLOGIC FEATURES The nature of the pigment causing skin discoloration has not been elucidated. It may be a photoisomer of bilirubin or photoproducts of copper-bound porphyrins that have been elevated in the serum of some patients.

Silver Deposition (Argyria) Slate-gray pigmentation, particularly on sun-exposed sites and the azure lunula of nails, develops after a prolonged ingestion or application to mucous membranes of silver salts. Absorption from mucous membranes may cause local as well as systemic argyria. Visceral organs accumulate silver and show blue discoloration. Localized argyria may occur as a result of wearing earrings with silver backs, the application of silver sulfadiazine cream for the treatment of burns, after acupuncture, with the use of silver wire for sutures, and after traumatic implantation of silver.211-213 HISTOPATHOLOGIC FEATURES Silver particles that have a dark brown to black granular appearance are scattered extracellularly in the dermis and are concentrated in the basement membranes of eccrine sweat glands, perifollicular sheath, nerves, capillary walls, and elastic fibers. Silver particles are best demonstrated by polarized light microscopy as refractile particles; silver sulfide deposits may be evident by electron microscopy.214 Silver particles are absent in the epidermis, but hypermelanosis of the epidermis, particularly in exposed areas, is evident. Actinic elastosis of sun-exposed skin also attracts silver particles.

HISTOPATHOLOGIC FEATURES In contrast to silver, gold particles are found in vascular endothelia and dermal phagocytes; polarized light microscopy demonstrates large, refractile particles in those locations. Light seems to intensify the color by making the gold particles larger.

Mercury Mercury-containing cream (ammoniated mercury) was once used extensively by dermatologists to treat bacterial and fungal infections and to bleach hyperpigmented skin.217 The chronic use of such cream caused slate-gray pigmentation that is most pronounced in skin folds of the eyelids, neck, and nasolabial folds. Filling teeth with silver-mercury amalgam also causes tattooing of mercury in the gingiva. Amalgam pigmentation occurs locally near the tooth or at some distance from it. HISTOPATHOLOGIC FEATURES The upper dermis contains small, refractile, brownblack mercury granules, either free or in macrophages. Epidermal melanization is either normal or slightly increased.

HISTOPATHOLOGIC FEATURES Small granules are found in the papillary and reticular dermis.

Titanium A topical cream containing 13.5% titanium dioxide has been applied to erosive herpes simplex lesions of the glans, sulcus, and prepuce, resulting in the development of yellowish lesions at the sites of cream application.220 Titanium dioxide is currently used as a light-scattering agent in some facial moisturizing and sunscreen creams sold over the counter. Pigmentation from these agents has not been reported. HISTOPATHOLOGIC FEATURES Many brown granules are found in the dermis that are brightly refractile by dark-field microscopy and correlate ultrastructurally with granular electron-dense bodies in dermal macrophages and also free in the connective tissue. Energydispersive analysis with x-rays of these dense granules has demonstrated a peak corresponding to the titanium spectrum.

Drug Deposits and Pigmentation

HISTOPATHOLOGIC FEATURES Dermal deposition of arsenic stimulates epidermal melanocytes, and the clinical hyperpigmentation is mainly due to hypermelanosis.

Many systemic and topical medications deposit in the skin and cause discoloration by themselves or by their metabolites and photoproducts.221 Many of these agents simultaneously stimulate melanocytes, and the discolorations observed are thus a combined effect of hypermelanosis and deposition of drugs or drug metabolites. Many of these drugs are photosensitizers or photostimulators, and the hyperpigmentation is a nonspecific postinflammatory phenomenon. In this section, only selected drugs are discussed. Readers are referred to Chapter 12 and to general reviews for a more comprehensive consideration.

Lead

Minocycline

A lead line at the gingival margin and nail pigmentation are associated with lead poisoning.218

Minocycline is notorious for generating skin discoloration, most often a blueblack pigmentation at sites of old acne scars or inflammation, because the antibiotic is used routinely for acne; a typical patient has taken the medication for 1 to 3 years in doses of 100 to 200 mg/day. Bluish macules also develop on previously normal skin of the anterior lower legs, around the eyes, or anywhere else and

Arsenic Diffuse bronze discoloration of the skin, which is prominent on the trunk, may be one of the sequelae of chronic ingestion of inorganic arsenics.217 In less pigmented areas, these pigment spots are described as “raindrops on a dusty road.”

HISTOPATHOLOGIC FEATURES The lead line is caused by submucosal deposition of lead.

Bismuth Generalized blue-gray discoloration resembling argyria has been reported

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

Because blue light effectively oxidizes bilirubin, infants with hyperbilirubinemia (>15 mg/dL) due to various causes, including extrahepatic biliary atresia, are treated with blue light. Within 3 to 4 days after the phototherapy, the patient’s serum, urine, and skin become graybrown-black, and this disappears in about 6 weeks after the discontinuation of treatment. It has been assumed that photodegradation products of bilirubin that are not metabolized properly due to hepatic dysfunction are retained in the skin, leading to the characteristic bronze discoloration. Newer reports indicate that photochemical alterations of high levels of copper porphyrins may be causative.209,210

after prolonged use of oral bismuth.219 A gingival pigment line and oral, conjunctival, and vaginal pigmentations have been reported.

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are accentuated by sun exposure. Generalized gray-brown discoloration (ie, “muddy skin syndrome”) may occur, particularly in exposed areas, the gingiva, the hard palate, the teeth, and the nails. These manifestations occur individually or in combination. HISTOPATHOLOGIC FEATURES Acne scar–associated lesions contain pigmented macrophages that are Prussian blue positive and negative for melanin by the Fontana-Masson stain. Macular lesions on the legs contain pigmented macrophages that are positive for iron and Fontana-Masson stains but fail to bleach with potassium permanganate, indicating that melanin is not present. The generalized muddy skin shows an increased epidermal basal layer melanization and melanophages in the upper dermis but is negative on staining for iron.222,223 A recent case report found pigmented lipomembranous changes in the subcutis of two patients with pretibial minocycline pigmentation.224

Antimalarials Quinacrine produces a diffuse lemonyellow color if taken for a long period, particularly in fair-skinned patients. The yellow color is probably the direct stain of quinacrine itself. Hydroxychloroquine has been reported to cause widespread slate-grey or bluish-grey macular hyperpigmentation.225,226 Chloroquine may cause irregular grayish macules on the shins and diffuse pigmentation of the face. Hard palate and nail discoloration may occur after chronic ingestion. The pigment is found in the dermis as a drug–melanin complex. Hemosiderin is deposited around capillaries.227-229

of continuous medication totaling about 250 g seems to be necessary to cause this discoloration.231 HISTOPATHOLOGIC FEATURES In addition to basilar melanization and melanocyte photoactivation, illustrated in Chapter 12 (see Fig. 12-7), endothelia and dermal macrophages may accumulate pigment demonstrable ultrastructurally in phagolysosomes in the form of lipid membranous structures, likely undigested drug metabolites stored as residual bodies.

Clofazamine Used in the treatment of atypical mycobacterial infection and leprosy, clofazamine may induce a reddish discoloration that represents the color of the drug and occurs in the conjunctivae and skin within four weeks of beginning the medication in 49% to 65% of patients. After two to three months of therapy, the infective lesions and occasionally even normal skin turn a brown or violaceous hue. This color may be due to a combination of epidermal and dermal melanin and a ceroidlike substance in the dermis.232

Psychotropic Drugs Prolonged use of phenothiazine and the tricyclic antidepressant imipramine may cause blue-gray to slate-gray discoloration, mainly in sun-exposed locations. HISTOPATHOLOGIC FEATURES The dark granules associated with chlorpromazine discoloration and scattered golden pigments in imipramine pigmentation are noted in the upper dermis and perivascular spaces (Fig. 15-12). Both melanosomes and electron-dense substances representing drug metabolites are found in dermal macrophages, fibroblasts, vascular endothelial cells, and dermal dendrocytes. The epidermis is hyperpigmented.233,234

Chemotherapeutic Drugs The ingestion of agents such as bleomycin, busulfan, cyclophosphamide, doxorubicin, and 5-fluorouracil or topical application of nitrogen mustard (mechlorethamine) and carmustine (BCNU) may result in diffuse hypermelanosis or, in the case of bleomycin, so-called “flagellate streaks” after long-term ingestion. Sunitinib, a multikinase inhibitor,

Carotinoids Oranges, apricots, carrots, and green vegetables contain carotinoids. Excessive intake of carotinoids causes yellowish discoloration of the palms, soles, and postauricular skin. Synthetic β-carotene is used commonly for photoprotection, as a cancer-preventive drug, and as a “tanning” agent. This tan is not sun protective. Synthetic β-carotene does not produce the same degree of discoloration as natural carotinoids. The pigment is deposited in the subcutaneous fat, skin, and retina.230

Amiodarone

356

Chronic use of amiodarone, an antiarrhythmia drug, may cause a blue-gray discoloration in sun-exposed areas such as the face and hands; at least 20 months

 FIGURE 15-12 Imipramine pigmentation. Yellow granules are scattered in the upper and mid-dermis

has been reported to cause transient yellow discoloration of the skin. Capecitabine is a prodrug of 5-fluorouracil that causes marked hyperpigmentation.235 HISTOPATHOLOGIC FEATURES The epidermis shows increased melanin, usually with some pigment incontinence (see Table 15-11).

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causes Naegeli-Franceschetti-Jadassohn syndrome. J Invest Dermatol. 2008;128(6): 1517-1524. 128. Gablen W: Dermatopathia pigmentosa reticulosa hypohidrotica et atrophica. Dermatol Wochenschr. 1964;34:193. 129. Grange DK, Lorch SM, Cole PL, et al: Cantu syndrome in a woman and her two daughters: further confirmation of autosomal dominant inheritance and review of the cardiac manifestations. Am J Med Genet A. 2006;140(15):16731680. 130. Cantu JM, Sanchez-Corona J, Fragoso R: A new autosomal-dominant genodermatosis characterized by hyperpigmented spots and palmoplantar hyperkeratosis. Clin Genet. 1978;14: 165-168. 131. Touraine A: Une nouvelle neuroectodermose congeniale: La lentiginose centrofaciale et les dysplasie associée. Ann Dermatol Syphiligre (Paris). 1941;8:453. 132. Kirschner LS, Carney JA, Pack SD, et al: Mutations of the gene encoding the protein kinase A type I- regulatory subunit in patients with the Carney complex. Nat Genet. 2000;26:89-92. 133. Horvath A, Bossis I, Giatzakis C, et al: Large deletions of the PRKAR1A gene in Carney complex. Clin Cancer Res. 2008;14(2):388-395. 134. Rees JR, Ross FGM, Keen G: Lentiginosis and left atrial myxoma. Br Heart J. 1973;35:874-876. 135. Atherton DJ, Pitcher DW, Wells RS, MacDonald DM: A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome. Br J Dermatol. 1980; 103:421-429. 136.Uhle P, Norvell SS: Generalized lentiginosis. J Am Acad Dermatol. 1988;18:444-447. 137. Berlin AL, Paller AS, Chan LS: Incontinetia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol. 2002;47:169-187. 138. Fusco F, Fimiani G, Tadini G, et al: Clinical diagnosis of incontinentia pigmenti in a cohort of male patients. J Am Acad Dermatol. 2007;56(2):264-267. 139. Ardelean D, Pope E: Incontinentia pigmenti in boys: a series and review of the literature. Ped Dermatol. 2006;23(6):523527. 140.Smahi A, Courtois G, Rabia SH, et al: The NF-κB signaling pathway in human diseases: From incontinentia pigmenti to ectodermal dysplasia and immunodeficiency syndromes. Hum Mol Genet. 2002;11:2371-2375. 141. Fusco F, Bardaro T, Fimiani G, et al: Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation. Hum Mol Genet. 2004;13(16):1763-1773. 142. Mancini AJ, Lawley LP, Uzel G: Xlinked ectodermal dysplasia with immunodeficiency caused by NEMO mutation: early recognition and diagnosis. Arch Dermatol. 2008;144(3):342-346. 143. Jean-Baptiste S, O’Toole EA, Chen M, et al: Expression of eotaxin, an eosinophilselective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti. Clin Exp Immunol. 2002;127:470-478.

144. Connor JM, Gatherer D, Gray FC, et al: Assignment of the gene for dyskeratosis congenita to Xq28. Hum Genet. 1986;72:348-351. 145. He J, Navarrete S, Jasinski M, et al: Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice. Oncogene. 2002;21:7740-7744. 146. Montanaro L, Chilla A, Trere D, et al: Increased mortality rate and not impaired ribosomal biogenesis is responsible for proliferative defect in dyskeratosis congenital. J Invest Dermatol. 2002;118:193-198. 147. Savage SA, Giri N, Baerlocher GM, et al: TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet. 2008;82(2):501-509. 148. Smith AG, Shuster S, Thoday AJ, Peberdy M: Chloasma, oral contraceptives, and plasma immunoreactive βmelanocyte-stimulating hormone. J Invest Dermatol. 1977;68:169-170. 149. Grimes P, Yamada N, Bhawan J, et al: Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol. 2005; 27(2):96. 150. Larsson P, Lidén S: Prevalence of skin diseases among adolescents 12 to 16 years of age. Acta Derm Venereol (Stockh). 1980;60:415-423. 151. Rhodes AR, Albert LS, Barnhill RL, Weinstock MA: Sun-induced freckles in children and young adults: a correlation of clinical and histopathologic features. Cancer. 1991;67:1990-2001. 152. Crowson AN, Magro CM, Mihm MC Jr: The freckles and lentigines, in Crowson AN, Magro CM, Mihm MC Jr (eds): The Melanocytic Proliferations: A Comprehensive Textbook of Pigmented Lesions. New York: Wiley 200l;49-72. 153. Barnhill RL: Pathology of Melanocytic Nevi and Malignant Melanoma. Boston: Butterworth-Heinemann; 1995. 154. Itin PH, Lautenschlager S, Meyer R, et al: Natural history of the NaegeliFranceschetti-Jadassohn syndrome and further delineation of its clinical manifestations. J Am Acad Dermatol. 1993;28:942-950. 155. Oriba HA, Lo JS, Dijkstra JWE, Bergfeld WF: Reticulate nonmelanocytic hyperpigmentation anomaly: a probable variant of Dowling-Degos disease. Int J Dermatol. 1991;30:39-42. 156. Erel A, Gurer MA, Edali N: Reticulate acropigmentation of Kitamura: two case reports. Int J Dermatol. 1993;32: 726-727. 157. Berth-Jones J, Graham-Brown RAC: A family with Dowling-Degos disease showing features of Kitamura’s reticulate acropigmentation. Br J Dermatol. 1989;120:463-466. 158. Kudo Y, Fujiwari S, Takayasu S, et al: Reticulate pigmentary dermatosis associated with hypohidrosis and short stature: a variant of NaegeliFranceschetti-Jadassohn syndrome? Int J Dermatol. 1995;34:30-31. 159. Riccardi VM: Neurofibromatosis: past, present, and future. New Engl J Med. 1991;324:1283-1285. 160. Obringer AC, Meadows AT, Zackai EH: The diagnosis of neurofibromatosis I in

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179. Danarti R, König A, Salhi A, et al: Becker's nevus syndrome revisited. J Am Acad Dermatol. 2004;51(6):965-969. 180. Nagashima J: Prurigo pigmentosa: clinical observations of our 14 cases. J Dermatol. 1978;5:61-67. 181. Shimizu H, Yamasaki Y, Harada T, Nishkawa T: Prurigo pigmentosa. J Am Acad Dermatol. 1985;12:165-169. 182. Asgari M, Daneshpazhooh M, Chams Davatchi C, Böer A: Prurigo pigmentosa: an underdiagnosed disease in patients of Iranian descent? J Am Acad Dermatol. 2006;55(1):131-136. 183. Gur-Toy G, Gungor E, Artuz F, et al: Prurigo pigmentosa. Int J Dermatol. 2002;41:288-291. 184. Erbagci Z: Prurigo pigmentosa in association with Helicobacter pylori infection in a Caucasian Turkish woman [letter]. Acta Derm Venereol (Stockh). 2002;82:302303. 185. Kim MH, Choi YW, Choi HY, Myung KB: Prurigo pigmentosa from contact allergy to chrome in detergent. Contact Dermatitis. 2001;44:289-292. 186. Chiam L, Lim K, Goh B: Prurigo pigmentosa: a report of 2 cases which responded to minocycline. J Am Acad Dermatol. 2008;58(suppl 2):AB118. 187.Matsumoto C, Kinoshita M, Baba S, et al: Vesicular prurigo pigmentosa cured by minocycline. J Eur Acad Dermatol Venereol. 2001;15:354-356. 188. Lacz NL, Vafaie J, Kihiczak NI, et al: Postinflammatory hyperpigmentation: a common but troubling condition. Int J Dermatol. 2004;43(5):362-365. 189. Tanigaki T, Hata S, Kitano Y, el al: Unusual pigmentation on the skin over trunk bones and extremities. Dermatologica. 1985;170: 235-239. 190. Siragusa M, Ferri R, Cavallari V, Schepis C: Friction melanosis, friction amyloidosis, macular amyloidosis, towel melanosis: many names for the same clinical entity. Eur J Dermatol. 2001;11: 545-548. 191. Sharquie KE, AL-Dorky MK: Frictional dermal melanosis (lifa disease) over bony prominences. J Dermatol. 2001;28: 12-15. 192. Al-Aboosi M, Abalkhail A, Kasim O, et al: Friction melanosis: a clinical, histologic, and ultrastructural study in Jordanian patients. Int J Dermatol. 2004;43(4):261-264. 193. Jambrosic J, From L, Hanna W: Lichen amyloidosus: ultrastructure and pathogenesis. Am J Dermatopathol. 1984;6:151158. 194. Konrad K, Woolf K: Pathogenesis of diffuse melanosis secondary to malignant melanoma. Br J Dermatol. 1974;91: 635-655. 195. Alexander A, Harris RM, Grossman D, et al: Vulvar melanoma: diffuse melanosis and metastasis to the placenta. J Am Acad Dermatol. 2004;50(2): 293-298. 196. Touart DM, Sau P: Cutaneous deposition diseases, part II. J Am Acad Dermatol. 1998;39:527-544. 197. Wyre HW: Alkaptonuria with extensive ochronosis. Arch Dermatol. 1979;115: 461-463. 198. Lawrence N, Bligard CA, Reed R, Perret WJ: Exogenous ochronosis in the United States. J Am Acad Dermatol. 1988;18: 1207-1211.

199. Spenny ML, Suwannarat P, Gahl WA, et al: Blue pigmentation and arthritis in an elderly man. J Am Acad Dermatol. 2005; 52(1):122-124. 200. Jacyk WK: Annular granulomatous lesions in exogenous ochronosis are manifestations of sarcoidosis. Am J Dermatopathol. 1995;17:18-22. 201. Goldstein N: IV. Complications from tatoos. J Dermatol Surg Oncol. 1979;5: 869-878. 202. Ajoka RS, Kushner JP: Hereditary hemochromatosis. Semin Hematol. 2002; 39:235-241. 203. Charlín R, Barcaui CB, Kac BK, et al: Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy. Int J Dermatol. 2008;47(1):19-23. 204. Moalem S, Percy M, Kruck T, Gelbart R: Epidemic pathogenic selection: an explanation for hereditary hemochromatosis? Med Hypotheses. 2002;59:325-329. 205. De Gobbi M, Roetto A, Piperno A, et al: Natural history of juvenile hemochromatosis. Br J Hematol. 2002;117:973-979. 206. Moodie SJ, Ang L, Stenner JM, et al: Testing for haemochromatosis in a liver clinic population: relationship between ethnic origin, HFH gene mutations, liver histology, and serum iron markers. Eur J Gastroenterol Hepatol. 2002;14:223-229. 207. Camaschella C, Roetto A, De Gobbi M: Juvenile hemochromatosis. Semin Hematol. 2002;39:242-248. 208. Brissot P, Troadec MB, Bardou-Jacquet E, et al: Current approach to hemochromatosis. Blood Rev. 2008;22(4):195-210. 209. Bertini G, Dani C, Fonda C, et al: Bronze baby syndrome and the risk of kernicterus. Acta Paediatr. 2005;94(7):968-971. 210. Ashley JR, Littler CM, Burgdorf WHC, Brann BS: Bronze baby syndrome. J Am Acad Dermatol. 1985;12:325-328. 211. Kaplan BS: Azure lunulae due to argyria. Arch Dermatol. 1966;94:333-334. 212. Prose PH: An electron microscopic study of human generalized argyria. Am J Pathol. 1963;42:293-297. 213. Espinal MC, Ferrando L: Asymptomatic blue nevus-like macule. Arch Dermatol. 1996;132:461, 464. 214. Jonas L, Bloch C, Zimmermann R, et al: Detection of silver sulfide deposits in the skin of patients with argyria after long-term use of silver-containing drugs. Ultrastruct Pathol. 2007;31(6):379-384. 215. Trotter MJ, Tron VA, Hollingdale J, Rivers JK: Localized chrysiasis induced by laser therapy. Arch Dermatol. 1995; 131:1411-1414. 216. Geist DE, Phillips TJ: Development of chrysiasis after Q-switched ruby laser treatment of solar lentigines. J Am Acad Dermatol. 2006;55(suppl 2):S59-S60. 217. Granstein RD, Sober AJ: Drug- and heavy metal-induced hyperpigmentation. J Am Acad Dermatol. 1981;5:1-18. 218. Zhu WY, Xia MY, Huang SD, Du D: Hyperpigmentation of the nail from lead deposition [letter]. Int J Dermatol. 1989;28:273-275. 219. Leuth HC, Sutton DC, McMullen CJ, Meuhlberger CW: Generalized discoloration of skin resembling argyria following prolonged oral use of bismuth: a case of “bismuthia.” Arch Intern Med. 1936;57:1115. 220. Dupre A, Touron P, Daste J, et al: Titanium pigmentation: an electron

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therapy with hydroxychloroquine. J Clin Rheumatol. 2007;13(2):113. Millar TP, Kirk A, Ratnavel R: Cutaneous hyperpigmentation during therapy with hydroxychloroquine. Clin Exp Dermatol. 2004;29:92-93. Lutterloh CC, Shallenberger PL: Unusual pigmentation developing after prolonged suppressive therapy with quinacrine hydrochloride. Arch Dermatol Venereol. 1946;53:349-354. Tuffanelli D, Abraham RK, Dubois EL: Pigmentation from antimalarial therapy: its possible relation to the ocular lesions. Arch Dermatol. 1963;88:419-426. Levantine A, Almeyda J: Drug-induced changes in pigmentation. Br J Dermatol. 1973;89:105-112. Gupta AK, Haberman JF, Pawlowski D, et al: Canthaxanthine. Int J Dermatol. 1985;24:528-532. Waitzer S, Butany J, From L, et al: Cutaneous ultrastructural changes and

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probe microanalysis study. Arch Dermatol. 1985;121: 656-658. Kang S, Lerner EA, Sober AI, Levine N: Pigmentary disorders from exogenous causes, in Levine N (ed): Pigmentation and Pigmentary Disorders. Boca Raton, FL: CRC Press; 1993:417. Gordon B, Sparano BM, Iatropoulos MJ: Hyperpigmentation of the skin associated with minocycline therapy. Arch Dermatol. 1985;121:618-623. Argenyi ZB, Finelli L, Bergfeld WF, et al: Minocycline-related cutaneous hyperpigmentation as demonstrated by light microscopy, electron microscopy, and xray energy spectroscopy. J Cutan Pathol. 1987;14:176-180. Bowen AR, McCalmont TH: The histopathology of subcutaneous minocycline pigmentation. J Am Acad Dermatol. 2007;57(5):836-839. Amichai B, Gat A, Grunwald MH: Cutaneous hyperpigmentation during

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CHAPTER 16 Deposition Disorders

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Franco Rongioletti Raymond L. Barnhill

Various substances may form deposits in the skin. They may be classified as endogenous and exogenous. Endogenous substances are the topic of this chapter. They include substances that are normal constituents of the skin but are abnormally deposited (eg, increased deposition of mucin) and substances that are not normal constituents of the skin (eg, amyloid). Exogenous materials, such as tattoos and heavy metals, and the special category of endogenous deposition, such as melanin depositions, are discussed in Chapter 15. Abnormal deposition of endogenous substances exhibits particular histochemical staining properties. However, different substances may show similar staining by the hematoxylin and eosin

CUTANEOUS MUCINOSES Mucin or protein–hyaluronic acid complex is a normal component of the dermal connective tissue produced by fibroblasts

and mast cells. In disease conditions, it is increased, and because hyaluronic acid holds water (hygroscopic), the dermal connective tissue is swollen (myxedema). If this condition persists, the dermis and sometimes the subcutaneous connective tissues react with production of excessive collagen, leading to scleroderma-like fibrosis (scleromyxedema). Mucin is usually present in early lesions and may diminish or even disappear in late stages. Also, during tissue processing, mucin may largely be washed out. If one suspects mucin deposition because of light blue staining between widely separated collagen bundles or empty spaces, special stains should be used such as Alcian blue at a pH of 2.5 (negative at 0.5), toluidine blue with metachromasia at a pH of 4.0 and 7.0 (negative below 2), and colloidal iron. Furthermore, mucin is hyaluronidase sensitive and periodic acid Schiff (PAS) negative. Fixation in absolute alcohol may improve detection.1,2 Monoclonal antibodies to hyaluronan, although not routinely indicated, have been used.3 The cutaneous mucinoses are a heterogeneous group of disorders in which an

Abnormal dermal depositions (H&E stain)

Pink-gray, amorphous PAS +

Hyaline EM: amorphous PAS + + +

Amyloid EM: filaments Congo red (+ + +) Greenish birefringence of Congo red stain

Pale blue, grayish blue, edematous

Colloid EM: amorphous Amyloid P (+) Adult colloid milium

Colloid EM: filaments Antikeratin (+ +) Congo red (+)

Colloidal iron (+) Alcian blue (+), pH 2.5 (–), pH 0.5 Toluidine blue metachromasia (+), >pH 2.0 PAS (–), hyaluronidase +

Hyalinosis cutis et mucosae

Various amyloidoses

Juvenile colloid milium

Mucin

Ig λ or κ chain

Potassium permanganate treatment Congo red (–)

Antikeratin antibody (+)

See Table 16-1

AL amyloid Primary systemic, nodular or Waldenstrom macroglobulinemia

Amyloid K AA amyloid

Secondary systemic amyloidosis

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(H&E) stain (Fig. 16-1). These deposits with similar staining properties are often grouped together and were once considered to be the same chemical substances. Examples are mucin, hyalin, and colloid. When a dermatopathologist examines H&E-stained tissue sections, he or she notices the color characteristics and common texture of a substance in one of these three groups. The dermatopathologist then focuses on the subset of conditions that manifests these particular characteristics. Special stains, immunostains, electron microscopy, and clinical information provide further aid in the differential diagnosis. In many instances, clinical knowledge is essential in the final synthesis of all data to reach a reasonable conclusion. This process is always at work in the experienced pathologist’s mind. An algorithmic approach to differential diagnosis is presented in Fig. 16-1. Tables 16-1 to 16-6 will assist in this analytical process.

 FIGURE 16-1 Abnormal dermal depositions.

Lichenoid macular or concha amyloidosis

Epithelial tumor amyloidoses (eg, BCC, AK, SK, Bowen)

Juvenile colloid milium

Pale blue-gray

Multicolor birefringence

Gouty tophi

Table 16-1 The Cutaneous Mucinoses DERMAL AND FOLLICULAR DEGENERATIVE/INFLAMMATORY MUCINOSES

ASSOCIATED DISORDERS

HISTOPATHOLOGIC FEATURES

Generalized waxiness, nonpitting, waxy facial edema

Hypothyroidism

Pretibial myxedema

Shin, dorsal feet

Thyrotoxicosis, treated

Scant mucin, upper dermis around blood vessels, hair follicles Prominent mucin lower two-thirds of dermis, hyperkeratosis, follicular plugging, mast cells

Generalized papules, including face, sclerodermoid features

Monoclonal gammopathy, systemic involvement

Diffuse mucin, upper dermis, increased collagen and fibroblasts

Papules on trunk and extremities

Sometimes HIV

Focal or diffuse mucin, upper dermis, variable increased numbers of fibroblasts Focal mucin, upper dermis, grenz zone, normal fibroblast number Mucin, upper dermis, increased fibroblasts, mast cells

Lichen myxedematosus (papular mucinosis) Scleromyxedema

Localized forms Discrete type

Acral persistent papular mucinosis

Papules on dorsa of hands and forearms

Self-healing juvenile mucinosis

Children, linear infiltrated plaques, head, trunk, thighs; deep periarticular nodules

Cutaneous mucinosis of infancy Scleredema

Focal mucinosis Digital mucous cyst Mucocele of the lip Oral mucous cyst Papular and nodular mucinosis associated with lupus erythematosus Follicular mucinosis

Sometimes rheumatologic symptoms

Firm papules on extremities Induration of upper back, nape

Solitary papulo-nodule Distal interphalangeal joint, posterior nail fold Mucosal side of lower lip

Diabetes, acute infection, monoclonal gammopathy

Arthrosis

Lumpy papulonodules, trunk and extremities

LE (mainly SLE)

Tumid plaques with follicular papules, alopecia, face and scalp

Mycosis fungoides

abnormal amount of mucin deposits in the skin. The cutaneous mucinoses are categorized into two groups: primary cutaneous mucinoses, in which the mucin deposit is the main histologic feature resulting in clinically distinctive lesions (Table 16-1), and secondary mucinoses, in which the mucin deposition is only an additional histologic finding. A typical example of secondary mucinosis is granuloma annulare, in which mucin deposition is associated with a necrobiotic palisaded granuloma, which is the diagnostic hallmark. Secondary mucinoses are not discussed in this chapter.1,2

Primary cutaneous mucinoses are further categorized into degenerative and inflammatory forms, which may be dermal or follicular (see Table 16-1), and hamartomatous and neoplastic forms.

DERMAL DEGENERATIVE AND INFLAMMATORY PRIMARY CUTANEOUS MUCINOSES These are the most frequent cutaneous mucinoses. Diagnosing a primary dermal mucinosis on histologic grounds alone is a difficult task and always requires

Focal mucin, papillary dermis Thickened dermis, fenestrated collagen, mucin may be absent on H&E stain, normal fibroblast number Focal mucin in dermis, clefts Focal mucin in dermis, collagen pseudocapsule Sialomucin (PAS+) with inflammatory reaction Diffuse mucin in reticular dermis, normal epidermis, lymphocytic infiltrate Mucin within pilosebaceous units, lymphocytes, eosinophils

CHAPTER 16 ■ DEPOSITION DISORDERS

DISTRIBUTION, CHARACTERIZATION

Generalized myxedema

clinicopathologic correlation. Three histologic clues should be considered: the pattern of mucin distribution, the level of mucin deposition in the dermis, and some additional findings (see Table 16-1). The pattern of mucin distribution may be diffuse or focal. In the latter, mucin is localized and well circumscribed (Fig. 16-2); in the former, it is interstitial and poorly circumscribed (Fig. 16-3).

Generalized Myxedema This condition is associated with a severe form of chronic hypothyroidism.1,2,4

363

fibrosis in the deep dermis and subcutis may simulate scleroderma. The diagnosis is mainly clinical, and histopathologic findings are only confirmatory.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Pretibial (Localized) Myxedema

364

 FIGURE 16-2 Pattern of focal dermal deposition of mucin in acral persistent papular mucinosis. Alcian blue stain; pH, 2.5.

CLINICAL FEATURES The face, particularly the eyelids and lips, are prominently swollen, and the entire skin is dry, pale, waxy, and edematous but not pitted with pressure. HISTOPATHOLOGIC FEATURES Histologic features include hyperkeratosis, occasional keratinous cysts, and only slight edema (mucinosis) of the dermis in most cases, usually requiring mucin stains for

confirmation. The mucin is frequently deposited around the blood vessels and hair follicles of the upper and mid-dermis only. In some instances, there is massive accumulation of mucin, resulting in the disruption of collagen bundles and accompanied by perivascular mononuclear cell infiltrates. Usually, fibroblasts are not increased. Elastic fibers are fragmented and reduced. In the late stages,

This is most commonly observed in patients with established hyperthyroidism (usually due to Graves disease) who have been treated.1,2,4 These patients are usually euthyroid by the time they develop this condition, although they may still exhibit exophthalmos. With regard to pathophysiology, a serum factor (unrelated to longacting thyroid-stimulating factor or hormone) seems to stimulate fibroblasts to produce mucin. Fibroblasts from the dermis of the lower extremities have been found to be more sensitive to this factor than are fibroblasts from other areas of the body. An insulinlike growth factor, trauma, and lymphatic obstruction due to mucin may be involved. CLINICAL FEATURES The anterior shins and occasionally dorsal feet demonstrate elevated, knobby plaques or dome-shaped nodules. The cutaneous surface is shiny or waxy, and peau d’orange follicular openings with follicular plugging are noted in new lesions. In severe cases, marked edema and verrucoid surface changes, possibly resembling elephantiasis nostras verrucosa, may be seen. Rarely, the condition affects the shoulder, arms, and abdomen. After biopsy, transparent, viscous fluid continues to ooze. HISTOPATHOLOGIC FEATURES The typical features consist of conspicuous, diffuse deposition of mucin (glycosaminoglycans) throughout the reticular dermis with attenuation of collagen fibers (Fig. 16-4). With extensive deposition of mucin, the collagen fibers are frayed, fragmented, and widely separated. Spindle-shaped and large stellate fibroblasts appear to float in the edematous areas, but the number of fibroblasts is not increased. Lymphatic dilated vessels can be seen. In chronic lesions, increased collagen production occurs in the deep dermis and subcutaneous fat, resulting in the replacement of fat lobules by fibrosis. Alcian blue stain is strongly positive and differentiates mucin from conventional lymphedema.4 Hyperkeratosis and follicular plugging, the presence of mast cells, and sparse lymphoid infiltrates with occasional eosinophils are additional findings.2

 FIGURE 16-3 Pattern of diffuse dermal deposition of mucin in pretibial myxedema. Alcian blue stain; pH, 2.5.

DIFFERENTIAL DIAGNOSIS Pretibial myxedema should be distinguished from lymphoedematous mucinosis associated with chronic obesity without thyroid

 FIGURE 16-4 Pretibial myxedema. In the reticular dermis, collagen bundles are widely separated by mucin. The epidermis is hyperkeratotic and acanthotic.

disease. In the latter, vesicles and bullae, semitranslucent papules, or woody plaques are found on the shins in the setting of morbid obesity and bilateral pitting edema of the distal lower extremities. Histologically, epidermal atrophy with effacement of the rete ridge pattern, mucin deposition within the superficial papillary dermis, perivascular glomeruloid neovascularization, and hemosiderin deposition are seen.5 (For other differential diagnoses, see Table 16-1.)

CLINICAL FEATURES In scleromyxedema, a widespread symmetric eruption of closely set papules, often arranged in a linear array and accompanied by skin thickening,

HISTOPATHOLOGIC FEATURES In scleromyxedema, patients have a characteristic triad that includes diffuse mucin deposition in the upper and mid-reticular dermis, increased collagen deposition, and a marked proliferation of irregularly arranged fibroblasts (Figs. 16-5 and 16-6).2,6 The epidermis is usually normal, but in old lesions, it may be thinned by the pressure of the underlying mucin and fibrosis; the follicles may be atrophic; and a slight perivascular, superficial lymphoplasmocytic infiltrate is often present. Rarely, eosinophils are found. The elastic fibers are fragmented and decreased in number. Reactive

CHAPTER 16 ■ DEPOSITION DISORDERS

involves the face, upper trunk, and peripheral extremities. Involvement of the glabella gives rise to leonine facies. The localized form, in which the papules are confined to only a few sites (usually the limbs and trunk) in the absence of paraproteinemia and systemic features, include four subtypes: a discrete papular form, acral persistent papular mucinosis, cutaneous mucinosis of infancy, and nodular lichen myxedematosus. An association of discrete lichen myxedematosus with HIV infection, toxic oil syndrome, eosinophilia myalgia syndrome, and hepatitis C virus (HCV) infection has been reported.1 Selfhealing papular mucinosis, both of the juvenile and adult types, previously considered as a subtype of localized lichen myxedematosus, is probably a mucinosis suis generis.1

Lichen Myxedematosus (Papular Mucinosis) and Scleromyxedema (Papular Mucinosis) Lichen myxedematosus is a chronic idiopathic disorder characterized by lichenoid papules, nodules, or plaques in the absence of thyroid disease, which includes two clinicopathologic subsets: a generalized and sclerodermoid form (also called scleromyxedema) with a monoclonal gammopathy and systemic, even lethal, manifestations and a localized form that does not run a disabling course.6 Occasional patients have overlapping or atypical features and fall between having scleromyxedema and localized lichen myxedematosus.

 FIGURE 16-5 Scleromyxedema. The characteristic triad of mucin deposition, fibroblast proliferation, and fibrosis in the upper and mid-dermis.

365

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS 366

 FIGURE 16-6 Scleromyxedema. Colloidal iron stain confirms increased mucin deposition in the upper dermis.

sweat gland proliferation is an occasional finding. The changes in the localized form are not as characteristic as in scleromyxedema but are still recognizable. The pattern of mucin distribution may be diffuse or focal, involving the upper and mid-reticular dermis. Fibroblast proliferation is variable. Fibrosis is not marked and may even be absent (Fig. 16-7). In acral persistent papular mucinosis, a large, focal, well-circumscribed amount of mucin sparing a subepidermal zone is seen (see Fig. 16-2). Fibroblast prolifera-

tion is lacking. In cutaneous mucinosis of infancy, sometimes the mucin deposition in the papillary dermis is pronounced as to appear “hugged” by the epidermis. DIFFERENTIAL DIAGNOSIS Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) is observed in patients with renal disease and more recently liver failure and a history of exposure to gadolinium-containing contrast agents. The latter entity is microscopically similar to scleromyxedema (see Chapter 17). Although the initial manifestations of this disorder

 FIGURE 16-7 Localized lichen myxedematosus (papular mucinosis) of the discrete type. Increased mucin deposition splitting collagen fibers in the upper dermis with slight fibroblast proliferation and absence of fibrosis.

may be cutaneous, this fibrosing reaction may involve extracutaneous sites, including the lungs, heart, and muscle, hence the more recent and preferred name nephrogenic systemic fibrosis. Infection at the time of gadolinium administration and the nature of the gadolinium used (ie, ionic versus nonionic preparations and linear versus macrocyclic chelates) define potential risk factors associated with the development of nephrogenic systemic fibrosis. Fibrosis and mucin deposition of the deep dermis and septa of the subcutis in concert with an increase of CD34+ stromal spindle cells that coexpress procollagen-I and CD45RO are more typical of the former (see Chapter 17).7 Scleromyxedema can only be distinguished from other mucinoses by clinical features and dermal fibrosis, which is not observed in the other mucinoses until the late stages. Granuloma annulare may resemble early papular mucinosis; however, in the former, the cells accompanying the deposit of mucin are histiocytes arranged in palisaded or interstitial pattern.

Reticular Erythematous Mucinosis CLINICAL FEATURES Mostly women are affected by reticulated erythematous macules in the central chest and upper back.1-3 The arms and face may be involved. More infiltrated papular lesions are called plaquelike cutaneous mucinosis. HISTOPATHOLOGIC FEATURES The epidermis is normal. Diffuse interstitial deposits of mucin in the upper dermis are associated with a superficial and mid-dermal perivascular and sometimes perifollicular mild to moderate mononuclear infiltrate, mainly composed of T lymphocytes with vascular dilation (Fig. 16-8).2,3 An increased number of FXIIIa-positive cells has been reported with co-localization of type II hyalaronan to these cells, suggesting that the accumulation of mucin in reticular erythematosus mucinosis is derived from dermal dendrocytes. Direct immunofluorescence results are usually negative, but sometimes granular deposits of IgM, IgA, and C3 are found at the dermal–epidermal junction, making the distinction from lupus erythematosus difficult. DIFFERENTIAL DIAGNOSIS In lupus erythematosus, patients have an involvement of the epidermis by an interface dermatitis. In lupus erythematosus tumidus, the lymphocytic infiltrate is heavier, and mucin deposits are more diffuse and deep throughout the reticular dermis. However, it is unclear if reticular erythematous

it often begins on the upper back with subsequent extension to the neck and occipital scalp. In advanced cases, nonpitting indurated edema elevates the skin of the shoulder blade area with deep associated vertebral folds. Such patients are usually obese, and the mobility of the neck and head may be severely restricted. The skin is shiny and often uneven. The course is usually chronic. Scleredema after a respiratory infection is typically acute and resolves rapidly. Very rarely, the tongue, skeletal muscle, pleura, or pericardium is involved.

mucinosis, Jessner lymphocytic infiltration, and lupus tumidus are distinctive entities or different expressions of cutaneous lupus erythematosus.

associated conditions are monoclonal gammopathies and acute streptococcal respiratory infections.1,9 The onset of the type related to diabetes is insidious, and

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-8 Reticular erythematous mucinosis. An interstitial mucin deposition between the collagen bundles associated with a moderate perivascular lynphocytic infiltrate in the upper dermis and vascular dilation under a normal epidermis.

HISTOPATHOLOGIC FEATURES The dermis is significantly thickened, sometimes up to two to three times normal, by increased collagen, which sometimes replaces subcutaneous fat.2,9 In general, the patient has thick, hyalinized collagen bundles that are widely separated (resulting in socalled “fenestrations”) by abundant interstitial deposits of mucin (Figs. 16-9 and 16-10). After the early stage of disease, mucin stains may become negative. However, frozen sections may be stained with Alcian blue at a pH of 2.5 or toluidine blue at a pH of 7.0. Sometimes multiple biopsies and cetylpyridinium chloride fixation are needed to demonstrate mucin in the dermis.10 No increase in the number of fibroblasts and no prominent

Cutaneous Lupus Mucinosis (Papular and Nodular Mucinosis in Lupus Erythematosus) This is a specific eruption seen in patients with lupus erythematosus (usually systemic lupus erythematosus), consisting of skin-colored and sometimes centrally depressed papules and nodules imparting a lumpy appearance to the skin or, more rarely, of plaquelike lesions on the upper extremities and trunk and independent from specific lesions of lupus.8 HISTOPATHOLOGIC FEATURES Mucin abounds in the upper and mid-dermis but may involve the subcutis as well. No inflammation is usually found, but sometimes a slight perivascular lymphocytic infiltrate is seen. The epidermal changes of lupus erythematosus are absent; however, granular deposits of immunoglobulins, C3, or both are detected at the dermal– epidermal junction on direct immunofluorescence.2,8

Scleredema Adultorum The most common cause of this disorder is chronic adult-onset diabetes. Other

 FIGURE 16-9 Scleredema. A thickened reticular dermis with sclerotic collagen bundles that are separated (fenestration).

367

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

forms on the dorsal skin on or near the distal interphalangeal joint of the finger. 1 It may present near the nail. Subungual and eruptive variants have been reported.13 There are two principal variants. One subtype is derived from synovial cells (ganglion) and is almost always localized to the surfaces of the interphalangeal joints, and the other major variant is derived from dermal-based fibroblasts is usually present between the interphalangeal joints. Puncture or biopsy results in the drainage of viscous, stringy mucin from the cyst.

Digital Mucous (Myxoid) Cyst

HISTOPATHOLOGIC FEATURES The lesion is not a true cyst. The variety that originates in the dermis shows a large deposit of mucin-containing stellate fibroblasts, some vascular spaces, and multiple clefts (Fig. 16-12). The less frequent variant of synovial origin is characterized by a large dermal cavity surrounded by a collagenous pseudocapsule. The overlying epidermis may be acanthotic at the peripheries of the cyst, sometimes forming a “collarette,” and effaced over the central part of the cyst (see Fig. 16-12). Transepidermal elimination of mucinous material may be seen.

A dome-shaped elevation with or without visible semitransparent contents

DIFFERENTIAL DIAGNOSIS See Table 16-1.

 FIGURE 16-10 Scleredema. Fenestration of collagen bundles that are widely separated by abundant interstitial mucin deposits, recognizable even with hematoxylin and eosin staining.

inflammatory infiltrates are present, and the elastic fibers are reduced in number. DIFFERENTIAL DIAGNOSIS Scleredema differs from other forms of mucinosis by showing marked thickening of the dermis, hypertrophied collagen bundles, and the fenestrations between collagen bundles filled with mucin. Scleromyxedema is distinguished by more superficial deposits of mucin in the dermis and fibroblastic proliferation. In contrast to scleredema, morphea and scleroderma tend to exhibit tightly packed hypertrophied collagen bundles without fenestrations or abundant mucin deposition and the presence of a superficial and deep perivascular lymphoplasmocytic infiltrate. However, an important caveat is that significant interstitial mucin deposition can be observed in very early biopsies of morphea and even in established lesions of morphea on occasion.

partially CD34 positive is also found. The elastic and reticulum fibers are absent in the mucinous area, and the capillaries are normal in number. DIFFERENTIAL DIAGNOSIS The major entity to be discriminated is cutaneous (angio)myxoma.

Cutaneous Focal Mucinosis This localized form of mucinosis is characterized by a benign, solitary, symptomless, skin-colored papule or nodule occurring anywhere on the body, except on the skin overlying the joints of the hands and feet, in adults and more rarely in children.11,12

368

HISTOPATHOLOGIC FEATURES Mucin deposition replaces the dermal collagen focally and spares the subcutaneous fat (Fig. 16-11). Spindle-shaped or stellate, vimentin-positive fibroblasts are noted in such mucinous materials.2,11 Cleftlike spaces, but no cysts, are seen. A minor population of dermal dendrocytes that are partially factor XIIIa positive and

 FIGURE 16-11 Cutaneous focal mucinosis. Large, focal deposit of mucin in the dermis with some fibroblasts floating in the mucinous material.

nent follicular openings or as a large indurated plaque in which coalesced follicular and nonfollicular papules are present. Follicular mucinosis may heal spontaneously after a few months to a few years or may have a chronic but benign course.1,2 Very recently, follicular mucinosis of Pinkus has been suggested to be a form of localized, “indolent” cutaneous T-cell dyscrasia rather than an idiopathic benign cutaneous mucinosis.16

Oral Mucous Cyst and Superficial Mucocele of the Lip The ordinary oral mucous cyst develops on areas prone to traumatic insult such as the lower lip, tongue, and bottom of the oral cavity. The superficial variant (called superficial mucocele) usually develops on the soft palate and buccal mucosa14 (also see Chapter 37). HISTOPATHOLOGIC FEATURES The oral mucous cyst forms below the basal membrane or in connective tissue and clinically appears as a submucosal nodule. The superficial mucocele forms in the mucous epithelium or immediately below the subepithelium and appears clinically as a vesicle or bulla. The mucin deposits are composed of sialomucin (neutral glycosaminoglycans) rather than acid glycosaminoglycans. HISTOPATHOLOGIC FEATURES Sialomucin is an epithelial-derived mucin (secreted by salivary glands) that is PAS positive and diastase resistant. Alcian blue stain is also positive, but hyaluronidase does not abolish this staining.14 In ordinary oral mucous cysts, multiple edematous pockets of sialomucin are present in the submucosa. An inflammatory cell reaction surrounds these foci. In an old lesion, one large cavity filled with faintly eosinophilic material is observed. In superficial mucocele of the lip, a blister containing sialomucin, neutrophils, and erythrocytes is present in the mucous epithelium. Also, a dermal infiltrate composed of neutrophils, mononuclear

lymphocytic cells, and eosinophils is present.

FOLLICULAR DEGENERATIVE AND INFLAMMATORY PRIMARY CUTANEOUS MUCINOSES Follicular mucinosis is arguably the most easily recognized histologic pattern of mucin deposition because the mucinous deposits are confined to the hair follicles (see Chapters 10 and 34). Why dermal mucin is deposited selectively in an epithelial structure, however, is unclear. Although follicular keratinocytes have been considered the source of mucin,15 an etiologic role for cell-mediated immune mechanisms has been proposed. Follicular mucinosis of Pinkus and urticaria-like follicular mucinosis are two disorders in which follicular mucinosis is the main histologic feature, resulting in clinically distinctive lesions (primary follicular mucinosis). Otherwise, secondary follicular mucinosis is a histologic epiphenomenon seen in many disorders, particularly the cutaneous lymphomas.

Follicular Mucinosis of Pinkus This condition predominantly affects the face and head and neck region of children and middle-aged adults.1,2,16 If terminal hairs of the beard or head are affected, a localized hair loss is noticed, hence the original term alopecia mucinosa. Vellus hairs may be lost but are not noticeable. These lesions may present as a group of individual follicular papules with promi-

DIFFERENTIAL DIAGNOSIS There are some clinicopathologic criteria for distinguishing Pinkus follicular mucinosis from lymphoma-associated follicular mucinosis. Classic follicular mycosis fungoides associated with follicular mucinosis presents as destructive infiltrative nodules, often with a cystic acneiform appearance and alopecia. The demographics are similar to classic mycosis fungoides, presenting in middle-aged and older adults. Although lymphoid atypia and even clonality may be seen in primary alopecia mucinosa or Pinkus follicular mucinosis, suggesting its categorization as a cutaneous T-cell dyscrasia, the degree of atypia is not as developed as that observed in true follicular mycosis fungoides.16 Although the infiltrate in some cases of alopecia mucinosa in young children may be very prominent, the young age of the patient and the localized nature of the process are helpful in discriminating the features from those of follicular mycosis fungoides.1 Secondary follicular mucinosis occurs in a wide variety of folliculocentric inflammatory lesions such as discoid lupus erythematosus, eosinophilic folliculitis, insect bite reactions, drug reactions associated with antidepressant therapy, follicular eczema, and staphylococcal folliculitis.

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-12 Digital mucous cyst. This is a pseudocyst with a large pool of mucin in the dermis and some vascular spaces and clefts. The epidermis is laterally acanthotic, forming a peripheral “collarette,” and centrally more atrophic.

HISTOPATHOLOGIC FEATURES Early changes consist of intra- and intercellular edema of follicular epithelium due to accumulation of mucin. The intercellular edema produces a reticular network pattern from the cell walls of the outer root sheath keratinocytes. The increased mucin eventually destroys cell walls and inventuates in a pool of mucin within the hair follicle and sebaceous gland (Fig. 16-13).2 The mucin in this condition can be stained with colloidal iron, Alcian blue, and Giemsa but is usually PAS negative. Hyaluronidase digestion abolishes all staining. In severe cases, the accumulated mucin extravasates to form perifollicular mucinosis. The perifollicular inflammatory reaction is variable and consists of lymphocytes, histiocytes, and eosinophils.

369

may be hyperplastic with elongation of the rete ridges and hyperkeratosis, as in an epidermal nevus. In the latter case, a mucinous nevus may be considered a combined hamartoma.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Cutaneous Myxoma A cutaneous myxoma is a benign acquired neoplasm. It may be solitary without systemic abnormalities or multiple. In the latter scenario, myxomas may represent a manifestation of Carney complex (cutaneous myxomas, cardiac myxoma, spotty pigmentation, and endocrine overactivity). Cardiac myxoma is fatal, and cutaneous myxoma may be an important first indication of this serious condition.2 Cutaneous myxomas and superficial angiomyxomas are very similar clinically and histomorphologically.

 FIGURE 16-13 Follicular mucinosis. The increased mucin accumulates within the hair follicle and sebaceous gland, forming intercellular edema and large cystic spaces. There is a slight perifollicular lymphocytic infiltrate. Mucin consists of hyaluronic acid.

HAMARTOMATOUS AND NEOPLASTIC CUTANEOUS MUCINOSES Although stromal mucin deposition may be found in a large number of cutaneous tumors (eg, basal cell carcinoma, neurofibroma) as an incidental finding, the mucin deposition is a distinctive histologic feature in mucinous nevus and cutaneous myxoma.

A

370

Mucinous Nevus A mucinous nevus is a benign hamartoma that may be either congenital or acquired. It consists of a cobblestoned plaque, usually in a unilateral nevoid pattern.1,2 HISTOPATHOLOGIC FEATURES A diffuse deposition of mucin is seen in the upper dermis, and collagen and elastic fibers are diminished or absent in the mucinous area.2 The epidermis may be normal or

HISTOPATHOLOGIC FEATURES Cutaneous myxoma is a lobulated lesion characterized by a mucinous matrix involving the dermis and subcutis, with variably shaped fibroblasts, mast cells, and a few collagen and reticulin fibers1,17 (Fig. 16-14A and 16-14B). Bizarre multinucleated cells and regular mitotic figures can be seen. Prominent dilated capillaries are a typical finding. An epithelial component consisting of keratinous cysts or epithelial strands with trichoblastic features is often entrapped in the lesion. Stromal cells are vimentin positive and smooth muscle α-actin positive, supporting myofibroblastic differentiation. DIFFERENTIAL DIAGNOSIS The major process to be distinguished is focal cutaneous mucinosis in which mucin involves only the dermis and spares the

B

 FIGURE 16-14 Cutaneous myxoma. (A and B) In this biopsy of a cutaneous myxoma, there is striking mucin deposition, resulting in a nodular distortion of the dermis with focal epidermal attenuation. There is increased vascularity, hence the alternative name, superficial angiomyxoma.

subcutis in the absence of increased vascularity.1 The differentiation is important because myxoma is a true neoplasm, although benign, which may recur after incomplete excision. Moreover, cutaneous myxoma may be a marker of Carney complex. Acral fibromyxoma is a distinct acral-based neoplasm that has many overlapping features with superficial acral angiomyxoma. The discriminating features include greater collagen deposition, and the stromal fibroblasts are typically CD34 and CD99 positive.

HYALINE DEPOSITIONS

Amyloid was once considered to be a single substance regardless of the differences in clinical presentations. It is now known that the origin and chemical nature of amyloid are quite diverse (see Table 16-2). Why then do we still use the term amyloid? The answer is that so-called “amyloid” defined by Virchow as a starchlike, iodine-stainable substance shares several common characteristics, including an eosinophilic amorphous appearance with the H&E stain (see Table 16-3); Congo red staining resulting in a doubly refractile green color under polariscopy; thioflavine T fluorescence; and straight, nonbranching filaments (6–10 nm in diameter) seen on electron microscopy.18 Keratin, immunoglobulin, insulin, thyrocalcitonin, and other chemical substances can produce β-pleated antiparallel polypeptide sheets and therefore are amyloidogenic. All amyloid deposits, irrespective of their chemical nature and the clinical type of amyloidosis, have a common component, amyloid P component, which is a nonfib-

rillar protein derived from a serum precursor, known as serum amyloid P (SAP). Amyloid can be detected by immunohistochemical stains on paraffin-embedded sections using antibodies against human component P (anti-SAP); however, the specificity of this reaction is limited because amyloid P is also present in elastic tissue. The current classification of amyloidoses is based on the chemical nature of the amyloids with significant consideration of the conventional clinical subclassification (see Table 16-2).

Systemic Amyloid Light Chain Amyloidosis Systemic amyloidosis is classified into a primary (idiopathic) type caused by an occult plasma cell dyscrasia and a myeloma-associated type.18 The precursor of amyloid light chain (AL) amyloidosis is a monoclonal immunoglobulin light chain, more frequently of the lambda type. This form of amyloidosis is mainly a systemic deposition disease (kidney, liver, heart), but cutaneous lesions

Table 16-2 Amyloid-Hyaline-Colloid Deposition DISORDER Amyloidoses Systemic AL amyloidosis

Systemic AA amyloidosis (secondary systemic amyloidosis) Familial amyloidotic neuropathy b2-microglobulin amyloid Colloid milium Hyalinosis cutis et mucosae

Porphyria

DISTRIBUTION AND CHARACTERIZATION Perioral papules and ecchymosis, macroglossia, pinch hemorrhage Subcutaneous fat, rectal submucosa

ASSOCIATED DISORDERS

SPECIAL STAINS

Kidney, liver, heart, muscle deposition

Congo red (green birefringence), crystal violet, thioflavine T fluorescence Same (Congo red – after permanganate) Same

Kidney, liver, spleen

Leg ulcers, atrophic scars, pinch hemorrhage Lichenoid papules on arms and trunk Face, hands, neck

Peripheral nerves kidney, pancreas, testes Long-term hemodialysis

Oral mucous membrane edges of eyelids and nostrils (string of beads), over joints Sun-exposed areas (face, dorsum of hands, arms)

Epilepsy

Gout (tophi)

Auricle, finger, elbow

Waldenstrom macroglobulinemia (storage papule)

Semitranslucent papules

None

Hepatitis C in PCT, hepatic fibrosis and gallstones in EPP, neuropathy in variegated and hereditary coproporphyria Arthritis (big toe), kidney stones, neuropathy IgM gammopathy

CHAPTER 16 ■ DEPOSITION DISORDERS

“Hyaline” is not a single substance. Traditionally, this term has included a variety of skin deposits that appeared eosinophilic and somewhat glassy because of the refraction of light. Therefore, the recognition of hyaline invokes the differential diagnosis of a limited yet diverse group of conditions (Tables 16-2 and 16-3). All hyalines described below are PAS positive, Congo red positive, and thioflavine T positive.

SYSTEMIC AMYLOIDOSES

Adult type: amyloid P component Juvenile type: antikeratin Ab PAS (diastase-resistant)

PAS (diastase-resistant)

Birefringence in alcohol-fixed tissue Anti-IgM stain

371

Table 16-3 Summary of Special Stains for Pink Amorphous Deposits AMYLOID

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Congo red Apple green birefringence Thioflavin T Yellow-green birefringence Crystal violet metachromasia Methyl violet (red) Pagoda red no. 9 (Dylon) Scarlet red no. 5 (RIT) PAS + diastase Amyloid P-component antibody Keratin antibody IgM antibody Colloidal iron (pH, 2.5) Alcian blue Sudan black (frozen sections) Oil red O

+ − +

+ + + − + + Cutaneous + − − − − −

+ − − − + + Juvenile + − − − − −

HISTOPATHOLOGIC FEATURES Amyloid deposition begins in the perivascular and periappendageal areas (surrounding the sweat glands and hair follicles) and adipose tissue with the formation of “amyloid rings” (about the fat cells). Amyloid eventually fills the papillary dermis and diffusely involves the entire dermis, often associated with hemorrhages due to blood vessel involvement by amyloid

A

372

+ + +

are observed in 30% to 40% of patients. Pinch hemorrhages, periorbital waxy papules and plaques with hemorrhage, enlargement of the tongue (macroglossia), and hardening of the oral mucous membranes are the most common signs.

LIPOID PROTEINOSIS

COLLOID

PORPHYRIA

WALDENSTROM MACROGLOBULINEMIA

+ Weak + Weak + Weak − + + − −

− − −

− − −

− − − − + − −

− − − _ +

− + + + +

− − − − −

+ − − − −

infiltration (Fig. 16-15A). In extensive infiltrates, diffuse or nodular eosinophilic deposits often have a fissured or cracked appearance, rendering smaller aggregates with facets. Fibroblasts are often attached to the fissured edges. The deposits are not usually associated with an inflammatory infiltrate. Congo red stain is strongly positive in dermal amyloid (Fig. 16-15B). Amyloid deposits are reactive with the antibodies against immunoglobulin light chains (Fig. 16-16). In a rare subtype called amyloid elastosis,19 which is seen in the setting of systemic amyloidosis, the amyloid deposits surround individual elastic fibers. These elastic fibers appear shortened and fragmented

−

and show no evidence of elastorrhexis and calcification. Abdominal subcutaneous fat and gingival biopsies may be useful in the absence of specific mucocutaneous lesions. DIFFERENTIAL DIAGNOSIS See Tables 16-2 to 16-5.

Systemic Amyloid A Amyloidosis or Secondary Systemic Amyloidosis This disorder occurs in association with a variety of chronic inflammatory and infectious diseases such as rheumatoid arthritis, familial Mediterranean fever,

B

 FIGURE 16-15 Systemic amyloid light chain amyloidosis. (A) A hyaline substance (ie, amyloid) occupies the entire dermis. There are some fissures and hemorrhages with vascular ectasia (B) Congo red stain is strongly positive in dermal amyloid.

lepromatous leprosy, hidradenitis suppurativa, and generalized arthropathic psoriasis. Visible skin lesions are rare, except in Muckle-Wells syndrome, in which geographic skin lesions are seen (probably not containing amyloid). The major sites of amyloid A (AA) deposition are not the skin but rather the parenchymatous organs such as the kidneys, liver (speckled or wax liver), and spleen (sago spleen). AA is not immunoglobulin but instead is derived from α-globulin called serum amyloid A (SAA), which is split into AA amyloid in chronic febrile conditions.

Table 16-4 Skin-Limited Amyloidoses CLINICAL FEATURES

Keratin-Derived Amyloidoses Macular amyloidosis

Lichen amyloidosis

Biphasic amyloidosis (macular and lichen amyloidosis) Friction amyloidosis (see macular amyloidosis) Epithelioma-associated keratin amyloidosis

Actinic amyloidosis Juvenile colloid milium Insulin-Derived Amyloidosis Insulin amyloidosis

Immunoglobulin-Derived Amyloidosis Nodular amyloidosis

HISTOPATHOLOGIC FEATURES

Rippled pigmentation on the upper back, scapular areas, often middle-aged women of color, often with pruritus Hyperkeratotic papules or plaques on the shins, extensor surfaces, pruritis

Scant eosinophilic globules in the papillary dermis, pigment incontinence, occasional dyskeratotic cells Hyperkeratosis, papillomatous epidermal hyperplasia, aggregates of eosinophilic globules in the papillary dermis

Various cutaneous neoplasms: basal cell carcinoma, Bowen disease, actinic keratosis, seborrheic keratosis Waxy or pearly papules or, nodules on sun-exposed skin

Deposition of eosinophilic globules in both the parenchyma and stroma

Sites of repeated insulin injection

Eosinophilic globules, reparative changes

Single or multiple nodules on the face, scalp, and legs of middle-aged women

Massive accumulation of pink amorphous material in the dermis and occasionally the subcutis, plasmocytes

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-16 Systemic amyloid light chain amyloidosis. Amyloid deposits are reactive with the antibodies against immunoglobulin light chains.

HISTOPATHOLOGIC FEATURES Deep-needle biopsy of the lower abdomen shows amyloid deposition around the subcutaneous fat cells (amyloid rings) and eccrine glands in about 66% of cases. As the amount of amyloid increases, the dermis may be diffusely infiltrated. Rectal biopsy shows amyloid deposition

DIFFERENTIAL DIAGNOSIS Postinflammatory hypermelanosis

Colloid milium, lipoid proteinosis

Large aggregates of pink eosinophilic material

Primary amyloidosis Waldenstrom macroglobulinemia

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Table 16-5 Comparison of Lichen Amyloidosis and Colloid Milium of Adults LICHEN AMYLOIDOSIS

COLLOID MILIUM OF THE ADULT

Small deposits within broadened dermal papillae Amyloid in small globules Amyloid is amphophilic or eosinophilic in sections stained with H&E Stellate fibroblasts and melanophages intimately associated with globules of amyloid No clefts within the globules of amyloid Vascular proliferation associated with amyloid Papillary epidermal hyperplasia usually with hyperkeratosis overlies amyloid Solar elastosis not usually seen

Large deposits within the upper half of the dermis Colloid in large, nodular accumulations Colloid is amphophilic or basophilic in sections stained with H&E A few fibroblasts associated with colloid, but no macrophages

in the submucosa. After treatment with potassium permanganate, AA amyloid becomes nonreactive for alkaline Congo red stain; amyloid L is not affected by this treatment.18 DIFFERENTIAL DIAGNOSIS See Tables 16-2 to 16-5.

Familial Amyloidotic Polyneuropathy The familial amyloidoses constitute a group of autosomal dominant diseases in which a mutant protein forms amyloid fibrils.18 The most common form is caused by mutant transthyretin. Skin changes consist of trophic leg ulcers and atrophic scars due to the accumulation of transthyretin-derived amyloid in peripheral nerves. This variety has long been confused with leprosy because of nerve involvement and the deformity of the joints. There are Portuguese, Japanese, and Swedish subtypes. HISTOPATHOLOGIC FEATURES In the skin, blood vessels, arrector pili muscles, and elastic fibers are infiltrated by amyloid in addition to cutaneous nerves. The pancreas and testes may be affected, but the liver and spleen are usually spared.

β2-Microglobulin Amyloid Small, shiny lichenoid papules develop on the arms and trunk of patients who have had long-term hemodialysis. Dermal deposition of amyloid is similar to that in patients with AL amyloidosis.

SKIN-LIMITED AMYLOIDOSES

374

All skin-limited amyloid depositions are of the keratin type, except nodular amyloidosis, which is derived from the light chain of immunoglobulins18 (see

Clefts within the nodules of colloid No vascular proliferation associated with colloid Thin epidermis with loss of the rete pattern and grenz zone overlies colloid Solar elastosis always present

Table 16-4). The source of keratins is either epidermal or from tumors of epidermal or hair follicle origin. Individuals of colo, such as African Americans, Asians, Latin Americans, and those of Middle Eastern origin, are more frequently affected than whites. Macular, lichenoid, and biphasic amyloidosis are the three most common variants. Rare variants include a poikilodermatous type called amyloidosis cutis dyschromica, an anosacral variant, a thermosensitive variant, and a familial primary cutaneous form.20

Macular Amyloidosis The upper back and scapular areas of middle-aged, dark-skinned women are most commonly affected by pruritic macules showing irregular pigmentation with a “rippled” pattern. The constant use of a nylon brush or towel is sometimes involved as a causal factor (frictional amyloidosis).

Lichen Amyloidosis Typical lesions are hyperkeratotic papules and plaques involving the shins and, in severe cases, the extensor surface of the arms, including the shoulders. Severe pruritus is a characteristic feature, and some authors have proposed that lichen amyloidosis is almost always a consequence of scratching in the setting of an underlying pruritic condition. Familial cases of lichen amyloidosus and cases associated with genetic diseases (eg, multiple endocrine neoplasia syndrome type 2A) have been reported.

Biphasic Amyloidosis Both lichenoid and macular amyloidoses are present in the same area or separate

locations in the same patient. The lichenoid lesions are commonly pruritic. HISTOPATHOLOGIC FEATURES Small numbers of eosinophilic globular deposits of amyloid, barely distinguishable from collagen, accumulate initially in the papillary dermis in macular amyloidosis, resembling the cytoid bodies of lichen planus. Although cytoid bodies or other evidence of keratinocyte degeneration are not routinely observed in the epidermis, a careful search may identify such cells. These epidermal cytoid bodies are considered to be the source of amyloid in these varieties of amyloidoses, breaking through the basement membrane and dropping into the dermis. In lichen amyloidosis, large clumps of amyloid expand dermal papillae, pressing the rete ridges into thin septae.20 Lichen amyloidosis may be distinguished from the macular form by hyperkeratosis, acanthosis with hyperpigmentation of the basal layer, and larger deposits of amyloid (Fig. 16-17). In the later stages, diffuse homogeneous eosinophilic amyloid fills the papillary dermis and infiltrates the upper reticular dermis. Adnexal structures and blood vessels are not involved. Some degree of pigment incontinence and hemorrhage is usually present in both forms of cutaneous amyloidosis. A characteristic feature of familial lichen amyloidosus is the transepidermal elimination of amyloid. Keratin amyloids (amyloid K) are strongly stained with polyclonal antikeratin antibodies that contain combinations of antibodies against basal cell keratins (K5, K14) and upper epidermal keratins (K1, K10). Amyloid P component is always positive. Maturation of degenerated keratin proteins into amyloid may require a digestion process in the lysosomes of dermal macrophages.

A

B

Routine Congo red, Dylon, thioflavine T (Fig. 16-18), toluidine blue, and crystal violet stains are positive, but they are not always reliable in formalin or alcohol fixed-tissue sections. These stains are more reliable in fresh-frozen sections. Electron microscopic demonstration of 6to 10-nm straight filaments is the most specific and reliable diagnostic method (Fig. 16-19). DIFFERENTIAL DIAGNOSIS A major condition confused with macular amyloidosis is postinflammatory hypermelanosis. However, postinflammatory hypermelanosis does not exhibit amyloid and is clinically distinctive. The differential diagnosis of lichen amyloidosis includes nodular amyloidosis, colloid milium and colloid degeneration, lipoid proteinosis, and Waldenstrom macroglobulinemia (see Tables 16-2 to 16-4). Nodular amyloidosis usually shows much more extensive amyloid accumulation in the dermis (and possibly the subcutis) and waxy or translucent nodules of the head and neck compared with lichen amyloidosis. In addition, immunoglobulin light chains can be demonstrated in nodular amyloidosis. Juvenile colloid milium may be histologically indistinguishable from lichen amyloidosis except by distribution and clinical features. Adult colloid milium differs from lichen amyloidosis by the features outlined in Table 16-5. Lipoid proteinosis (and erythropoetic porphyria) shows a perivascular pattern of accumulation of amorphous pink material that is PAS+D and weakly Congo red positive. The storage papules of Waldenstrom macroglobulinemia may closely resemble adult colloid milium and lichen amyloidosis

because of the presence of clefts and fissures. The hyaline material in such storage papules is PAS+D positive and Congo red negative and reacts with antibodies against IgM.

Epithelioma-Associated Keratin Amyloidosis Skin tumors derived from the epidermis or hair follicle produce keratin amyloid. Clinically, there is no definitive way to differentiate the amyloid contained in such tumors from other forms of keratin-derived amyloid. The same keratin proteins that are found in lichenoid and

macular amyloidoses (K1, K5, K10, K14) are also found in these tumors, both in the parenchyma and stroma. Common tumors that produce amyloid are basal cell carcinoma, Bowen disease, actinic keratosis, and seborrheic keratosis. It is believed that the growth control of the tumor cell population by apoptosis induces filamentous degeneration of keratin intermediate filaments, resulting in the formation of cytoid bodies, which become amyloidogenic. It is probably necessary for such cytoid bodies to persist without perturbation such as from an inflammatory reaction; similar keratin cytoid bodies occurring in the lichenoid

 FIGURE 16-18 Lichen amyloidosus. Thioflavine T fluorescence is seen in amyloid deposition in the papillary dermis.

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-17 Lichen amyloidosus. (A) Hyperketotic papules present on the extremities. (B) Under the hyperkeratotic epidermis, pale pink hyaline material (ie, amyloid), barely distinguishable from the collagen, is deposited mainly in the papillary dermis.

375

HISTOPATHOLOGIC FEATURES In juvenile colloid milium subepidermal, eosinophilic, fissured colloid masses abut the epidermis without a grenz zone (Fig. 16-20). Colloidlike material appears to develop in basal keratinocytes and drop off into the papillary dermis. Histiocytes and melanophages are noted within the colloid material. Epidermal cytoid bodies and dermal amyloid can be stained with polyclonal antikeratin antibodies in addition to standard amyloid stains. The filaments derived from these cytoid bodies meet the ultrastructural criteria for amyloid filaments.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Insulin Amyloidosis It is known that insulin can be converted into amyloid in insulinoma or pancreatic islets in individuals with diabetes. Such amyloid is designated islet amyloid polypeptide. In the skin, insulin amyloid is formed at the sites of repeated insulin injection.

Nodular Amyloidosis  FIGURE 16-19 Filamentous degeneration (f ) of keratinocytes is observed in the lower epidermis. Normal tonofilaments (t ) lose their electron density (*) and become wavy (curved arrow ). Some cellular organelles (arrowheads ) are intact (x2000).

dermatoses, such as lupus erythematosus, do not transform into amyloid. When apoptotic cells are eliminated from the epidermis or tumor parenchyma to the dermis or stroma, the components of the basement membrane become entangled in the amyloidogenic filament mass and can be demonstrated within the mature amyloid; thus, PAS-positive substances and laminin and type IV and VII collagens can be stained in mature keratin amyloid.

sis of the inner auricle or helix of the ear is clinically an aggregation of cobblestonelike waxy or pearly papulonodules.22 Severe keratinocyte degeneration into cytoid bodies is present in the epidermis.

Single and sometimes multiple nodules may occur anywhere on the cutaneous surface, but the face, scalp, and leg of middle-aged women are the most common sites.18 Individual nodules are firm, waxy and tumorlike, or appear semitransparent, amber colored, or hemorrhagic (Fig. 16-21B). About 7% of these patients develop multiple myeloma. Nodular amyloidosis may be associated with Sjögren syndrome and subacute cutaneous lupus erythematosus. In such cases, serum autoantibodies Sjogren

Actinic Amyloidosis

376

These conditions include juvenile colloid milium and amyloidosis of the auricular concha.21,22 Ultraviolet rays have a severe injurious effect on keratinocytes, as evidenced by sunburn cells. Chronic sun exposure of the skin leads to the amyloidal degeneration of the epidermal keratinocytes. For example, actinic keratosis is often associated with the deposition of keratin amyloid. Whereas the “colloid” substance in juvenile colloid milium is actually keratin amyloid, adult-type colloid milium contains severely degenerated elastic fibers. An association of juvenile colloid milium with ligneous conjunctivitis has been identified.1 Concha amyloido-

 FIGURE 16-20 Juvenile colloid milium. Pink-stained hyaline substance (ie, amyloid) occupies widened dermal papillae. Round cytoid body–like amyloid globules can be recognized at the periphery.

B

 FIGURE 16-21 Nodular amyloidosis. (A) Characteristic infiltrative firm, waxy nodules on the face. (B) A massive deposition of amorphous amyloid substance throughout the entire dermis. There are many fissures and cracks caused by processing artefact due to the lack of elasticity in amyloid.

syndrome antigen A/Sjogren syndrome antigen B (SSA/SSB) are positive. HISTOPATHOLOGIC FEATURES A massive deposition of weakly eosinophilic amorphous amyloid substance is noted throughout the entire dermis, often extending into the subcutis (see Fig. 16-21A) and around the blood vessels and the dermal appendages.18,23 Greenish birefringence of Congo red stain makes contrast with white birefringence of collagen fibers (Fig. 16-22). Numerous plasma cells, some with large Russell bodies, are often seen, but they are sparse or absent in nodular lesions of systemic primary and myeloma-associated amyloidosis. Monoclonality of infiltrating plasma cells by polymerase chain reaction has been detected. Giant cells and focal calcification may be found. Contrary to the other localized cutaneous amyloidoses, the amyloid deposits are AL type, derived from immunoglobulin light chains. In all types of amyloid, immunoglobulins are present, probably passively trapped in the meshwork of amyloid filaments. These immunoglobulins can be eluted in acidic buffer without disrupting the filamentous nature of

amyloid or altering the standard amyloid stains. In nodular amyloidosis, the same elution procedure abolishes amyloid staining, suggesting that this amyloid is immunoglobulin itself. However, the

CHAPTER 16 ■ DEPOSITION DISORDERS

A

origin of immunoglobulin is not always elucidated. DIFFERENTIAL DIAGNOSIS See Tables 16-4 and 16-5.

 FIGURE 16-22 Nodular amyloidosis. Congo red stain observed under polarized light. Greenish birefringence of Congo red–stained amyloid makes contrast with white birefringence of collagen fibers.

377

Soft Tissue Amyloidoma (Tumoral Amyloidosis)

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Amyloidoma is defined as a solitary, localized, tumorlike deposit of amyloid in the absence of systemic amyloidosis. Amyloid deposition may be of the AL or AA type.24 It has been reported in many anatomic sites, including the soft tissues and the skin, mainly on the extremities. Some cases have been associated with local trauma, surgery, infection, peripheral vascular disease, and diabetes.

378

HISTOPATHOLOGIC FEATURES Amyloid deposition fills the dermis and subcutis and is sometimes associated with a giant cell granulomatous reaction, a patchy lymphocytic infiltrate, and focal microcalcification. Plasma cells are not a prominent component; however, in some cases of localized amyloidosis, a light chain–restricted plasma cell infiltrate has been identified, suggesting its classification as a form of low-grade B-cell lymphoproliferative disease. The persistence or absence of congophilia after pretreatment with permanganate is useful in differentiating the type of amyloid. AL amyloid remains positive with Congo red stain after pretreatment.

Hyalinosis Cutis et Mucosae (Lipoid Proteinosis) This is a rare autosomal recessive (OMIM 247100) or sporadic (new mutation) disease.25 In the hereditary form, which is caused by mutations in the extracellular matrix protein 1 gene, the initial symptom is hoarseness due to hyaline infiltration of the vocal cords. A diffuse infiltration of the pharynx, larynx, and oral mucosa (including the tongue) produces extensive induration of the mouth. Early lesions consist of bullae and varicelliform scars on the face and arms, which are similar to those of erythropoietic protoporphyria. The free edges of the eyelids and nostrils show small, waxy, semitransparent papulonodules resembling a “string of beads.” Large plaque-type infiltration may occur on the face and over the joints. The nonfamilial type occurs in an older age group and is typified by similar lesions except bullae and scars on the face are present. HISTOPATHOLOGIC FEATURES Hyalin deposition begins around the dermal blood vessels and eccrine glands where PASpositive diastase-resistant hyaline is demonstrated in concentric rings (onionskin pattern). This material, which also stains with Alcian blue at a pH of 2.5 and

stains only very weakly or negatively with Congo red, may be seen around pilosebaceous units and in arrector pili muscles.25 Hyaline deposits oriented perpendicularly to the dermoepidermal junction gradually fill the entire dermis (Figs. 16-23 and 16-24). Small lipid droplets may be demonstrated with the scarlet red stain, particularly around the blood vessels in late lesions. The epidermis may show hyperkeratosis and papillomatosis in verrucous lesions. Calcified foci and a failure of mucocutaneous lymphangiogenesis have also been described.26 Electron microscopy demonstrates multiplication of lamina densa (basal lamina) in perivascular and periglandular spaces. The hyaline substance is mainly homogeneous, but some filament components are also admixed. Significant degeneration of collagen fibers are seen as longitudinal splitting or fragmentation of fibers. The dermal deposits contain type IV collagen, laminin, neutral muchopolysacchrides, hyaluronic acid, and ceramide or more complex lipids, but the precise pathogenesis of the disease remains unknown. DIFFERENTIAL DIAGNOSIS PAS-positive material in lipoid proteinosis is differentiated from amyloid by its negative or weak staining on Congo red stain. In erythropoetic protoporphyria, the deposits are more limited in distribution, being perivascular only, and the sweat glands are not involved.

Colloid Milium Colloid milium is divided into three clinical types: colloid milium of the adult,

juvenile colloid milium (see earlier in the chapter in Actinic Amyloidosis), and nodular colloid degeneration. A fourth variant, pigmented colloid milium associated with hydroquinone use, is also seen.27

Colloid Milium of the Adult Yellowish semitransparent papules and plaques occur on the face and dorsum of the hands. Interestingly, the left side of the face and left hand are more frequently and severely affected because of more sun exposure on that side while driving. The condition usually occurs in older men with fair skin, particularly farmers and other outdoor workers, sportsmen, and truck drivers. A verrucous variant after exposure to mineral oil and a unilateral variant have been described. The lesions are soft, and a small incision and pressure allow the expression of the gelatinous substance. Hemorrhage is common in large lesions. HISTOPATHOLOGIC FEATURES Colloid in colloid milium of the adult type is the final degeneration product of elastic fibers. H&E-stained sections show a hyaline substance in large sheets occupying the papillary and upper reticular dermis (Fig. 16-25).28 Many cracks and fissures within the colloid material and fibroblasts are commonly seen along the lines of fissuring. Inflammation is lacking. Solar elastosis is always present. A narrow grenz zone of normal collagen separates the atrophic epidermis from the colloid substance. Histochemical studies have shown that the material is PAS positive and only weakly positive

 FIGURE 16-23 Hyalinosis cutis et mucosae. A widened dermal papilla is entirely occupied by vertically oriented hyaline material. Several dilated blood vessels are seen. The tissue reaction against this massive deposition is minimal. (Courtesy of A. Amantea, MD, and P. Donati, MD.)

the two conditions. A good clinicopathologic correlation and electron microscopy are helpful29 (see Table 16-5).

Nodular Colloid Degeneration Single or multiple large nodules occur on the face or head and neck region. The sun-protected skin of the trunk may be involved.

or negative with Congo red or thioflavine T. The disparity in the results of Congo red stain could be due to the different technical procedures performed. An elastic fiber stain is largely negative in the main body of colloid and positive in the grenz zone and at the periphery of the colloid deposition (actinic elastosis). Amyloid P component, which is present in normal elastic fibers, is strongly stained in the lesion with the immunoperoxidase method. On electron microscopy the colloid substance is a moderately electron-dense

amorphous substance with some granules and fine filaments. These findings in contrast to the colloid of juvenile colloid milium despite the clinical and histologic similarity of the juvenile and adult types. As already discussed, juvenile colloid milium contains typical keratin-derived amyloid filaments. DIFFERENTIAL DIAGNOSIS Adult colloid milium may be confused with lichen amyloidosis because both conditions show fissured, homogeneous eosinophilic material and special stains are sometimes similar in

WALDENSTROM MACROGLOBULINEMIA In this condition, extramedullary lymphatic tissues are involved by a B-cell lymphoma that produces monoclonal IgM. The lymph nodes, liver, and spleen are enlarged, and the skin may show purpura. Large plaques and nodules develop in the skin. In some patients, small semitransparent “storage papules” are seen.

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-24 Hyalinosis cutis et mucosae. Periodic acid Schiff stain is strongly positive in the hyaline deposition in the upper dermis.

HISTOPATHOLOGIC FEATURES Colloid material occupies the entire dermis, extending more deeply than in individuals with colloid milium. Scattered fibroblasts, dilated blood vessels, clefts, and fissures are present. These features are similar to amyloid deposition of the dermis. However, on electron microscopy, a predominantly amorphous substance is admixed with fine filaments (3–4 nm in diameter) that are smaller than amyloid filaments (6–10 nm). The amorphous masses stain positively with Verhoeff-Van Gieson stain for elastin.30

HISTOPATHOLOGIC FEATURES The storage papules in this condition are similar to the amyloid deposition in lichen amyloidosus and the colloid in adult colloid milium because the substance contained in these papules is eosinophilic and amorphous with H&E stain and occupies the papillary and upper reticular dermis.31 Furthermore, large deposits show clefts and fissures. The material is PAS positive and strongly reactive with antihuman IgM antibody. The large plaques or nodules show involvement by lymphoma. DIFFERENTIAL DIAGNOSIS See Tables 16-2 and 16-3.

PORPHYRIA

 FIGURE 16-25 Adult colloid milium. Hyaline substance (ie, colloid) occupies dilated dermal papillae. There are many fissures in these masses.

These diseases are caused by defective enzymes involved in heme synthesis. Seven of eight subtypes, except the acute intermittent type, exhibit a variety of photosensitivity and related skin changes. The most common subtype is porphyria

379

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

cutanea tarda (PCT) in which serum uroporphyrin is elevated due to a deficiency of uroporphyringogen decarboxylase. Vesicles and blisters occur on the face and dorsum of the hands. Hypertrichosis of the face may be pronounced and may account for the appearance suggesting a “wolfman.” (see Chapter 8 for more detailed discussion). HCV infection may be a major factor in the etiology of PCT. Hepatitis B virus and HIV infection have also been frequently associated. Patients with erythropoietic protoporphyria show blisters and thickening of the facial skin and the dorsum of the hands. The condition appears to be caused mainly by an autosomal dominant mutation of heme synthase gene located on chromosome 18q21.3. HISTOPATHOLOGIC FEATURES The histopathologic features are similar among all photosensitive subtypes. The primary change in all types of porphyrias is a perivascular deposit of hyaline material stainable with PAS; this staining is resistant to diastase digestion (neutral polysaccharides). 32,33 In mild cases, the hyaline deposition is limited to the capillaries of the upper dermis, and in severe cases, it fills the papillary dermis and extends into the lower dermis. Subepidermal blisters develop. The dermal papillae are hardened by this deposition, and when subepidermal blistering occurs, the stiff dermal papillae remain in place instead of collapsing; this has been termed festooning of dermal papillae (Fig. 16-26). Sometimes peculiar, elongated eosinophilic structures in a linear array in the roof of PCT and EPP bullae are seen and have been termed caterpillar bodies. Scleroderma-like diffuse thickening of the dermal collagen may occur in chronic lesions.

A

B

DIFFERENTIAL DIAGNOSIS See Tables 16-2 and 16-3.

HYALINE ANGIOPATHY This histologic change has been described in the oral cavity and the skin. It is characterized by eosinophilic amorphous material within and around dermal vessels. This material differentially stains for light chain products or collagen. The process has been considered both a reaction associated with acute and chronic inflammation and an unusual form of microvasculopathy.34,35

GOUT 380

This dominantly inherited abnormality of purine metabolism produces a high

C  FIGURE 16-26 Porphyria cutanea tarda. (A) In this patient with porphyria cutaneous tarda, foci of subepidermal bulla formation are seen. (B and C) The dermal papillae capillaries exhibit basement membrane zone reduplication, resulting in a hyaline-like appearance to the vessels. The basis of the microvascular injury is one of complement activation via irradiated porphyrins with c5b-9 as the effector mechanism of microvascular injury. (From Vasil KE, Magro CM: Cutaneous vascular deposition of C5b-9 and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda. J Am Acad Dermatol. 2007;56:96-104.)

collagen bundles and are surrounded by a variable histiocytic response. Without any clinical history, such deposition is puzzling. The material may be weakly PAS positive and negative for mucin stains.

HISTOPATHOLOGIC FEATURES Grayish amorphous material with needlelike clefts in the dermis is surrounded by palisading granulomas37 (Fig. 16-27A). The nuclei in macrophages may be altered by crystals and appear atypical. If fixed in alcohol, uric acid crystals are preserved and yield characteristic multicolor birefringence under polarized light (Fig. 16-27B). Upon examination with a red condenser, these crystals assume a yellow color when parallel to the condenser and blue when perpendicular to the plane of projected light. In formalinfixed tissues, the crystals are less obvious, and no birefringence is observed. With the De Galantha stain, the crystals appear brown to black. Secondary calcification or even ossification is common. Late-stage tophi are surrounded by a fibrous pseudocapsule and contain mucopolysaccharides.

Calcium deposition in the skin occurs in variety of clinical situations (Table 16-6). Four subsets occur: metastatic calcinosis (including calciphylaxis), dystrophic calcinosis, idiopathic calcinosis, and iatrogenic calcinosis.36,38

CORTICOSTEROID INJECTION SITES The cutaneous injection sites of corticosteroids often show multiple pools of eosinophilic hyaline material between

A

CALCIUM, BONE, AND CARTILAGE

Calcinosis Cutis

Metastatic Calcinosis Cutis Metastatic calcification occurs when the final metabolic defects give rise to elevated serum calcium or phosphate levels. This may result from hypercalcemia due to hyperparathyroidism secondary to an adenoma or malignant neoplasms secreting parathyroid-like hormones, hypervitaminosis D, milk alkali syndrome, or hyperphosphatemia caused by renal failure or renal dialysis in which excretion of phosphorus is diminished (see Table 16-6). Because the product of serum calcium and phosphorus levels is physiologically constant, this hyperphosphatemia results in a compensatory decline in serum calcium ion levels and the resulting stimulation of parathyroid secretion to mobilize calcium from bone. The direct destruction of bone and the release of calcium may occur in individuals with sarcoidosis, osteomyelitis,

bone metastases in cancer, and multiple myeloma. The clinical appearance of metastatic calcification in the skin ranges from hard papules and nodules to subcutaneous diffuse hardening. When these lesions are ulcerated, chalky white material may be discharged. When blood vessels are calcified, hard, linear, clinically palpable cords may ensue. In calciphylaxis (calcific uremic arteriolopathy)39 (see Chapters 9 and 11), patients affected by hyperparathyroidism secondary to chronic renal failure present with violaceous, painful, necrotic, and ulcerated lesions with a livedoid pattern on the buttocks and extremities. In patients with normal calcium and phosphate levels, it has been suggested that parathyroid hormone (PTH) sensitizes the vessels of the tissue, and subsequent exposure to various triggering agents (ie, metallic salts, albumin, trauma) results in calcification. HISTOPATHOLOGIC FEATURES Calcium stains deep blue to violet in H&Estained tissue sections, black with the von Kossa stain, and red with Alizarin red. Calcium deposition in the skin may be massive in the deep dermis to subcutaneous tissue and in small foci in the upper dermis. Exclusive involvement of the sweat ducts has been reported. A foreign body reaction with fibrosis may develop around larger calcium deposits. In calciphylaxis, intramural calcium deposition occurs in the media of subcutaneous arteries and arterioles in addition to epidermal ulceration and dermal necrosis. Less commonly, vessels are not involved, and calcium is seen in

CHAPTER 16 ■ DEPOSITION DISORDERS

level of serum uric acid, which deposits as monosodium urate crystals in small joints, typically those of the great toe.36 Increased serum purine levels may be secondary to decreased renal function, diuretic therapy, or an increased purine synthesis in myeloproliferative diseases. Skin deposition of uric acid (called gouty tophi) occurs most frequently on the auricle. The elbow and finger joints are also commonly affected.

B

 FIGURE 16-27 Gouty tophus. (A) The deposition of urate is surrounded with foreign body giant cells. (B) Under polarized light, urate crystals give rise to multicolored birefringence. (Figure 16-27B is courtesy of Min W. Lee, MD.)

381

Table 16-6 Calcium and Bone Deposits DISORDER Calcinosis cutis Metastatic

Dystrophic

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Idiopathic

Calciphylaxis

Ossification of the skin Primary

Secondary Albright hereditary osteodystrophy

Subungual exostosis

CLINICAL FEATURES

ASSOCIATED DISORDERS

HISTOPATHOLOGY

Papules, nodules Any location

Hypercalcemia due to hyperparathyroidism hyperphosphatemia, hypervitaminosis D, milk alkali syndrome Normal serum calcium Collagen-vascular diseases None

Massive deposition in subcutis Small foci in dermis

Any location preceding tissue damage, skin tumors and cysts Subepidermal calcified nodule, idiopathic calcinosis (genital), tumoral calcinosis, milia-like calcinosis Abdomen, buttocks, thighs, livedoid pattern

Plaque type, nodular Multiple miliary type on the face Other types anywhere Any location depending on preceding condition Any location

Distal toe and finger

the septa of the subcutaneous tissue (calcifying septal panniculitis).

Dystrophic Type

382

Dystropic calcification is characterized by normal serum calcium and phosphorus levels and the internal organs are spared; that is, this is strictly a cutaneous phenomenon secondary to local tissue disruption, necrosis, or “dystrophy.” Widespread cutaneous calcification (calcinosis universalis) may occur in collagen vascular diseases, such as childhood dermatomyositis, progressive systemic sclerosis (particularly CREST [calcinosis, Raynaud syndrome, esophageal dysmotility, sclerodactyly, and telangiectasia] syndrome), and systemic lupus erythematosus. Localized forms (calcinosis circumscripta) may also occur in patients with these diseases, particularly in the digits of patients with acrosclerosis and in acne and stasis ulcers. Inherited diseases such as pseudoxanthoma elasticum and Ehlers-Danlos syndrome (gravis

Individual condition determines the calcification pattern Papillary dermis, acanthosis Well-demarcated areas Massive subcutaneous calcification Intramural deposition in subcutaneous vessels

Down syndrome Renal failure Sensitizer: hyperparathyroidism Challengers: albumin, metallic salts, vitamin D, parathyroid hormone None Acne, scars

Lamellar bone in dermis or fat

Skin appendage tumors, collagen-vascular disease Short stature, round face, absence of some knuckles Mental retardation, hypercalcemia (pseudohypoparathyroidism) or normocalcemia (pseudopseudohypoparathyroidism) None

Metaplastic ossification and calcification Lamellar bone

type), may be associated with calcinosis cutis. Subcutaneous fat necrosis of the newborn, frostbite or trauma of the auricle, old lesions of nodular amyloidosis, and repeated venipuncture of the heels of infants for blood tests are followed by localized calcification. Many appendage tumors of the skin with hair follicle differentiation, notably calcifying epithelioma or pilomatricoma, trichilemmal (pilar) cysts, basal cell carcinoma, and trichoepithelioma, often show calcium deposition. HISTOPATHOLOGIC FEATURES Calcium deposition is usually slight in the upper dermis with localized granular deposits. The deposition in the deep dermis and subcutaneous tissue is usually substantial or massive. Vascular involvement is not a feature. Each of the individual preceding conditions usually determine the pattern of calcification. For example, necrotic fat cells are primarily calcified in subcutaneous fat necrosis of the newborn, and tumor parenchyma is initially calcified in pilar tumors. Leakage of calcium

Enchondral bone

into the connective tissue elicits various degrees of foreign body reactions.

Idiopathic Type TUMORAL CALCINOSIS Calcification of the skin may occur without apparent cause or antecedent tissue injury. “Tumoral calcinosis” is usually a familial condition in which numerous subcutaneous calcified nodules can be palpated in otherwise healthy patients (Fig. 16-28). Hyperphosphatemia may be present. This condition resembles clinically dystrophic calcinosis universalis of dermatomyositis and tends to affect the bony prominences. It is more common in Africa and Papua-New Guinea than North America and Europe. SUBEPIDERMAL CALCIFIED Localized, solitary nodular calcification (subepidermal calcified nodule or cutaneous calculus) is found in infants as a congenital tumor (Fig. 16-28). The face, particularly the ear, or limbs are common sites.

B

 FIGURE 16-28 Tumoral calcinosis. (A) There are nodular foci of calcification with associated fibrosis and foreign body reaction compatible with tumoral calcinosis. (B) In this child, a biopsy of a hard cheek nodule revealed nodular collections of calcium in the dermis with associated transepidermal elimination of calcium through the epidermis.

In rare instances, multiple lesions occur. Adults may be affected. Idiopathic calcinosis of normal skin has been reported to involve the scrotum, penis, and vulva and in patients with Down syndrome (milialike calcinosis).

of the subcutaneous fat, in the spaces between adipocytes, in connective tissue septa (Fig. 16-29), and in the media of small arteries.40

HISTOPATHOLOGIC FEATURES As the dystrophic type, massive calcification is present in the subcutaneous tissue in tumoral calcinosis with multiloculated cystlike structure containing a milky fluid with calcium granules. In subepidermal calcified nodules, multiple granules and islands of calcification are seen just beneath a hyperkeratotic and acanthotic epidermis (Fig. 16-28B). Transepidermal elimination through the hair canals and eccrine sweat ducts may be observed ( Fig. 16-28B). Idiopathic calcinosis of the genital areas and milia-like calcinosis display homogeneous discrete areas of calcification with well-demarcated contours.

Cutaneous ossification is an unusual event that may be primary or secondary to either inflammatory or neoplastic processes41 or systemic conditions with a genetic basis (Albright hereditary osteody-

CUTANEOUS OSSIFICATION

strophy, progressive osseous heteroplasia, fibrodyslasia ossificans progressive) (see Table 16-6).42 The osteoblast, a modified fibroblast, produces type I collagen in a similar fashion to dermal fibroblasts. However, posttranslational alterations of osteoblast-derived type I collagen probably make it more suitable for phosphorylation to initiate ossification. Activators of bone formation, such as osteonectin and transforming growth factor β, are produced by osteoblasts.

CHAPTER 16 ■ DEPOSITION DISORDERS

A

Iatrogenic Calcinosis Iatrogenic calcinosis has been described at the sites of extravasation of calcium associated with the administration of intravenous calcium solutions, at the sites of subcutaneous injection of lowmolecular-weight heparins such as nadroparin,40 and even in patients after liver transplantation. HISTOPATHOLOGIC FEATURES An extensive, widespread calcification with a characteristic “feathery” alteration of collagen and elastic fibers is observed in the dermis. Multiple foci of microcalcification may develop within the lobules

 FIGURE 16-29 Primary cutaneous osteoma cutis. Well-circumscribed nodule of mature lamellar bone with trabecular projections and stromal component of fat cells.

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Primary Cutaneous Ossification (Osteoma Cutis) This condition may occur in early life or in adults as widespread multiple nodules or as a single, large plaquelike osteoma. The late onset varieties occur as a single small nodule anywhere in the skin or as “multiple miliary osteoma of the face.” The latter lesions are most commonly encountered in older woman, but the condition has recently been reported in elderly men as well. The face, particularly the forehead, is involved by multiple hard, tiny papules of normal to blue color occurring in acne lesions and scars. Small, pebbly bone chips can be extracted from these papules. HISTOPATHOLOGIC FEATURES Fragments of bone that vary in size and shape are present in the deep dermis or subcutaneous tissue (see Fig. 16-29). This type of bone develops by membranous ossification without the presence of a cartilage precursor and is called lamellar bone. It exhibits a laminated fibrous structure (cement lines) indicating underlying collagen bundles. Osteoblasts are embedded within the bone and are also noted at the peripheries where nonmineralized, condensed collagen islands (osteoid) are still present. Connective tissue and mature fat cells accompanied by blood vessels are enclosed in the bone and form Haversian canals. However, osteoclasts, which are multinucleated giant cells resembling foreign body giant cells, are only rarely observed. Hematopoiesis may occasionally be seen in the marrow spaces. Ulceration and epidermal elimination may occur.

and blood vessels are present. In chondroid syringoma, ossification occurs by the replacement of preformed cartilage (ie, enchondral bone formation).

Subungual Exostosis (Osteochondroma) This is a solitary tender nodule under the distal end of the nail, most commonly at the free edge of the great toe. The lesion is composed of mature trabecular bone with an overlying cap of mature cartilage as the osteogenesis occurs by enchondral ossification.

Albright Hereditary Osteodystrophy This dominantly inherited disorder of bone, caused by mutations in the GNAS1 gene, is also termed pseudohypoparathyroidism or pseudopseudohypoparathyroidism, depending on whether abnormal or normal calcium metabolism is present. The former is characterized by hypocalcemia that does not respond to PTH; in the latter condition, the response is unaltered. These patients show characteristic round facies, diminished stature, and shortened metacarpal bones. Ossifications of any size may occur anywhere in the skin and subcutaneous tissue. Bone may be extruded through cutaneous ulcerations. HISTOPATHOLOGIC FEATURES The bone formation is of the lamellar type, that is, developing by the ossification of

compacted collagen (osteoid) in which lamellar sheets are still visible.

ENDOGENOUS PIGMENT DEPOSITS

Alkaptonuria and Ochronosis Alkaptonuria is a rare autosomal recessive disorder of homogentisic acid catabolism due to loss-of-function mutations in the homogentisate 1,2-dioxygenase gene (HGO). Because of the enzymatic block, homogentisic acid deposits on collagen, especially in the skin and cartilage, and is then oxidized and polymerized to ochronotic pigment. Alkaptonuria is characterized by the triad of homogentisic acid present in the urine, ochronosis, and ochronotic arthropathy.43 Ochronosis refers to the deposition of ochre-colored pigment in the skin and other tissues, giving rise to a blue-black appearance. The ear cartilage is usually the first site affected; the axillae and groin are also commonly involved. HISTOPATHOLOGIC FEATURES Yellowbrown, ochre-colored masses with bizarre (sausage- or banana-shaped structures) and irregular shapes are deposited in the mid-dermis, often in association with solar elastosis (Fig. 16-30).36,43 Degenerated collagen appears as amorphous, fragmented clumps, sometimes associated with a granulomatous reaction. Transepidermal elimination of

Secondary (Metaplastic) Cutaneous Ossification Many conditions in which calcium deposition occur (eg, calcinosis cutis) are prone to ossification. Some examples are skin appendage tumors, notably calcifying epithelioma (pilomatricoma) and chondroid syringoma, melanocytic nevi (osteonevus of Nanta), collagen vascular diseases (particularly CREST syndrome), and childhood dermatomyositis. The chronic stage of fibrosis (eg, scars and scleroderma) seems to induce ossification.

384

HISTOPATHOLOGIC FEATURES The laminated layers of eosinophilic bone are the result of mineralization of type I and, to a lesser extent, type III and V collagens. Osteoblasts are found within and along the periphery of the bone. In larger lesions, Haversian canals with collagen

 FIGURE 16-30 Alkaptonuric ochronosis. Yellow-brown, ochre-colored, bizarre (banana-shaped) masses deposited in the upper dermis with solar elastosis and a granulomatous reaction.

ochronotic fibers has been seen. Fine granular pigment may lie free in the dermis or in the endothelial cells and sweat glands. The pigment stains black with crystal violet or methylene blue stains.

MUCOPOLYSACCHARIDOSES

HISTOPATHOLOGIC FEATURES In the thickened skin or in the grouped papular areas (pebbling) of patients with Hunter and Hurler syndromes, an increased amount of mucin-containing sulfated glycosaminoglycans in the reticular dermis and plump fibroblasts containing vacuoles and granules stained with colloidal iron and Alcian blue (both at a pH of 4.0 and a pH <2.0) and demonstrating metachromasia with Giemsa or toluidine blue stain are seen.45 Therefore, these fibroblasts sometimes resemble mast cells. Metachromatic granules may be noted in vacuolated cells in the epidermis and eccrine glands and ducts. Electron

REFERENCES 1. Rongioletti F, Rebora A: Mucinoses. In: Bolognia J, Jorizzo JL, Rapini RP et al (eds). Dermatology, 2nd ed. St. Louis: Mosby Elsevier; 2008:611. 2. Rongioletti F, Rebora A: Cutaneous mucinoses: microscopic criteria for diagnosis. Am J Dermatopathol. 2001; 123:257. 3. Tominaga A, Tajima S, Ishibashi A, et al: Reticular erythematous mucinosis syndrome with an infiltration of factor XIIIa+ and hyaluronan sythase 2+ dermal dendrocytes. Br J Dermatol. 2001; 145:141. 4. Smoller BR, Horn TH: Endocrine abnormalities and the skin. In: Smoller BR, Horn TH (eds). Dermatopathology in Systemic Diseases. New York: Oxford, University Press; 2001:179. 5. Tokuda Y, Kawachi S, Murata H, Saida T: Chronic obesity lymphoedematous mucinosis: three cases of pretibial mucinosis in obese patients with pitting oedema. Br J Dermatol. 2006;154:157. 6. Rongioletti F, Rebora A: Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol. 2001;44:273. 7. Introcaso CE, Hivnor C, Cowper S, Werth VP: Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: a case series of nine patients and review of the literature. Int J Dermatol. 2007; 46:447. 8. Rongioletti F, Parodi A, Rebora A: Papular and nodular mucinosis as a sign of lupus erythematosus. Dermatologica. 1990;180:221. 9. Beers W, Ince A, Moore T. Scleredema adultorum of Buschke: a case report and review of the literature. Semin Arthritis Rheum. 2006;35:355. 10. Cole HG, Winkelmann RK: Acid mucopolysaccharide staining in scleredema. J Cutan Pathol. 1990;17:211. 11. Wilk M, Schmoeckel C: Cutaneous focal mucinosis—a histopathological and immunohistochemical analysis of 11 cases. J Cutan Pathol. 1994;21:446. 12. Nebrida ML, Tay YK: Cutaneous focal mucinosis: a case report. Pediatr Dermatol. 2002;19:33. 13. Butler D, Davis G, Greene J: Multiple mucinous (myxoid) cysts of a single finger. J Am Acad Dermatol. 2005;53:914. 14. Inoue A, Ikeda S, Mizuno Y, Ogawa H: Superficial mucoceles of the soft palate. Dermatology. 2005;210:360. 15. Kaya G, Augsburger E, Chavaz P, Saurat JH: CD44 and hyaluronate expression in follicular mucinosis. J Cutan Pathol. 2006; 33:227.

16. Cerroni L, Fink-Puches R, Back B, Kerl H: Follicular mucinosis: a critical reappraisal of clinicopathologic features and association with mycosis fungoides and Sézary syndrome. Arch Dermatol. 2002;138:182. 17. Wilk M, Schmoeckel C, Kaiser HW, et al: Cutaneous angiomyxoma: a benign neoplasm distinct from cutaneous focal mucinosis. J Am Acad Dermatol. 1995; 33:352. 18. Black MM, Upjohn E, Albert S: Amyloidosis. In: Bolognia J, Jorizzo JL, Rapini RP et al (eds). Dermatology, 2nd ed. St. Louis: Mosby Elsevier; 2008:623. 19. Bocquier B, D’Incan M, Joubert J, et al: Amyloid elastosis: a new case studied extensively by electron microscopy and immunohistochemistry. Br J Dermatol. 2008;158(4):858-860. 20. Garg A, Mahalingam M, Alavian C: Pruritic patches on the back and papules on the legs. Primary localized cutaneous amyloidosis (PLCA) (cutaneous lichen amyloidosis and macular amyloidosis). Arch Dermatol 2007;143:255. 21. Chowdhury MM, Blackford S, Williams S: Juvenile colloid milium associated with ligneous conjunctivitis: report of a case and review of the literature. Clin Exp Dermatol. 2000;25:138. 22. Mahalingam M, Palko M, SteinbergBenjes L, Goldberg LJ: Amyloidosis of the auricular concha: an uncommon variant of localized cutaneous amyloidosis. Am J Dermatopathol. 2002;24:447. 23. Moon AO, Calamia KT, Walsh JS: Nodular amyloidosis. review and longterm follow-up of 16 cases. Arch Dermatol. 2003;139:1157. 24. Pasternak S, Wright B, Walsh N: Soft tissue amyloidoma of the extremities: report of a case and review of the literature. Am J Dermatopathol. 2007;29:152-155. 25. Hamada T: Lipoid proteinosis. Clin Exp Dermatol. 2002;27,624. 26. Uchida T, Hayashi H, Inaoki M, et al: A failure of mucocutaneous lymphangiogenesis may underlie the clinical features of lipoid proteinosis. Br J Dermatol. 2007; 152,156. 27. Pourrabbani S, Marra DE, Iwasaki J, et al: Colloid milium: a review and update. J Drugs Dermatol. 2007;6:293. 28. Touart DM, Sau P: Cutaneous deposition diseases. Part I. J Am Acad Dermatol. 1998; 39:149. 29. Desai AM, Pielop JA, Smith-Zagone MJ, Hsu S: Colloid milium: a histopathologic mimicker of nodular amyloidosis. Arch Dermatol. 2006;142:784. 30. Patterson JW, Wilkin JK, Schatzki PF: Nodular colloid degeneration. Cutis. 1985;6:355. 31. Libow LF, Mawhinney JP, Bessinger GT: Cutaneous Waldenstrom’s macroglobulinemia: report of a case and overview of the spectrum of cutaneous disease. J Am Acad Dermatol. 2001;45(suppl):S202. 32. Maynard B, Peters MS: Histologic and immunofluorescence study of cutaneous porphrias. J Cutan Pathol. 1992;19:40. 33. Murphy GH: The cutaneous porphiria: a review. Br J Dermatol. 1999;140:573. 34. Martin RW, Lumadue JA, Corio RL, et al: Cutaneous giant cell hyalin angiopathy. J Cutan Pathol. 1993;20:356. 35. Salama S, Rosenthal D: Cutaneous collagenous vasculopathy with generalized telangiectasia: an immunohistochemical and ultrastructural study. J Cutan Pathol. 2000;27:40.

CHAPTER 16 ■ DEPOSITION DISORDERS

Among the about 10 types of mucopolysaccharidoses (MPS), the Hurler and Hunter types show significant skin changes.44 Patients with Hunter syndrome (MPS II) have a unique cutaneous finding with agminate, skin-colored papules on the scapular area and extremities (pebbling of the skin). In Hurler syndrome, thickened plaques with hyperpigmentation are observed, and grouped papules are rarely reported. Individuals with Hurler and Hunter disease exhibit dwarfism, skeletal deformities, corneal opacity, hepatosplenomegaly, hirsutism, and coarse facial features (gargoylism). In severe cases, the nervous system is affected, resulting in mental retardation. The basic defect in these diseases is a genetic mutation of lysosomal enzymes involved in the degradation of mucopolysaccharides (glycosaminoglycans). Unmetabolized large molecules of MPS accumulate in many organs, and the unavailability of essential metabolites disturbs the normal growth of bones and cartilages. There seem to be slightly different variations in these mutations; therefore, the clinical severity of the disease may vary from case to case. Hurler and Hunter diseases share similar enzyme deficiencies (α1-iduronidase and α1-iduronate sulfatase, respectively), resulting in an accumulation of dermatan and heparan sulfate. In both diseases, dermatan sulfate and heparan sulfate are detected in the urine, and this test is used for the diagnosis. Hurler disease is inherited in an autosomal recessive mode, and Hunter disease is transmitted in an X-linked recessive mode.

microscopy is probably most helpful for the identification of unmetabolized MPS in the lysosomes of dermal fibroblasts, perivascular macrophages, and endothelial cells as electron-dense, laminated membrane structures. These cells also contain many vacuoles and electrondense granular substances. The dermal Schwann cells also contain laminated dense bodies that resemble “zebra bodies,” as described in the brains of patients with these diseases.

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36. Touart DM, Sau P: Cutaneous deposition diseases. Part II. J Am Acad Dermatol. 1998;39:527. 37. Lesesky EB, Pelle MT, O'Grady TC. Diffuse nodules in a woman with renal failure: chronic tophaceous gout. Arch Dermatol. 2007;143:1201. 38. Fairley JA. Calcifying and ossyfing disorders of the skin. In: Bolognia J, Jorizzo JL, Rapini RP et al (eds). Dermatology, 2nd ed. St. Louis: Mosby Elsevier; 2008:653. 39. Essary LR, Wick MR: Cutaneous calciphylaxis. An underrecognized clinicopathologic entity. Am J Clin Pathol. 2000; 133:280. 40. Campanelli A, Kaya G, Masouyé I, Borradori L: Calcifying panniculitis fol-

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lowing subcutaneous injections of nadroparin-calcium in a patient with osteomalacia. Br J Dermatol. 2005;153, 657. 41. Conlin PA, Jimenez-Quintero LP, Rapini RP: Osteomas of the skin revisited: a clinicopathologic review of 74 cases. Am J Dermatopathol. 2002;24:479. 42. Davis MD, Pittelkow MR, Lindor NM, et al: Progressive extensive osteoma cutis associated with dystrophic features: a new syndrome? Case report and review of the literature. Br J Dermatol. 2002;146: 1075. 43. Ferreira M, Sanches M, Lobo I, Selores M: Alkaptonuric ochronosis. Eur J Dermatol. 2007;17:336.

44. Neufeld E, Muenzer J: The mucopolysaccharidoses. In: Scriver C, Beaudet A, Sly W, et al (eds), The Metabolic and Molecular Basis of Inherited Disease, vol 3, 8th ed. New York: McGraw-Hill; 2000:3421. 45. Mallory SB, Krafchik R, Lonergan CL, et al: What syndrome is this? Hunter syndrome. Pediatr Dermatol. 2004;21:679. 46. Vasil KE, Magro CM: Cutaneous vascular deposition of C5b-9 and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda. J Am Acad Dermatol. 2007;56:96-104.

CHAPTER 17 Alterations of Collagen and Elastin Kapil Gupta Laurence Verneuil Clifton R. White, Jr. Raymond L. Barnhill

ALTERATIONS OF COLLAGEN Dermal collagen consists of fibers of 2 to 15 μm in diameter. In the papillary and periadnexal (adventitial) dermis, collagen consists of delicate interwoven fibers; collagen of the reticular dermis consists of thick bundles. Whereas type I collagen, which is distributed throughout the dermis, provides tensile strength to the skin, type III collagen (15% of the dermis by dry weight) is primarily a constituent of the adventitial dermis, where it participates in anchoring the epidermis and adnexae to the dermis.3 Collagen is composed of three polypeptides, or alpha chains, that assume a stabilizing triple-helical conformation depending on glycine residues located at every third position of the polypeptides. Hydroxyproline (synthesized from proline) is necesary for triple-helix stability at physiologic temperatures.4 Conditions resulting in decreased levels of reducing agents such as ascorbic acid and oxygen, which are required for hydroxylation of prolyl residues, lead to deficient collagen production, resulting in scurvy (poor wound healing, skin fragility, easy bruising, and bleeding) and sometimes stasis ulcers.4,5 Alterations of collagen, which often exist in concert with deficient elastin and ground substance, are present in a diverse group of diseases manifesting

SCLERODERMA Scleroderma (“hard skin”) is the result of a deposition of excess collagen in the dermis and may be classified as primary, including morphea and its variants, such as atrophoderma of Pasini and Pierini and eosinophilic fasciitis (Shulman syndrome), and systemic scleroderma (progressive systemic sclerosis), or secondary scleroderma (ie, sclerodermoid disorders), as in sclerodermoid porphyria cutanea tarda, sclerodermoid graftversus-host reaction, and acro-osteolysis, among others.

Morphea (Localized Scleroderma) Morphea (“localized” or “circumscribed scleroderma”) is the most common form of scleroderma and has diverse clinical presentations, including localized (guttate or plaque), generalized, linear, segmental, and subcutaneous. In some cases, systemic involvement, such as of the musculoskeletal system, may occur. Rarely, patients with morphea may develop systemic scleroderma. As with systemic scleroderma, morphea affects women with greater frequency than men and white individuals more often than black individuals, with most cases beginning between the second and fifth decades of life. The cause of morphea, although unknown, is considered (like scleroderma) by some to be immunologic in nature (eg, morphea coexists with other autoimmune diseases, and antinuclear antibodies are found in patients with morphea, particularly those with linear morphea).6 Other controversial evidence suggests a causative relationship between Borrelia burgdorferi and morphea, including the presence of

spirochetes in histologic sections of morphea as well as their recovery from cultured lesional tissue,7 findings not confirmed by other investigators.8 CLINICAL FEATURES Morphea presents as indurated, smooth-surfaced, whitish to dusky-appearing plaques, often with a peripheral violaceous rim (“lilac ring”) suggesting inflammation. Plaques vary from small (guttate) to large, confluent or generalized lesions and may be hyper- or hypopigmented (Fig. 17-1A). Unusual presentations of morphea include nodular (keloid), 9 bullous, 10 linear (en coup de sabre),11 and facial hemiatrophy,12 as well as aggressive mutilating (pansclerotic) morphea13 and morphea profunda.14 Most likely, atrophoderma of Pasini and Pierini and eosinophilic fasciitis also represent variants of morphea. HISTOPATHOLOGIC FEATURES The epidermis may be uninvolved, atrophic, or hyperplastic. Characteristically, there is thickening and sclerosis of the reticular dermis with increased width of collagen bundles, narrowing or obliteration of interbundle spaces, and a superficial and deep perivascular lymphocytic infiltrate containing plasma cells and occasionally eosinophils (Figs. 17-1 to 17-3). As sclerosis increases, collagen replaces small fat lobules encircling eccrine glands (which become “entrapped”), pilosebaceous units may be atrophic, and the cellular infiltrate often diminishes. Subcutaneous septa and fasciae are sclerotic, and nodular lymphoplasmacytic aggregates are often present at the dermal–subcutaneous and septal–lobular junctions (Table 17-1). Small blood vessels may develop thickened walls and narrowed lumina. In some instances, subcutaneous (morphea profunda) or fascial (eosinophilic fasciitis) involvement may predominate. DIFFERENTIAL DIAGNOSIS Morphea and cutaneous scleroderma are indistinguishable histologically. However, the early lesions of morphea, termed inflammatory morphea, exhibit greater edema and more prominent inflammatory cell infiltrates. These inflammatory infiltrates usually involve the reticular dermis in perivascular and interstitial patterns. On occasion, the histologic features of morphea may be quite similar to those of lichen sclerosus et atrophicus (diseases reported to coexist in some patients15), including prominent papillary dermal edema and sclerosis; in these patients,

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

The major function of the skin is to serve as a barrier to various exogenous substances, chemicals, and microbes. Collagen, ground substance, and elastic fibers are the three major components of the dermis and are crucial to maintaining the integrity and elasticity of the skin. Collagen is the most abundant of the three components of the dermis (80% by dry weight), consisting primarily of type I collagen, one of more than 19 distinct collagens now recognized (types I to XIX).1,2

in some individuals as sclerosis, including scleroderma and a number of diseases that produce changes histologically indistinguishable from scleroderma (sclerodermoid disorders). In other conditions, such as those preceding scar and keloid formation, collagen is produced in greater quantities than normal, and in still other conditions, such as aplasia cutis congenita and focal dermal hypoplasia, collagen is deficient, resulting in atrophy. Rarely, cutaneous diseases may result from the loss of connective tissue fibers to the skin surface (eg, “perforating” diseases); other conditions are characterized by collagen defects at the molecular level (eg, Ehlers-Danlos syndrome, osteogenesis imperfecta).

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS 388

A

B

 FIGURE 17-1 Morphea. (A) Large, confluent, smooth-surfaced, whitish to ivory plaque with hyperpigmention and ill-defined margins on the arm. (B) Scanning magnification shows dermal sclerosis throughout the reticular dermis and fat septa as well as a dense, superficial, and deep perivascular and interstitial lymphocytic infiltrate containing plasma cells with nodular accumulations at the dermal–subcutaneous junction.

reticular dermal sclerosis present in morphea distinguishes it from the uninvolved reticular dermis of lichen sclerosus et atrophicus, in which changes are limited to papillary dermal sclerosis. Nonetheless, it must be emphasized that morphea and lichen sclerosus et atrophicus may be closely related such that the latter constitutes a superficial expression of the same disease process that results in morphea and eosinophilic fasciitis.

Systemic Scleroderma (Progressive Systemic Sclerosis) Systemic scleroderma (progressive systemic sclerosis [PSS]) involving the skin

develops in limited16 as well as diffuse cutaneous patterns,17 each resulting from excess deposition of collagen. Although the cause of scleroderma is unknown, collagen synthesis, deposition, and degradation are elevated, as is collagen urinary excretion.18 Collagen fibrils in scleroderma have smaller diameters than normal (30–40 nm versus 70–140 nm),19 and scleroderma fibroblast cultures show a higher-than-normal rate of DNA synthesis.20 Other potential etiologic factors are autoimmune causes; speckled or nucleolar pattern antinuclear antibodies are present in 80% to 95% of patients with PSS. 21 Finally, dermal vessels show alterations by electron

 FIGURE 17-2 Morphea. Closer view of the lower reticular dermis demonstrates thickened, sclerotic collagen bundles with eccrine glands (right) completely entrapped. Note the nodular collections of lymphocytes and plasma cells at the dermal–subcutaneous junction and a sclerotic, thickened septum in the subcutis.

microscopy, including the formation of gaps between and destruction of endothelial cells with basal lamina reduplication and perivascular lymphocytes, often preceding fibrosis.22 CLINICAL FEATURES Systemic scleroderma involving the skin is an uncommon disease frequently presenting initially as nonpitting edema of the extremities, especially the fingers (“sausage fingers”) or the face and trunk, areas that become indurated and then atrophic and sclerotic, with a “bounddown,” palpable quality. Involvement may be limited to acral locations (acrosclerosis), or less commonly, rapid, progressive, diffuse cutaneous sclerosis may develop, often associated with significant involvement of internal organs (Fig. 17-2A; Table 17-2). The indurated cutaneous plaques of systemic scleroderma are not as sharply demarcated as those in morphea and may be hypo- or hyperpigmented. The skin becomes taut, immobile, and difficult to grasp. Involvement of the overlying joints often leads to ulcerations, flexion contractures, and bone resorption. Raynaud phenomenon (Fig. 17-2B) and internal organ involvement often occur.17 Digital soft tissue calcification may accompany Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST syndrome).23 HISTOPATHOLOGIC FEATURES Systemic scleroderma and morphea are characterized by similar histologic changes, including a superficial and deep primarily perivascular, predominantly lymphocytic infiltrate usually containing plasma

Table 17-1 Morphea (Localized Scleroderma)

A

occur in patients with other sclerodermoid conditions such as sclerodermoid porphyria cutanea tarda and sclerodermoid graft-versus-host disease (GVHD). Conventional scleroderma and morphea differs from sclerodermoid GVHD by the usual development of sclerosis in the deep reticular dermis near the interface with the subcutis; the sclerosis in GVHD develops initially in the superficial dermis (the papillary and superficial reticular dermis).

B

Table 17-2 Scleroderma

C

 FIGURE 17-3 Morphea. (A) Acrosclerosis in systemic sclerosis. Note the “bound-down” appearance of the digits. (B) Raynaud phenomenon in systemic sclerosis.A striking blanching of the distal fingers is seen. (C) High-power magnification of collagen sclerosis with perivascular lymphocytes and plasma cells.

cells and eosinophils that extends into the subcutaneous fat. As lesions evolve, the inflammatory infiltrate decreases, and collagen bundles thicken throughout the dermis, often more prominently in the middle to deep reticular dermis, with characteristic involvement of subcutaneous fat septa by sclerosis. Increasing sclerosis occurs coincident with loss of adnexal epithelial structures. Presumably, the involvement of the subcutaneous fat and fasciae result in the “bound-down” clinical character of the skin in patients with scleroderma.

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

Clinical Features Adult women > men Sclerotic plaques with “lilac ring” Localized, generalized, linear (en coup de sabre), segmental, subcutaneous, nodular (keloid), bullous, facial hemiatrophy, pansclerotic, morphea profunda Histopathologic Features Epidermis uninvolved or atrophic (rarely, hyperplastic) Sclerosis of reticular dermis and fat septa Superficial and deep lymphoplasmacytic infiltrate with occasional eosinophils Nodular lymphocytic collections at dermal–subcutaneous junction Differential Diagnosis Scleroderma Eosinophilic fasciitis Atrophoderma of Pasini and Pierini Sclerodermoid disorders

Dermal calcification develops rarely. Vascular changes may include intimal and adventitial fibrosis and thrombosis of small arteries and arterioles.24 The epidermis often shows either a diminished number or absence of melanocytes or increased basal layer melanin. DIFFERENTIAL DIAGNOSIS Distinction histologically between systemic scleroderma and morphea is not possible on a consistent basis (see preceding discussion under Differential Diagnosis of Morphea), but virtually identical histologic changes may

Clinical Features Adult women > men Nonpitting edema of extremities and digits Acrosclerosis versus diffuse sclerosis of the face and trunk Internal organ involvement CREST syndrome Histopathologic Features Epidermis uninvolved, hypo- or hyperpigmented Dermal sclerosis often accentuated in the lower half of the reticular dermis and fat septa Superficial and deep lymphoplasmacytic infiltrate with eosinophils Atrophic to absent adnexal structures Differential Diagnosis Morphea Mixed connective tissue disease Eosinophilic fasciitis Sclerodermoid disorders

389

Other entities to be considered in the differential diagnosis include radiation dermatitis and sclerosis secondary to other physical injury such as thermal burns. Chronic radiation dermatitis is distinguished from scleroderma by the presence of hyperkeratosis, usually concomitant epidermal hyperplasia or atrophy, enlarged “radiation” fibroblasts, and perivascular foamy histiocytes on occasion. Scarring from other injuries such as thermal burns is nonspecific and must be discriminated by clinical history.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Mixed Connective Tissue Disease

390

CLINICAL FEATURES As the name implies, mixed connective tissue disease (MCTD) presents with combined clinical features of systemic lupus erythematosus, scleroderma, and dermatomyositis. Circulating antibodies to ribonucleoprotein (extractable nuclear antigen) are typically present,25 but those directed against Sm antigen and double-stranded DNA are not.26 Patients characteristically develop acrosclerosis, Raynaud phenomenon, and arthritis. Patients with MCTD usually respond to systemic corticosteroids. HISTOPATHOLOGIC FEATURES Reticular dermal sclerosis indistinguishable from PSS characterizes well-developed acrosclerotic lesions with some vessel wall thickening. An atrophying interface dermatitis is frequently present.

Eosinophilic Fasciitis (Shulman Syndrome) CLINICAL FEATURES Eosinophilic fasciitis (Shulman syndrome) is characterized by rapid development, often after vigorous exercise, of scleroderma-like cutaneous, subcutaneous, and fascial changes, usually involving the extremities. Patients typically lack Raynaud phenomenon and visceral involvement and follow a typical clinical course of spontaneous remissions, relapses, and recurrences. Peripheral eosinophilia, an elevated sedimentation rate, and hypergammaglobulinemia are often present.27 Systemic corticosteroid therapy sometimes provides improvement (Table 17-3). Some observers believe that eosinophilic fasciitis represents a “deep” variant of morphea or morphea profunda, just as atrophoderma of Pasini and Pierini is considered to be an “atrophic” form of morphea. HISTOPATHOLOGIC FEATURES The histologic characteristics of eosinophilic fasciitis include thickened, sclerotic fascia, often accompanied by a mixed inflammatory cell infiltrate of lymphocytes,

Table 17-3 Eosinophilic Fasciitis (Shulman’s Syndrome)

Clinical Features Rapid onset Exercise related often Scleroderma-like changes on extremities Absent Raynaud phenomenon and visceral involvement Steroid responsive Histopathologic Features Indistinguishable from morphea/scleroderma Sclerosis of dermis, fat septa, and fascia Peripheral and tissue eosinophilia Differential Diagnosis Morphea Scleroderma (PSS) Sclerodermoid disorders

plasma cells, and eosinophils (which may be few in number or absent), with sclerosis of the overlying dermis and subcutaneous fat septa indistinguishable from that seen in patients with morphea and systemic scleroderma.28

SCLERODERMOID DISORDERS Sclerodermoid changes may be seen in a group of exceedingly heterogeneous conditions (Table 17-4), including Winchester syndrome, a rare inherited disorder of connective tissue in which patients develop thick, leathery skin,29 and pachydermoperiostosis (primary hypertrophic osteoarthropathy), which affects both the skin and the bones of the extremities, face, and scalp, where thickened, deeply furrowed skin (cutis verticis gyrata) develops. Both diseases are characterized by a thickened dermis with hyalinized collagen and prominent subcutaneous fibrous septa. Recent studies have revealed accumulation of acid mucopolysaccharides and dermal fibrillary material apparently representing disorganized elastic tissue microfibrils, with collagen synthesis and degradation markers unaltered.30 Occasionally, porphyria cutanea tarda may result in sclerodermoid changes of sun-exposed skin that are indistinguishable histologically from scleroderma except for the usual presence of solar elastosis in porphyria.31 Extensive sclerodermoid changes may occur in the skin and subcutaneous tissue after pentazocine,32 bleomycin,33 or phytonadione (vitamin K) injections34,35; after injection or leakage of silicone for augmentation mammoplasty36; in both inherited and acquired acro-osteolysis,

Table 17-4 Sclerodermoid Disorders

Clinical Features Variable induration of skin Histopathologic Features Indistinguishable from morphea/scleroderma Differential Diagnosis Winchester’s syndrome Pachydermoperiostosis (cutis verticis gyrata) Sclerodermoid porphyria cutanea tarda Sclerodermoid graft-versus-host reaction Sclerodermoid reaction to injections (pentazocine, bleomycin, phytonadione [vitamin K], silicone) Acro-osteolysis, inherited and acquired Sclerodermoid reaction to ingestion of olive oil substitute (denatured rapeseed oil) and L-tryptophan Sequela of phenylketonuria

including spontaneous37 and occupationally induced38; in some graft-versus-host reactions39,40; and after ingestion of an olive oil substitute (rapeseed oil) denatured with aniline41,42 or L-tryptophan.43-45 Finally, scleroderma-like changes may be one sequela of phenylketonuria.46 In each, the pathologic changes precisely mimic those of idiopathic scleroderma.

Nephrogenic Fibrosing Dermopathy The term nephrogenic fibrosing dermopathy (NFD) has recently been coined to describe a seemingly unique clinicopathologic entity that develops in patients with renal insufficiency.47,48 Virtually all patients have undergone hemodialysis and many have undergone renal transplantation. The etiology of the process has thus far not been definitively elucidated; however recent reports suggest a etiologic link between systemic administration of gadolinium-containing magnetic resonance imaging contrast agents in patients with renal insufficiency and the development of NSF. 130,131 CLINICAL FEATURES The patients observed thus far have been adults ranging in age from the fourth to eighth decades of life.47,48 The usual history includes extensive thickening and hardening of the skin of recent onset. The process is a systemic fibrosing disorder preferentially involving the extremities followed by the trunk in a symmetrical distribution with sparing of the face and may appear cobblestoned or peau d’orange in texture.48 Patients may show involvement of other organs, including the muscles, lungs, pleura, pericardium, and bones. Debilitating joint contractures may ensue in some patients. 48

A

B

 FIGURE 17-4 Nephrogenic fibrosing dermopathy. (A and B) Nodular foci of fibrosis are seen. The collagen bundles exhibit a haphazard pattern, and the fibrocytes are increased in number, manifesting an activated appearance. (C) In nephrogenic fibrosing dermopathy, the fibrosis may extend deep to involve the interlobular septa of the fat, resulting in a morphology reminiscent of eosinophilic fasciitis.

HISTOPATHOLOGIC FEATURES Early lesions exhibit increased numbers of interstitial fibrocytes in the dermis (Fig. 17-4) and fibrous trabeculae of the subcutis followed by progressively greater numbers of the latter cells, thickening of dermal collagen bundles and fibrous septa of the panniculus, variable mucin deposition, and increased numbers of elastic fibers.48 The dermal and subcutaneous cellular population may include epithelioid, stellate, and multinucleate cells. Many of the dermal spindle cells express both CD34 and procollagen.48 Nonetheless the spectrum of cutaneous histological findings observed in this entity is quite varied. 48 For example, the number of CD34positive fibrocytes may range from few to many, collagen bundles may vary from thin to thick, mucin deposits from scant to abundant, and finally one may observe varying degrees of vascular proliferation, inflammation, and expression of CD68 and Factor XIIIa. On occasion extensive calcification and ossification occur. DIFFERENTIAL DIAGNOSIS This condition must be distinguished from scle-

romyxedema, morphea/scleroderma and related conditions, eosinophilic fasciitis, and even spindle cell neoplasms such as a sarcoma and desmoplastic melanoma.48 NFD is most closely mimicked by scleromyxedema because of thickened dermal collagen bundles, spindle cell proliferation, and dermal mucin deposition. The later condition can usually be differentiated from NFD by the presence of a paraproteinemia and facial involvement. Morphea/scleroderma usually differs from NFD owing to the clinical presentation, reduced cellular density, and (the usual) lack of mucin deposition.

OTHER HYPERTROPHIC COLLAGENOSES

Connective Tissue Nevi Connective tissue nevi are rare hamartomas that involve alterations of collagen, elastic tissue, glycosaminoglycans (ground substance), or all three substances.49 Collagen may be increased in amount (“collagenoma”), and elastic tissue may be increased (“elastoma”), nor-

mal, or decreased. Connective tissue nevi are usually present at birth or appear in childhood but uncommonly in adult life. They may be inherited or acquired.50 Familial connective tissue nevi may occur as solitary lesions or associated with osteopoikilosis (radiographic bone densities or “stippling”) in Buschke-Ollendorff syndrome, an autosomal dominant condition.51 Patients with tuberous sclerosis often have a type of connective tissue nevus called collagenous plaques (shagreen patches) over the lower back as well as other fibrous skin lesions, including angiofibromas (adenoma sebaceum), of the central face and periungual or subungual locations (Koenen tumor). CLINICAL FEATURES Connective tissue nevi typically involve the chest, back, buttocks, or arms, presenting as small papules or plaques (at times multiple) distributed in a zosteriform or systematized fashion. Plaques are composed of coalescent papules with an ivory or light tannish color, sometimes having an orange peel (peau d’orange) or cobblestone

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

C

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Table 17-5 Connective Tissue Nevi

392

Clinical Features Papules or plaques Solitary or multiple Zosteriform or systematized Ivory to tan color Orange peel (peau d’orange) or cobblestone surface Histopathologic Features Thickened homogenized collagen bundles (“collagenoma”) Increased elastic tissue (“elastoma”)–need elastic tissue stains Comparison to uninvolved skin helpful Differential Diagnosis Normal skin Dermatofibroma Pseudoxanthoma elasticum Scar Fibrous hamartoma of infancy

appearance, at times with perifollicular orientation (Table 17-5). HISTOPATHOLOGIC FEATURES Microscopically, connective tissue nevi often show extremely subtle changes, with the increased amount of collagen difficult to ascertain with routinely stained specimens. In most instances, the epidermis is normal in appearance, but the changes of epidermal nevus have been reported. The dermis may be increased in thickness, and there may be involvement of the subcutaneous fat by the hamartomatous process. Some lesions are characterized by thickened and homogenized collagen bundles; in some instances, the collagen bundles appear disordered and haphazardly arranged.52 There may be concomitant alterations in the elastic tissue, including a dilutional effect, that is, the elastic fibers are more widely spaced; they may be increased in quantity as in elastoma; and they may be fragmented and attenuated. Connective tissue nevi in BuschkeOllendorff syndrome, which are of the elastic tissue type (dermatofibrosis lenticularis disseminata), show a characteristic increase in elastic fibers that are broad and interlacing, often apparent with hematoxylin and eosin (H&E)– stained specimens (Fig. 17-5). In some cases, the elastic fibers take on a clumped morphology. DIFFERENTIAL DIAGNOSIS The most common difficulty is distinguishing connective tissue nevi from normal skin, and a biopsy of uninvolved skin for comparison, as well as special stains for collagen (trichrome) and elastic fibers, is often very helpful. Elastic tissue–type connective

 FIGURE 17-5 Connective tissue nevus (Buschke-Ollendorff syndrome). At scanning power, thickened, distorted elastic tissue fibers are seen arranged in a haphazard fashion throughout the reticular dermis (dermatofibrosis lenticularis disseminata).

tissue nevi are distinguished from pseudoxanthoma elasticum because the elastic fibers usually are not fragmented and distorted and show no calcium deposition. Other entities to be considered include reparative changes or scars, scleroderma/morphea, systemic scleredema, and fibrous hamartoma of infancy. Scars usually differ from connective tissue nevi by being well defined and showing a horizontal disposition of collagen. Scleroderma/morphea usually exhibits diffuse homogenization of collagen, obliteration of appendageal structures, and possibly inflammatory infiltrates. Systemic scleredema displays much greater dermal thickening (often two to three times normal), separation of collagen bundles (“fenestration”), and frequent but not invariable mucin deposition. Fibrous hamartoma shows three components to variable extent: distinct bands of collagen, whorled foci of mesenchymal cells, and an intimate admixture of adipose tissue.

Fibrosis, Hypertrophic Scars, and Keloids Fibrosis characteristically represents the late stage of an intense inflammatory process, perhaps resulting in collagen destruction due to the inflammation. Fibrosis may be merely microscopic or, when more prominent, may result in a clinically visible scar. Typically, elastic fibers are reduced in quantity and in appearance in fibrosing conditions. Hypertrophic scars and keloids are manifestations of abnormal wound-healing responses that share some clinical simi-

larities.53 Both are raised, flesh-colored to red, firm nodules. Hypertrophic scars are usually symptomless and confined to the site of injury. Keloids often are symptomatic (including pruritus and tenderness) and frequently extend beyond the area of healing trauma. The cause of keloids is unknown; various hypotheses suggest associations with race, age, skin tension lines, trauma, and hormonal factors. HISTOPATHOLOGIC FEATURES Hypertrophic scars, similar to their more common atrophic relatives, are characterized by fibrillary collagen arranged parallel to the skin surface, with associated numbers of increased fibroblasts having the same alignment (Fig. 17-6). Blood vessels are typically prominent with a vertical arrangement perpendicular to the skin surface and the predominant collagen bundle pattern. Usually, the epidermis overlying hypertrophic or atrophic scars is thinned, lacking rete ridges. Newly developed scars have increased mucin content, imparting a bluish to amphophilic color with routine stains. A keloid differs from a hypertrophic scar by the presence of distinctive, characteristically thickened, eosinophilic, homogeneous collagen bundles associated with fibroblasts having plumper nuclei than those seen in scars. Mucin may be present between the thickened collagen bundles in a keloid that frequently displays evidence of a preexisting scar, often at the periphery of the lesion (Figs. 17-7 and 17-8). Rarely, calcification may develop in keloids. Elastic tissue is diminished to absent in both scars and keloids.54

DIFFERENTIAL DIAGNOSIS The differential diagnosis of hypertrophic scars and keloids includes dermatofibroma; morphea and cutaneous scleroderma; con-

 FIGURE 17-7 Keloid. Within the background of fibrosis (scar), broad collagen bundles are arranged haphazardly throughout the mid-dermis.

nective tissue nevus; fibromatosis; and other desmoplastic tumors, especially desmoplastic melanoma. In general, scars are distinctive because of the

constellation of features present: effacement of the epidermis, horizontally displaced fibrillary collagen, vertically oriented microvessels, and the sharply delimited character of the process. Older scars may be more difficult to distinguish from some of the preceding entities. Dermatofibroma is typically a dermal nodular lesion with overlying epidermal hyperplasia and a characteristic storiform pattern in the dermis with “entrapment” of collagen bundles by fibrocytes. Connective tissue nevi usually exhibit a normal epidermis; are poorly defined; and may show abnormal collagen, elastic fibers, or both. Fibromatosis differs from a scar by demonstrating fairly distinct linear bands of mature collagen. Desmoplastic melanoma enters into the differential diagnosis of some scarring processes and is an important entity to exclude. The presence of an intraepidermal melanocytic component, melanin, and positive immunostaining with S-l00 protein and other markers for melanocytes may aid in this discrimination (see also Chapter 27)

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

 FIGURE 17-6 A scar. At low power, a scar shows numerous spindled fibroblasts associated with collagen bundles arranged primarily parallel to the skin surface with vertically oriented blood vessels. The scar has replaced virtually the entire reticular dermis.

Striae Distensae  FIGURE 17-8 Keloid. Higher power view shows the contrast between the broad, pale-staining keloidal collagen bundles surrounded by fibrotic collagen of the preexisting scar.

Striae distensae (“stretch marks”) are the result of a variety of factors, including mechanical stretching of the skin such as from heavy lifting and pregnancy, as well as the effects of both topically and systemically administered corticosteroids.

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CLINICAL FEATURES Newly developed striae are linearly arranged, reddish to purplish, fibrosing lesions that, with age, become atrophic and whitish. There is a predilection for development on the buttocks, thighs, back, abdomen, and breasts. HISTOPATHOLOGIC FEATURES In their early stages, striae distensae are characterized by fragmented collagen bundles separated by edema and altered elastic fibers that have a short and fragmented appearance. There is a sparse, predominately lymphocytic infiltrate around dilated blood vessels, the latter imparting the characteristic livid color. In chronic striae, collagen bundles are arranged parallel to the skin surface as in other scarring processes; elastic tissue stains show increased numbers of apparently newly formed elastic fibers and dilated vessels, particularly in the upper dermis.55 DIFFERENTIAL DIAGNOSIS In contrast to hypertrophic and atrophic scars, increased amounts of elastic tissue, best visualized with elastic tissue stains, are present in later-stage striae distensae as opposed to little to no elastic tissue in scars.56 Blood vessels may be horizontally rather than vertically oriented in striae as well.

Fibroblastic Rheumatism Fibroblastic rheumatism (FR) is a rare, relatively recently described idiopathic dermatosis–arthritis syndrome. In one patient, studies demonstrated an increase in fibronectin and tenascin deposition in both involved and uninvolved skin.57 Some of the dermal cells in FR have ultrastructural features, suggesting mild fibroblastic differentiation. Biochemical studies of cultured fibroblasts revealed a reduction in collagen and noncollagen protein synthesis, distinguishing FR from other fibrotic skin conditions such as scleroderma. CLINICAL FEATURES FR is a rare disease involving a combination of rheumatologic and cutaneous manifestations. Patients present with symmetric polyarthralgia leading to joint stiffness, as well as cutaneous nodules and sclerodactyly.

394

HISTOPATHOLOGIC FEATURES Biopsies of nodular lesions demonstrate increased numbers of fibroblasts associated with collagen fibers arranged in a whorled fashion extending into the subcutaneous fat.58 A zone of uninvolved papillary dermis separates the epidermis from the deeper fibrosis. Dermal appendages are

reportedly present, and elastic tissue stains show a marked decrease in elastic tissue in some areas and irregularly clumped elastic fibers in others. DIFFERENTIAL DIAGNOSIS The differential diagnosis of FR includes scleroderma, which shares some clinical similarities. FR shows characteristic whorled fibrosis rather than sclerosis as in scleroderma. Skin nodules also have been reported in localized and generalized morphea and Shulman syndrome. Finally, some pediatric fibromatoses have similarities to FR, including juvenile hyaline fibromatosis, Winchester syndrome, and Francois syndrome.

Collagenosis Nuchae CLINICAL FEATURES Collagenosis nuchae was first described in 1988 as diffuse induration and swelling of the posterior neck areas of two men with some suggestion of accompanying inflammation.59 HISTOPATHOLOGIC FEATURES Two reported patients had dense masses of disordered and thickened collagen bundles with few fibroblasts or inflammatory cells. There was no evidence of increased acid mucopolysaccharide with special stains. The histologic appearance resembled “hyalinized scar tissue.”

Radiation Dermatitis Ionizing radiation may produce radiodermatitis. Previously, most skin reactions occurred as a result of ionizing radiation at orthovoltage levels (90–100 kV); radiation dermatitis now is seen less frequently owing to the use of deeperpenetrating megavoltage (2–4 MV). CLINICAL FEATURES Radiodermatitis typically is divided into acute (early) and chronic (late) stages. Acute radiodermatitis is characterized by the sequential appearance of erythema, vesicle formation, and hyperpigmentation with frequent ulceration. In chronic radiodermatitis, shiny, atrophic patches with numerous telangiectases impart a poikilodermatous appearance. Within areas of chronic radiodermatitis, cutaneous carcinomas may develop, including basal and squamous cell carcinomas, adnexal carcinomas, melanoma, and sarcomas. HISTOPATHOLOGIC FEATURES Chronic radiodermatitis is characterized by sclerosing changes throughout the dermis, often with prominent edema in the papillary dermis. The quality of sclerosis

and edema in chronic radiodermatitis has marked similarity to lichen sclerosus et atrophicus. Prominent fibroblasts, some with large, hyperchromatic, and in some cases bizarre nuclei, are scattered throughout the dermis beneath an epidermis thinned in some areas and hyperplastic in others. Fibrin deposition may be present subepidermally and within and around dermal vessel walls as well. DIFFERENTIAL DIAGNOSIS As mentioned earlier, lichen sclerosus et atrophicus shares many histologic similarities with chronic radiodermatitis in the epidermis and superficial dermis, the latter distinguished by reticular dermal sclerosis as well as scattered stellate and atypical fibroblasts and endothelial cells.

ATROPHIC COLLAGENOSES

Aplasia Cutis Congenita Aplasia cutis congenita (congenital localized absence of skin) is a focal absence of skin noted at the time of delivery, most commonly manifested as a solitary or a few ulcers of the scalp that heal after birth. Occasionally, intrauterine healing occurs, and the involved area presents as a scar. Aplasia cutis congenita represents a heterogeneous group of diseases that includes genetic disorders and diseases related to chromosomal abnormalities, teratogens, and intrauterine insults (infections, vascular accident), but the majority are due to unknown causes.60 CLINICAL FEATURES The scalp lesions vary in size from a few millimeters to many centimeters in diameter and may extend as deeply as the dura or meninges. Most lesions are solitary, but approximately 20% of them are multiple and have an eroded to ulcerated, frequently crusted membranous covering over the defect. Healed areas (scars) typically have permanent alopecia. Rarely, aplasia cutis congenita may present with other abnormalities, including cleft lip and palate, tracheoesophageal fistula, double cervix and uterus, vascular abnormalities, limb defects, mental retardation, and epidermolysis bullosa.60 HISTOPATHOLOGIC FEATURES Ulcers are characterized by a loss of epidermis and dermis extending to and through the subcutaneous fat, which may be absent as well. Healed areas show a reepithelialized epidermis overlying a dermal scar with diminished elastic tissue and an absence of rudimentary adnexal structures61 (Fig. 17-9).

Focal Facial Dermal Dysplasia CLINICAL FEATURES Focal facial dermal dysplasia is a rare genodermatosis presenting as symmetric scarred areas involving the temple, typically present at birth, and at times associated with other facial abnormalities. Most likely, focal facial dermal dysplasia represents a variant of aplasia cutis congenita with similar histopathology.65

Pseudoainhum Constricting Bands

Focal Dermal Hypoplasia Focal dermal hypoplasia (Goltz syndrome, Goltz-Gorlin syndrome), which is likely due to an X-linked dominant gene that is lethal in hemizygous males, is seen mainly in females. When it occurs in males, it may be the result of a new rather than an inherited mutation.62 CLINICAL FEATURES Focal dermal hypoplasia is characterized by linear areas of dermal thinning giving reticular or cribriform patterns, often with hyper- or hypopigmentation. In addition, soft yellow nodules, which also may be in a linear arrangement, and ulcers, due to congenital absence of skin, may be present and heal with atrophic scars (Table 17-6). Patients frequently have absence of a digit, at times associated with syndactyly, which results in the characteristic “lobster-claw deformity,” and loss of or abnormal hair, nails, and teeth. Osteopathia striata, representing radiographic longitudinal striations in long bone metaphyses, is a diagnostic marker of Goltz syndrome.63,64 HISTOPATHOLOGIC FEATURES Beneath a normal epidermis, there is marked thinning of the dermis with loose collagen bundles. The soft yellow nodules histologically represent adipocytes extending upward from subcutaneous lobules that

replace most of the dermis, resulting in fat located close to the undersurface of the epidermis, imparting the characteristic color.64 DIFFERENTIAL DIAGNOSIS Nevus lipomatosus of Hoffmann and Zurhele is also characterized by subcutaneous fat extending into the upper dermis, but it lacks the marked attenuation of collagen bundles seen in focal dermal hypoplasia.

Table 17-6 Focal Dermal Hypoplasia (Goltz Syndrome, Goltz-Gorlin Syndrome)

Clinical Features Cribriform or retiform linear dermal thinning Soft yellow nodules Ulcers “Lobster-claw” deformity with syndactyly Abnormal (or absence of) hair, nails, teeth Osteopathia striata Histopathologic Features Markedly thinned dermis Loose collagen bundles Superficial extension of adipocytes (yellow nodules) Differential Diagnosis Nevus lipomatosus superficialis (Hoffmann and Zurhele)

HISTOPATHOLOGIC FEATURES The constricting bands are characterized by a depression at the site of the constriction beneath which is fibrosis composed of increased numbers of fibroblasts and collagen bundles within a thinned dermis.

Keratosis Pilaris Atrophicans Keratosis pilaris atrophicans more than likely represents a group of disorders (Table 17-7) characterized by follicular hyperkeratotic papules and perifollicular atrophy, including keratosis pilaris atrophicans facie (ulerythema ophryogenes), which is characterized by lesions located adjacent to and within lateral eyebrow regions where there is perifollicular erythema, follicular hyperkeratosis, and perifollicular fibrosis, with similar changes extending onto the cheeks. Keratosis follicularis spinulosa decalvans also begins at an early age as marked follicular plugging on the cheeks and nose with resulting perifollicular atrophy as well as a scarring scalp alopecia, generalized keratosis pilaris, hyperkeratosis of the palms and soles, photophobia, and corneal abnormalities. Finally, atrophoderma vermiculatum (folliculitis ulerythematosa reticulata) develops in later childhood, again on the cheeks and preauricular skin, with tiny, follicular

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

 FIGURE 17-9 Aplasia cutis congenita. Biopsy from a healed site of previous aplasia cutis shows fibrosis throughout the dermis with almost complete loss of follicles, sebaceous glands, and eccrine glands.

Pseudoainhum constricting bands are fibrous constrictions of the digits (or rarely limbs) that occasionally develop in patients with severe, usually inherited keratoderma and frequently result in autoamputation.66 Pseudoainhum also refers to the development of constricting bands around the toes in nonhereditary conditions such as leprosy, syphilis, and scleroderma. Mutilating keratoderma of Vohwinkel, an autosomal dominant trait characterized by onset in infancy of keratoderma having a diffuse, honeycomb pattern, may lead to these digital fibrous constrictions.67 Ainhum refers to similar bandlike constrictions, usually leading to spontaneous amputation of the fifth toe, affecting West African natives.

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Table 17-7 Keratosis Pilaris Atrophicans

Clinical Features Follicular hyperkeratotic papules with perifollicular atrophy involving: Early childhood, lateral eyebrows and cheeks (keratosis pilaris atrophicans facie, ulerythema ophryogenes) Early childhood, cheeks and nose with scalp alopecia, generalized keratosis pilaris, palmoplantar hyperkeratosis, photophobia, and corneal abnormalities (keratosis folliculosis spinulosa decalvans) Later childhood, cheeks and preauricular skin (atrophoderma vermiculatum, folliculitis ulerythematosa reticulata) Histopathologic Features Horn-filled patulous follicular orifices Perifollicular fibrosis Atrophy of follicular and sebaceous epithelium Differential Diagnosis Lichen planopilaris Discoid lupus erythematosus Pseudopelade of Brocq

plugging leading to atrophy that develops in a reticular pattern. Atrophoderma vermiculatum may represent an end stage of the preceding two diseases.68 HISTOPATHOLOGIC FEATURES Histologically, the group of diseases known as keratosis pilaris atrophicans shows typical changes of keratosis pilaris, including patulous follicular orifices often in the shape of an inverted cone filled with basket-weave to laminated cornified cells that characteristically protrude above the surrounding cornified surface, and perifollicular fibrosis with atrophy of follicular and sebaceous epithelium. Comedones and milia may develop. DIFFERENTIAL DIAGNOSIS When keratosis pilaris atrophicans is associated with scarring alopecia, lichen planopilaris, discoid lupus erythematosus, and pseudopelade of Brocq are in the histologic differential diagnosis (see also Chapter 10).

Corticosteroid Atrophy CLINICAL FEATURES Corticosteroid atrophy characteristically develops at injection sites of corticosteroids as well as from long-term topical application.69,70 The atrophy may be related to diminished production as well as increased degradation of collagen.

396

HISTOPATHOLOGIC FEATURES A thinned epidermis with effacement of rete ridges

overlies dilated superficial vessels with atrophy of the reticular dermis in severe cases. Individual collagen bundles may be attenuated or homogenized in appearance.

Atrophoderma of Pasini and Pierini Atrophoderma of Pasini and Pierini likely represents a variant of morphea,71,72 although its existence as a specific disease remains controversial. CLINICAL FEATURES Atrophoderma lesions are typically seen on the trunk and present as areas of slight depression having a slategray color but no other epidermal changes. Usually up to 10 cm in diameter, the lesions are sharply demarcated, imparting (by palpation) a “cliff drop” edge with central induration similar to morphea. HISTOPATHOLOGIC FEATURES In welldeveloped plaques of atrophoderma, there may be epidermal depression with a slightly thinned dermis (compared with nonlesional skin) showing sclerosis, diminished interbundle spaces, and eosinophilia of collagen bundles. DIFFERENTIAL DIAGNOSIS Because atrophoderma of Pasini and Pierini represents morphea, the diseases are virtually indistinguishable histologically.

Acrodermatitis Chronica Atrophicans Acrodermatitis chronica atrophicans is a manifestation of late-stage borreliosis typically seen in Europe. Consequently, a history of preceding erythema chronicum migrans may be available in some patients. High titers of IgG antibodies against Borrelia spp. are usually found in the sera of patients with acrodermatitis chronica atrophicans. Occasionally, spirochetes may be identified by dark-field examination or tissue culture. CLINICAL FEATURES Acrodermatitis chronica atrophicans almost always involves the extensor surfaces of the lower extremities. Initially, the skin becomes red and slightly edematous and then subsequently atrophic with a bluish red to brown, atrophic, wrinkled appearance. As a result of dermal and adipocyte atrophy, subcutaneous veins are apparent clinically. Occasionally, fibrosis develops in linear or plaquelike distribution as indurated bands over the legs or dorsa of the feet or as nodules near joints. HISTOPATHOLOGIC FEATURES After an initial inflammatory stage characterized by a perivascular lymphocytic infiltrate mixed with plasma cells, the more classic findings include a thinned epidermis

overlying an uninvolved papillary dermis, and collagen bundles in the midreticular dermis appear degenerated and split into smaller fibers. Destruction of elastic fibers may be demonstrated by elastic tissue stains. Adnexal structures, including follicles and sebaceous glands, become atrophic, as do, eventually, eccrine glands. Subcutaneous fat likewise becomes atrophic. The indurated bands and plaques are characterized histologically by fibrosis. There is a dense superficial and mid-dermal infiltrate of lymphocytes, histiocytes, and many plasma cells. Warthin-Starry silver stains may reveal perivascular spirochetes.

PERFORATING COLLAGENOSES

Reactive Perforating Collagenosis Reactive perforating collagenosis, a controversial entity, has been described as showing autosomal recessive inheritance occurring in siblings.73 An acquired, spontaneously developing variant in adults also has been described, and a second variant termed collagenoma perforant verruciforme (perforating verruciform collagenoma) has similar clinical and histologic features to reactive perforating collagenoses, although only a single occurrence, without genetic influence and due to more severe trauma, is characteristic.74 The acquired form of reactive perforating collagenosis has been reported as having associations with systemic conditions, including diabetes mellitus,75 AIDS,75 hypothyroidism,77 chronic liver disease,77 and glomerulonephritis.77 Some speculate that, in the case of diabetes mellitus, for instance, a cutaneous response to superficial trauma acts in concert with a vasculopathic etiology, as evidenced by the identification of periodic acid Schiff– positive thickened vascular walls in the superficial dermis.78 CLINICAL FEATURES The lesions appear first in early childhood, apparently in response to superficial trauma, and consist of dome-shaped papules with a central umbilication filled with an adherent, firm, cornified plug. The lesions heal spontaneously within a few months, but new lesions may continue to appear in haphazard distribution. HISTOPATHOLOGIC FEATURES Well-developed dome-shaped lesions show a central crusted ulceration adjacent to which irregular epidermal hyperplasia is present. At the base of the ulceration, collagen bundles have a basophilic appearance

or anthelix.79 The nodules are remarkably tender for their bland clinical appearance, and attempts to examine them are frequently met with a prominent withdrawal response by the patient. A central, small, crusted or plugged umbilication is usually present.

DIFFERENTIAL DIAGNOSIS More than likely, reactive perforating collagenosis represents ulceration secondary to trauma with a pronounced epidermal hyperplasia response simulating prurigo nodulelike changes.

HISTOPATHOLOGIC FEATURES Within the center of a lesion of chondrodermatitis is usually a dilated, horn-filled follicular infundibulum, often with perforation of the infundibular epithelium at its base.80 Scale crust may also overlie an epidermal ulceration, adjacent to which are features simulating prurigo nodularis or lichen simplex chronicus, including hyperkeratosis, hypergranulosis, irregular epidermal hyperplasia, and dense fibrosis of the papillary dermis. At the base of the ulceration or perforation is prominent fibrin deposition. At times, the dermis has a chondroid appearance with fibroblasts simulating chondrocytes, and there is adjacent fibros-

Chondrodermatitis Nodularis Chronica Helicis CLINICAL FEATURES Chondrodermatitis nodularis chronica helicis presents as one or two and rarely several, at times bilateral, small 2- to 3-mm dome-shaped papules, usually at the apex of the helix

ing granulation tissue. Ear cartilage at the base of the lesion is often uninvolved. DIFFERENTIAL DIAGNOSIS The histologic appearance of chondrodermatitis is distinctive, and because of the absence of definitive changes within the cartilage, the disorder may be diagnosed with a superficial shave biopsy.

VARIABLE COLLAGEN CHANGES

Ehlers-Danlos Syndrome (Cutis Hyperelastica) Ehlers-Danlos syndrome is a heterogeneous group of inherited connective tissue disorders primarily affecting the skin, gastrointestinal (GI) tract, and musculoskeletal system. The syndrome is now divided into 11 subtypes based on clinical, genetic, and biochemical information (Table 17-8). Molecular or enzyme abnormalities of collagen

Table 17-8 Ehlers-Danlos Syndrome (Cutis Hyperelastica)

Clinical Features Type I (gravis type) Autosomal dominant Hyperextensibility, skin fragility Atrophic scars, molluscoid pseudotumors Biochemical defect unknown Type II (mitis type) Autosomal dominant Hyperextensibility Aortic dilatation Biochemical defect unknown Type III (benign hypermobile type) Autosomal dominant Minimal skin changes Marked joint hypermobility Biochemical defect unknown Type IV (arterial, ecchymotic type) Autosomal recessive (four subtypes) Aortic rupture, GI hemorrhage and rupture Ecchymoses, skin fragility, and mild hyperextensibility Absent or reduced type III collagen due to genetic mutation Type V X-linked Clinical features similar to type I Easy bruisability Lysyl oxidase deficiency (reduced collagen cross-linking) Type VI (ocular type) Autosomal recessive Ocular rupture Kyphoscoliosis and joint laxity Lysyl hydroxylase deficiency Type VII (arthrochalasis type; corresponds to dermatosparaxis in cows, sheep) Autosomal recessive or dominant Marked joint and ligament laxity and dislocations

Hyperextensible and velvety skin Deficient conversion of procollagen to collagen Procollagen N peptidase deficiency Type VIII (periodontal type) Autosomal dominant Severe periodontosis Skin fragility and scarring Biochemical defect unknown Type IX (X-linked cutis laxa) X-linked Joint laxity and hyperextensibility Diverticulosis Defective copper metabolism leads to lysyl oxidase deficiency and defective collagen cross-linking Type X (fibronectin type) Autosomal recessive Skin extensibility and striae Platelet aggregation defect Plasma fibronectin deficiency and dysfunction Type XI Unknown inheritance pattern Familial joint instability syndrome Biochemical defect unknown Histopathologic Features Normal skin by light microscopy Variably sized and distorted collagen fibrils, “collagen flowers” by electron microscopy Differential Diagnosis Normal skin Anetoderma

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

and may be present within the “epidermal perforation” or the ulcer bed, often oriented perpendicular to the surface. Elastic tissue stains show no increase in elastic fibers in the adjacent dermis and no evidence of elastic fibers in the keratotic plug or areas of epidermal perforation.

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synthesis have now been identified in more than half of the subtypes, although precise classification of individual patients remains challenging. CLINICAL FEATURES Common to many patients with Ehlers-Danlos syndrome are skin fragility, hyperextensibility, skin that has a velvety texture and a tendency to bruise easily, delayed wound healing leading to “cigarette paper” scars, and hypermobile joints.81 Although most forms of the disorder usually are compatible with a normal life span, the so-called “ecchymotic” form of Ehlers-Danlos syndrome often leads to premature death from arterial or intestinal rupture. Occasionally, raisinlike (molluscoid) pseudotumors, which are raised, soft, and with a wrinkled surface, develop at the sites of trauma. Finally, in some patients, firm, spheroid subcutaneous nodules form at sites of traumatic fat necrosis. HISTOPATHOLOGIC FEATURES Other than having areas of skin altered by trauma, patients with types I to III Ehlers-Danlos syndrome show no abnormalities histologically either in skin thickness or in appearance of collagen or elastic fibers. Occasionally, patients show thin collagen fibers not united in bundles, with a reduction in thickness and a relative increase in numbers of elastic fibers. These changes tend to be more prominent in patients with type I (gravis) than in those with types II and III. Type IV Ehlers-Danlos syndrome is characterized by the most pronounced dermal thinning, usually resulting in a one half to three-quarters normal-thickness dermis with an abundance of elastic fibers that appear shortened and fragmented. The latter change may be secondary to changes in collagen fiber morphology. Electron microscopy reveals nonspecific changes in collagen fiber morphology and distribution, including “collagen flowers” (loosely associated fibrils). Raisinlike pseudotumors that develop at hematoma sites demonstrate fibrosis and numerous capillaries, as well as occasionally multinucleated histiocytes. Spheroid subcutaneous nodules are composed of fat lobules with a thick surrounding collagen layer that may contain aggregates of calcium (nodulocystic fat necrosis).

with defects of various types of type I collagen.82 HISTOPATHOLOGIC FEATURES A markedly thinned dermis is seen in severely affected patients with clinically atrophic skin.

Marfan Syndrome CLINICAL FEATURES Patients with Marfan syndrome rarely have prominent cutaneous findings, although they are characteristically tall with skeletal malformations, arachnodactyly, lens dislocations, and aortic aneurysms and mitral valve prolapse. The findings are explained by abnormalities in the primary structure of fibrillin-l, a component of elastic tissue normally present in large quantities in muscular vessels, periosteum, skin, and lens ligaments.83 HISTOPATHOLOGIC FEATURES Occasionally, patients with Marfan syndrome may have dermal atrophy characterized by a diminished amount of collagen with morphologically thinner collagen bundles.

Relapsing Polychondritis Relapsing polychondritis is typically a progressive, episodic inflammatory process involving most commonly auricular cartilage in up to 90% of patients who also have polyarthritis, nasal chondritis, ocular inflammation, and respiratory tract chondritis. Mortality may be up to 25%,

usually the result of respiratory tract involvement or from cardiac valvular chondritis. CLINICAL FEATURES Painful erythema and edema involving both the ears and nose develop intermittently, ultimately leading to soft and flabby ears and saddle-nose deformity due to cartilage degeneration. Cutaneous lesions occur rarely and are described as purpuric or erythema nodosum–like. HISTOPATHOLOGIC FEATURES There is characteristically a mixed inflammatory infiltrate of lymphocytes, neutrophils, and plasma cells in the dermis surrounding deeper cartilage structures (Figs. 17-10 and 17-11). Cartilage changes include vacuolization and pyknosis of chondrocytes with eventual loss of cartilage basophilia. Elastic stains reveal destruction of elastic fibers within cartilage. With each succeeding attack, more chondrocytes are destroyed and replaced by fibrous tissue. Cutaneous lesions have shown vasculitis with fibrin deposition involving vessels that are surrounded by lymphocytes and eosinophils.

SYNDROMES OF PREMATURE AGING Table 17-9 lists the syndromes of premature aging.

Osteogenesis Imperfecta

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CLINICAL FEATURES Osteogenesis imperfecta is characterized by bone fragility as well as short stature, loose joints, blue sclerae, and (occasionally) thin skin. Osteogenesis imperfecta represents a group of genetically inherited disorders

 FIGURE 17-10 Relapsing polychondritis. At low power, a mixed inflammatory infiltrate is seen in the perichondrial connective tissue.

units. The subcutaneous fat is replaced by collagen. DIFFERENTIAL DIAGNOSIS Distinguishing the skin of patients with Werner syndrome from scleroderma is exceedingly difficult, and clinicopathologic correlation may be necessary.

Progeria (Hutchinson-Gilford Syndrome)

 FIGURE 17-11 Relapsing polychondritis. At higher power, a mixed inflammatory infiltrate of neutrophils, lymphocytes, plasma cells, and eosinophils is seen adjacent to the auricular cartilage with some loss of normal staining (devitalization) of the cartilage.

Werner Syndrome (Adult Progeria) Werner syndrome results from an autosomal recessive trait that first appears in patients in their teens or twenties. Death typically occurs in the fifth decade of life due to atherosclerosis.84 It is caused by a mutation in the WRN gene that results in abnormalities in DNA replication and repair.85 CLINICAL FEATURES Patients with Werner syndrome are of short stature and develop atrophy of the subcutaneous fat and extremity musculature, presenting with birdlike facies and thin arms and legs. The skin on the extremities gradually becomes taut, and leg ulcers may develop. Premature senility, graying of the hair and pattern alopecia, cataracts, and atherosclerosis develop in early adult life, and late-onset-type diabetes and hypogonadism due to interstitial fibrosis of the testes are common. The cause of Werner syndrome is unknown, but some reports suggest altered control of collagen synthesis.86 HISTOPATHOLOGIC FEATURES Patients with well-developed changes have an atrophic epidermis lacking rete ridges. The dermis shows fibrosis and at times hyalinization of the collagen in sclerodermoid areas, as well as loss of pilosebaceous

Table 17-9 Premature Aging Syndromes

Clinical Features Werner syndrome (adult progeria) Autosomal recessive Onset second to third decade of life Premature death due to atherosclerosis Birdlike facies Thin arms and legs Premature senility, pattern alopecia Hypogonadism Progeria (Hutchinson-Gilford syndrome) Autosomal recessive Onset 6–12 months Growth retardation Alopecia Atrophy of muscle, fat Birdlike facies Normal intelligence No sexual maturation Acrogeria (Gottran syndrome) Onset early childhood Thin, dry, wrinkled skin Elastosis perforans serpiginosa Subgroup of Ehlers-Danlos type IV Histopathologic Features Epidermal atrophy Fibrosis and collagen hyalinization Atrophy of subcutaneous fat Differential Diagnosis Scleroderma

CLINICAL FEATURES Patients with progeria appear prematurely aged, and all show a striking resemblance to one another. Onset typically begins between 6 and 12 months of age and is characterized by growth retardation; scalp, eyebrow, and lash alopecia; prominent scalp veins; and generalized atrophy of muscle and subcutaneous tissues. The face is small, the chin is shortened, and the nose reveals prominent nasal cartilage, resulting in a birdlike appearance. Frequently, nasolabial and circumoral cyanosis occur. The nails may be atrophic, and the skin thin except for areas with scleroderma-like plaques. Skeletal changes include prominent joints, thin bones, small clavicles, and defective ossification of the skull.88 Although intelligence is normal and thyroid, parathyroid, pituitary, and adrenal gland function is normal, there is absence of sexual maturation.

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

Progeria is a rare disease transmitted as an autosomal recessive trait and first described by Hutchinson in 1886. There is no gender predilection, and rarely, only a single family member is affected. Conflicting results have occurred after attempts to culture skin fibroblasts, with some cultured cells showing a normal life span and others surviving only briefly.87

HISTOPATHOLOGIC FEATURES In areas of scleroderma-like plaques, the dermis shows thickened homogenized collagen bundles extending into the subcutaneous tissue with atrophic or absent follicles. Eventually, subcutaneous tissue atrophy occurs with only a few small fat lobules surrounded by connective tissue.

Acrogeria (Gottran Syndrome) A rare disease appearing first in early childhood, acrogeria is characterized by thin, dry, and wrinkled skin most prominently on the face and extremities.89 Some bony abnormalities, as well as elastosis perforans serpiginosa and perforating elastomas, have been described. Acrogeria may represent a subgroup of type IV Ehlers-Danlos syndrome.90

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HISTOPATHOLOGIC FEATURES Dermal atrophy with collagen abnormalities is characteristic, including thickened and homogeneous bundles extending into subcutaneous fat.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

ALTERATIONS OF ELASTIN Elastic tissue is one of the three major components of the dermis, with collagen and ground substance, and is crucial to maintaining the integrity and elasticity of the skin. Elastic fibers constitute approximately 3% of the dermis by dry weight, measuring 1 to 3 μm in diameter.91,92 Elastic fibers are wavy and appear fragmented when examined by light microscopy; visualization requires special stains such as silver, orcein, or resorcinfuchsin. Abnormalities of elastic tissue often result in dramatic clinical changes. Three types of elastic fibers can be identified: oxytalan, elaunin, and elastic. Elastic tissue of the papillary dermis is composed of a plexus of elaunin fibers that are oriented primarily parallel to the dermal–epidermal junction, to which they are connected by oxytalan fibers, which are thin and oriented perpendicular to the junction. The thickest fibers, elastic fibers, are the predominant elastic tissue component in the reticular dermis, where they appear fragmented and are arranged parallel to the surface.91,92

INCREASED ELASTIC TISSUE

Elastoma Elastoma (juvenile elastoma, nevus elasticus) is a variant of connective tissue nevus discussed previously.

Elastofibroma Elastofibroma is a peculiar unilateral asymptomatic proliferation of collagen and abnormal elastic tissue with an anatomic predilection for the subcutaneous tissue inferior to the scapulae (elastofibroma dorsi) usually found in older patients.93,94 Elastofibromas present as flesh-colored nodules that may reach significant size (5–10 cm in diameter).

400

HISTOPATHOLOGIC FEATURES Elastofibromas are characterized by prominent thickened collagen bundles within which are many, more darkly eosinophilic, irregularly shaped, and fragmented elastic fibers. Adipocytes are often scattered throughout the nodule. The elastic fibers stain characteristically with elastic tissue reagents. Elastofibroma has been reported to express vimentin, CD34, factor XIIIa, prominin 2 (CD133), and MEF-2-positive fibroblastic

stromal cells ultrastructurally connected by Cx43-type gap junctions.95

Elastosis Perforans Serpiginosa Elastosis perforans serpiginosa is an uncommon noninherited disorder characteristically affecting younger individuals. Commonly, elastosis perforans serpiginosa may be associated with other connective tissue disorders, including pseudoxanthoma elasticum, Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome, and Down syndrome96 (Table 17-10). Clinically similar lesions may develop in patients receiving penicillamine, although the histologic characteristics are distinctive and allow differentiation from idiopathic elastosis perforans serpiginosa. CLINICAL FEATURES Numerous small 4- to 6-mm keratotic papules, many with peripheral erythema, develop in unusual annular or circinate configurations, most commonly around the nape of the neck and on the face and arms; and rarely, these papules are widely disseminated. HISTOPATHOLOGIC FEATURES Numerous elastic fibers, increased in number, are present in the papillary dermis, frequently in aggregations (“papillary elastoma”). The elastic fibers are thickened, fragmented, and eosinophilic. The clinical papules are reflected histologically by transepidermal channels, most likely representing portions of follicular infundibulae, that are hyperplastic and often characterized by focal perforation into the

Table 17-10 Elastosis Perforans Serpiginosa

Clinical Features Rare, noninherited Associated with pseudoxanthoma elasticum, Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome, Down syndrome Dome-shaped hyperkeratotic papules Annular or circinate configuration on neck, face, arms Histopathologic Features Increased elastic fibers in papillary dermis Epidermal or follicular hyperplasia forming transepidermal channels Perforation from channels into papillary dermis Altered elastic fibers within perforations and channels Differential Diagnosis Kyrle disease/perforating folliculitis Reactive perforating collagenosis

papillary dermis, with abnormal elastic fibers present not only in the surrounding dermis but also within the epithelial perforation and transepidermal channel.97 DIFFERENTIAL DIAGNOSIS Kyrle disease or perforating folliculitis has striking clinical and histopathologic similarities to elastosis perforans serpiginosa, including dome-shaped papules with central keratotic plugs that histologically reveal infundibular hyperplasia and perforations. However, the clinical distribution of Kyrle disease or perforating folliculitis is more generalized, frequently on the extremities, with individual lesions scattered discretely. Histologically, Kyrle disease or perforating folliculitis shows no evidence of increased or abnormal elastic tissue, particularly in dermal papillae or within the epidermal perforations.97

Pseudoxanthoma Elasticum Pseudoxanthoma elasticum may be inherited as an autosomal recessive or dominant trait, with the inheritance pattern and disease severity varying widely from patient to patient. Apparently, two recessive and two dominant forms of pseudoxanthoma elasticum exist.98 It is reported to be caused by mutations in the ABC66 gene on chromosome 16p13.1.99 In pseudoxanthoma elasticum, genetically abnormal elastic fibers develop prominent calcium deposition and are present in the skin; retina; and arterial walls, including those supplying gastric mucosa and myocardium, as well as larger peripheral arteries. Rupture of Bruch membrane results in angioid streaks of the ocular fundus, and calcification and degeneration of elastic tissue fibers in internal organs lead to GI bleeding, renal hypertension, angina pectoris, and intermittent claudication of the extremities.100 CLINICAL FEATURES Patients with pseudoxanthoma elasticum develop yellowish plaques with pebbly surfaces (“chicken skin”) primarily involving the flexures, such as the anticubital fossae, groin, axillae, and especially the lateral neck. In white skin, the cutaneous lesions may be mistaken for actinic elastosis or xanthomas. HISTOPATHOLOGIC FEATURES With H&E stain, the middle third of the reticular dermis is filled with numerous short, wavy, fragmented, irregularly shaped, granular elastic fibers that are frequently deeply basophilic due to prominent calcium deposition (Figs. 17-12 and 17-13). Consequently, the fibers stain deeply black with both elastic (orcein or Verhoef) and calcium (von Kossa) stains. Some cases with marked elastic fiber calcification

CLINICAL FEATURES Actinic elastosis presents as papular to plaquelike areas with a distinctly yellowish hue, often separated by exaggerated skin folds and furrows. Patulous follicular orifices around the lateral forehead and cheeks, as well as open and closed comedones (nodular elastosis with cysts and comedones, FavreRacouchot syndrome), are frequently present, and geometric shapes may result from prominent and deeply fissured skin folds on the posterior and lateral neck (cutis rhomboidalis nuchae).103

Elastotic Nodules of the Ears Elastotic ear nodules are another manifestation of solar elastosis that are small, skin-colored papules predominantly found on the anthelix, frequently bilaterally. Occasionally, elastotic nodules may be painful, simulating chondrodermatitis nodularis.106,107

 FIGURE 17-13 Pseudoxanthoma elasticum. Higher magnification shows the characteristic fragmented elastic fibers with calcium deposition.

result in a granulomatous infiltrate. Electron microscopy shows abnormalities of small elastic fibers, even those spared calcification, and most of the larger fibers show dense calcium deposition. DIFFERENTIAL DIAGNOSIS Solar elastosis also demonstrates abnormal elastic tissue located in the upper third of the dermis, usually beneath a small zone of spared papillary dermis, rather than the midreticular dermal location characteristic of the abnormal elastic fibers of pseudoxanthoma elasticum. Calcium deposition does not occur in solar elastosis.

Elastic Globes Elastic globes are small amphophilic collections present within the upper dermis of

clinically normal skin that stain positively for elastic fibers. Elastic globes in large numbers have been reported in an epidermolysis bullosa patient with wrinkled skin and in one patient with cartilage-hair hypoplasia syndrome with hyperextensible skin.101,102 Most likely, elastic globes represent a variation of solar elastosis.

SOLAR ELASTOTIC SYNDROMES

Solar Elastosis (Actinic Elastosis) Actinic elastosis, as the name implies, develops on sun-exposed skin, most prominently the lateral forehead, malar cheeks, neck, and extensor surfaces of the forearm and dorsal hands. Genetic pigmentation provides some protection from development of actinic elastosis.

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

 FIGURE 17-12 Pseudoxanthoma elasticum. Within the middle third of the dermis, numerous small, fragmented, distorted elastic fibers are seen.

HISTOPATHOLOGIC FEATURES Elastic fibers in patients with solar elastosis have an eosinophilic to amphophilic to gray-blue appearance with H&E stain. Solar elastosis stains prominently with elastic tissue stains, which reveal thick, tangled elastic fibers within amorphous ground substance beneath a thin subepidermal zone of apparently uninvolved dermis. Electron microscopy shows irregularly aggregated electron-dense material rather than characteristic arrangement in septa with ultimately complete degeneration of elastic material and transformation into an amorphous substance identical to colloid, as seen in patients with colloid milium.104,105

HISTOPATHOLOGIC FEATURES Elastotic nodules are characterized by prominent solar elastosis, including coarse elastotic fibers intermixed with larger accumulations.

Collagenous and Elastotic Plaques of the Hands Collagenous and elastotic plaques of the hands (keratoelastoidosis marginalis, degenerative collagenous plaques of the hands) are irregular, linear plaques that occur at the junction of the palmar and dorsal skin of the hands, particularly along the medial thumb and lateral index finger, where they resemble acrokeratoelastoidosis.108 Most likely, collagenous and elastotic plaques of the hands represent another manifestation of marked solar elastosis. HISTOPATHOLOGIC FEATURES With routine stains, increased numbers of thick collagen bundles are seen arranged haphazardly throughout the dermis, some perpendicular

401

to the epidermis intermixed with solar elastotic fibers, which may be confirmed by elastic tissue stains.

Erythema ab Igne

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Erythema ab igne is a pattern of persistent reticulated pigmentation and telangiectasia over anatomic sites that have been exposed repeatedly to a heat source insufficient to cause burning. Use of and close approximation to space (gas or electric) heaters, electric heating pads, and hot water bottles are commonly implicated.109 Rarely, squamous cell carcinoma may evolve within preexisting erythema ab igne.110 HISTOPATHOLOGIC FEATURES Histopathologic changes in erythema ab igne may be subtle, including epidermal atrophy with occasional atypical keratinocytes, focal vacuolar changes, telangiectasias, and often prominent elastotic fibers in the middermis. A sparse mixed-cell infiltrate containing melanophages and hemosiderin is often present in the upper dermis.

DISORDERS OF DERMAL ELASTOLYSIS The pathogenesis of disorders of dermal elastolysis remains poorly understood at

present.104-107 The net loss, gain, or maintenance of elastic fibers in the skin results from a balance of elastogenesis orchestrated by mesenchymal cells and elastolysis owing to the actions of unopposed proteases particularly elastase. Elastolytic conditions may be classified in a number of ways including whether the condition is inherited or acquired, clinical characteristics, pathogenesis if known, and finally the histological pattern or degree of elastolysis in the skin ( Table 17-11). Historically many elastolytic conditions have some relationship to or follow inflammatory or autoimmune processes in the skin.

Naevus Anelasticus Naevus anelasticus most likely represents localized anetoderma.111

Perifollicular Elastolysis Perifollicular elastolysis is characterized by tiny pinpoint lesions with finely wrinkled perifollicular atrophy that may bulge outward with lateral pressure. Most likely, perifollicular elastolysis results from preceding follicular inflammation, explaining its common occurrence in patients with follicular diseases such as

acne vulgaris and its anatomic distribution involving the face and upper back.112 HISTOPATHOLOGIC FEATURES As the name implies, elastic stains demonstrate a markedly diminished number to absence of elastic fibers within the dermis immediately surrounding hair follicles associated with little inflammation.

Macular Atrophy (Anetoderma) Macular atrophy may be classified as primary, where it may either be preceded by inflammation (Jadassohn-Pellizzari type) in which the atrophic cutaneous lesions appear initially red and demonstrate an inflammatory infiltrate on histologic examination, or the lesions may lack clinical and histologic evidence of inflammation (Schweninger-Buzzi type).113 Primary anetoderma has been associated with a number of conditions, the most significant of which is antiphospholipid antibodies.114-116 Secondary anetoderma has been reported after numerous cutaneous conditions. No hereditary forms of macular atrophy have been established. The cause of anetodermas is controversial, but elastolysis is a likely candidate.117

Table 17-11 Elastolytic Disorders of the Skin ELASTOLYSIS IN DERMIS

DISORDER

CLINICAL FEATURES

HISTOPATHOLOGICAL FEATURES

Total

Cutis laxa

Coarsely wrinkled, loose redundant skin folds

Loss of elastic fibers throughout dermis and fragmentation of remaining fibers

Blepharochalasis

Recurrent eyelid edema leading to atrophy of periorbital skin Small papules and cobblestone plaques

Almost complete loss of elastic fibers in dermis, epidermal atrophy, and thinned collagen fibers Absent elastic fibers in the dermis; elastophagocytosis may be present; perivascular inflammatory infiltrate may be present in clinically inflammatory lesions Complete loss of elastic fibers in the papillary dermis Almost complete loss of elastic fibers from papillary dermis and atrophic epidermis

Anetoderma

Zonal

Papillary elastolysis Papillary pseudoxanthomalike elastolysis Mid-dermal elastolysis

Focal

Perifollicular elastolysis

Striae

Scars

Small papules and cobblestone plaques Multiple small yellow nonfollicular papules that coalesce to form plaques resembling pseudoxanthoma elasticum Type I: fine wrinkling arranged parallel to skin cleavage lines; type II: papular perifollicular protrusions Small finely wrinkled macules in association with hair follicle associated with acne vulgaris Linear atrophic depression along skin cleavage lines, initially violaceous then fade

Focal loss of elastic fibers in the reticular dermis

Almost complete loss of elastic fibers confined to the immediate vicinity of hair follicle; no inflammation Reduction of elastic tissue in early lesions and thickened elastic fibers in older lesions; epidermis flattened, atrophic blunted rete ridges, dermal thickness decreased, collagen bundles thinned and parallel to epidermis, and absent subepidermal appendages Elastic fibers initially absent; thinned elastic fibers present at 3 months; absent subepidermal appendages

402 SOURCE: Martin LK, Kossard S, Murrell DF. Reticular variant of mid-dermal elastolysis. AMJ Dermatopathol. 2008;30:287-290.

Table 17-12 Macular Atrophy (Anetoderma)

CLINICAL FEATURES In all forms of macular atrophy, round to oval atrophic patches primarily involving the upper trunk develop and are characterized by thin skin that bulges with movement. Palpation of macular atrophy transmits the sensation of a soft depression suggesting an orifice (Table 17-12). HISTOPATHOLOGIC FEATURES In inflammatory macular atrophy, early lesions show a moderately dense perivascular, predominately lymphocytic infiltrate. Occasionally, plasma cells and eosinophils

DIFFERENTIAL DIAGNOSIS The differential diagnosis of the various elastolytic disorders is related to time of onset and inheritance pattern, the characteristics and distribution of the clinical lesions, presence or absence of systemic involvement, and finally the pattern and extent of elastic tissue loss in the dermis (Table 17-11).

Cutis Laxa (Generalized Elastolysis) Cutis laxa (dermatochalasis, generalized elastolysis, dermatomegaly) may be congenital or acquired, affecting people of both genders, with autosomal dominant, recessive, and linked forms described. Cutis laxa is characterized by degenerative changes in elastic fibers. some patients show normal microfibrils and a deficiency of elastin, in other patients elastin is preserved and microfibrils are absent. Cutis laxa may be preceded by an inflammatory rash or may develop spontaneously118-120 (Table 17-13).

 FIGURE 17-14 Anetoderma (macular atrophy). Elastic tissue stain shows loss of normal elastic tissue throughout the papillary and upper reticular dermis that allows the skin to bulge (elastic stain).

CLINICAL FEATURES Cutis laxa is characterized by loose, pendulous skin imparting a prematurely aged appearance. In both the congenital and acquired types, systemic involvement is seen frequently, involving the lungs (pulmonary emphysema), bladder, and GI tract (diverticula and rectal prolapse) with inguinal, umbilical, and hiatal hernias. In some congenital cases, growth retardation and multiple joint dislocations involving the hip joints may also be present. HISTOPATHOLOGIC FEATURES The elastic fiber abnormalities vary depending on the stage and severity of the disease, either with elastic fibers diminished throughout the dermis or the decrease in elastic tissue confined to the upper or the lower dermis (Figs. 17-16 and 17-17). The remaining elastic fibers may be shortened, fragmented, and strikingly variable in diameter. Elastic tissue stains may be used to demonstrate the abnormalities. In severe examples, no elastic fibers may be present, and only fine, dustlike or dotlike particles are scattered through the dermis.121,122 In cases preceded by an inflammatory eruption such as urticaria, erythematous plaques, or vesicles, the inflammatory infiltrate may be mononuclear (lymphocytes and histiocytes) or mixed, containing neutrophils. When vesicles are present, they

 FIGURE 17-15 Anetoderma (macular atrophy). A higher power view shows markedly reduced elastic tissue (elastic stain).

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

Clinical Features May develop after inflammatory rash (Jadassohn-Pellizzari) or spontaneously (Schweninger-Buzzi type) Round to oval atrophic patches on trunk Skin bulges with movement Palpation suggests orifice Histopathologic Features Absence of elastic tissue (elastic stains) Early lesions may have plasma cells, eosinophils, neutrophils, or epithelioid histiocytes Differential Diagnosis Atrophoderma

predominate, and rarely, neutrophils and epithelioid histiocytes may be present. In chronic noninflammatory lesions, elastic tissue stains show a virtually complete loss of elastic tissue either in the upper reticular and papillary dermis or confined to the upper reticular dermis (Figs. 17-14 and 17-15). Inflammatory cells may surround degenerated elastic fibers.

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Table 17-13 Cutis Laxa (Generalized Elastolysis)

404

Clinical Features Congenital or acquired Autosomal dominant, recessive, or X-linked Loose, pendulous skin giving prematurely aged appearance May be preceded by inflammatory eruption Systemic involvement (lungs, bladder, GI tract, hernias) Histopathologic Features Elastic fibers diminished throughout dermis or loss confined to upper or lower dermis (elastic stains) Remaining elastic fibers short and fragmented Lymphocytes, histiocytes, or neutrophils may be present Differential Diagnosis Granulomatous slack skin Anetoderma

are subepidermal, with papillary collections of neutrophils and eosinophils mimicking dermatitis herpetiformis. Involved internal organs show granular changes in elastic fibers similar to those seen in the skin. Collagen abnormalities have also been described but are ultrastructurally nonspecific.

Mid-Dermal Elastolysis Mid-dermal elastolysis is a rare acquired disorder of elastic tissue degradation

first described in 1977 by Shelly and Wood.105 To date less than 100 cases have been described in the literature, and there is growing evidence that the entity represents a rather characteristic histological reaction pattern to a wide variety of (predominately inflammatory) pathological processes.106,107 As the term implies the cardinal feature marking this entity is the well-defined obliteration of elastic fibers in the mid-dermis. CLINICAL FEATURES Affected individuals usually adult women aged approximately 30 to 50 years present with asymptomatic and generally symmetrical skin lesions in one of three, sometimes concurrent, patterns: 1) welldefined or diffuse patches characterized by fine-wrinkling of skin, 2) discrete perifollicular papules, and 3)reticular and annular patches with central atrophy.104-107 Sites of predilection include the neck, trunk, and extremities. The pathogenesis of the condition has not been clearly delineated but has been been linked to ultraviolet light exposure and a wide variety of inflammatory and autoimmune processes including connective tissue disease, HIV, urticaria, neutrophilic dermatoses, and granulomatous reactions such as granuloma annulare and actinic granuloma (annular elastolytic giant cell granuloma). HISTOPATHOLOGIC FEATURES The essential histological criterion needed for

 FIGURE 17-16 Cutis laxa. Elastic tissue stain of normal skin from a patient with cutis laxa showing the expected pattern of elastic tissue (elastic stain).

recognition of this entity is a welldemarcated band-like absence of elastic fibers in the mid-dermis.105-107 Loss of elastic fibers is verified by elastic tissue staining, eg, Orcein stain, or potentially immunohistochemical staining for elastin. Characteristically the elastic fibers are intact in the overlying papillary and underlying deep reticular dermis in lesional skin. Lesions early in their evolution may show a number of inflammatory histological patterns including, eg, urticarial reactions, perivascular lymphocytic infiltrates, and granulomatous reactions with features of granuloma annulare and elastophagocytosis.

Menkes Syndrome Menkes kinky hair syndrome is a rare X-linked deficiency of copper metabolism resulting either in increased or decreased intracellular copper metabolism in various tissues, the latter leading to decreased activity of certain copper-dependent enzymes (eg, tyrosinases, dopamine hydroxylase, cytochrome oxidase, and lysil oxidase). Diminished enzyme activity results in the clinical features of Menkes syndrome, such as twisted (kinky, steely) and hypopigmented hair.123,124 Other changes include mental retardation, degeneration of elastic tissue within the walls of large blood vessels, and hypopigmentation involving Blaschko lines in female carriers. HISTOPATHOLOGIC FEATURES Diminished activity of lysil oxidase, which is necessary

 FIGURE 17-17 Cutis laxa. Elastic tissue stain from the involved skin of a patient with cutis laxa shows virtually no elastic tissue remaining with little evidence of an inflammatory infiltrate (elastic stain).

for elastin cross-linking, may result in fragmentation of internal elastic lamina of vessels, although dermal elastic tissue is not affected. A number of hair shaft abnormalities, such as pili torti, monilethrix, and trichorrhexis nodosa, may be present.

small, hyperkeratotic papules of the hands and feet. Small, shiny papules develop over the dorsal surfaces, usually in groups overlying the knuckles as well as the margins of the palms and soles.

Fragile X Syndrome

HISTOPATHOLOGIC FEATURES There is slight hyperkeratosis overlying an epidermal dell with diminished, fragmented elastic fibers within the reticular dermis.

Fragile X syndrome is another X-linked disorder resulting in mental retardation, characteristic facies, and connective tissue abnormalities similar to those seen in cutis laxa and Ehlers-Danlos syndromes.125

Granulomatous Diseases In rare instances, anetoderma may result from preceding granulomatous inflammation such as sarcoidosis, leprosy, or tuberculosis. In addition, diminished elastic fibers may result from other granulomatous disorders, at times lacking clinical evidence of the underlying elastolysis, such as in actinic granuloma (elastolytic giant cell granuloma) and Meischer granulomatous disciformis of the face (atypical necrobiosis lipoidica of the face and scalp). Elastotic fibers are frequently present within the cytoplasm of mononuclear and multinucleated epithelioid histiocytes in patients with these conditions, presumably resulting in the focal elastolysis.

Granulomatous Slack Skin It is now appreciated that granulomatous slack skin, initially termed progressive, atrophying, chronic granulomatous dermohypodermatis,126 represents a peculiar, rare presentation of cutaneous T-cell lymphoma in most patients, who develop striking, pendulous flexural skin folds indistinguishable from cutis laxa.127 Diminished elastic tissue is present that is similar to idiopathic cutis laxa.

Myxedema Dermal elastic tissue is prominently diminished in both hypothyroid and hyperthyroid (pretibial) myxedema. Ultrastructurally, elastic fibers show a marked variability in diameter as well as a decrease in microfibrils.128

Acrokeratoelastoidosis Acrokeratoelastoidosis is an autosomal dominant condition characterized by

Leprechaunism Leprechaunism is a rare syndrome characterized by unusual facies, phallic enlargement, and diminished subcutaneous fat, as well as wrinkled skin, resulting in prominent periorificial folds. Acanthosis nigricans and hypertrichosis may also be present.129 HISTOPATHOLOGIC FEATURES Both diminished collagen and elastic fibers have been reported in patients with leprechaunism, but thickened elastic fibers involving the dermis and subcutaneous fat septa also have been reported.

Syndromes of Premature Aging Elastic tissue may be increased in Werner syndrome, in which ultrastructural changes have been described as granular and filamentous alterations of elastic tissue. Acrogeria may be characterized by diminished elastic fibers as well as elastosis perforans.

Marfan Syndrome Marfan syndrome is a rare autosomal dominant disease characterized by abnormalities in tissues containing elastic fibers, such as the skin and aorta, as well as ocular and skeletal abnormalities. Cutaneous manifestations include elastosis perforans serpiginosa and striae distensae, which are of little clinical significance in contrast to the systemic findings. The underlying cause of the protean manifestations of Marfan syndrome has been determined to be abnormalities in the primary structure of fibrillin-1, a large protein forming part of the elastic fiber–microfibrillar complex, as well as capable of independent microfibrillar bundle formation within the dermis.83 Fibrillin-l is present in the periosteum, lens ligaments, and elastic tissue within cardiovascular structures and the skin, explaining the clinical manifestations.

REFERENCES 1. Kielty CM, Hopkinson I, Grant ME: The collagen family: structure, assembly, and organization in extracellular matrix, in Royce PM, Steinmann B (eds). Connective Tissue and Its Heritable Disorders. New York: Wiley-Liss; 1993:103-147. 2. Kivirikko KI: Collagens and their abnormalities in a wide spectrum of diseases. Ann Med. 1993;25:113-126. 3. Mauch C, Kreig T: Collagens: their structure and metabolism, in Lapiere CM, Kreig T (eds). Connective Tissue Diseases in the Skin (Clinical Dermatology Series No. 9). New York: Marcel Dekker; 1993:1. 4. Prockop DJ, Berg RA, Kivirikko KI, et al: Intracellular steps in the biosynthesis of collagen, in Ramachandran GN, Reddi AJ (eds). Biochemistry of Collagen. New York: Plenum Press; 1976:163-273. 5. Uitto J, Prockop DJ: Synthesis and secretion of underhydroxylated procollagen at various temperatures by cells subject to temporary anoxia. Biochem Biophys Res. Commum. 1974;60:414-423. 6. Ruffatti A, Peserico A, Glorioso S, et al: Anticentromere antibody in localized scleroderma. J Am Acad Dermatol. 1986;15:637-642. 7. Aberer E, Klade H, Stanek G, et al: Borrelia burgdorferi and different types of morphea. Dermatologica. 1991;182:145-154. 8. Halkier-Sorensen L, Kragballe K, Hansen K: Antibodies to the Borrelia burgdorferi flagellum in patients with scleroderma, granuloma annulare, and porphyria cutanea tarda. Acta Derm Venereol (Stockh). 1989;69:116-119. 9. Jablonska S, Rodnan GP: Localized forms of scleroderma. Clin Rheum Dis. 1979;5:215-241. 10. Su WPD, Greene SL: Bullous morphea profunda. Am J Dermatopathol. 1986;8: 144-147. 11. Hulsmans RFHJ, Asghar SS, Siddiqui AH, Cormane RH: Hereditary deficiency of C2 in association with linear scleroderma “en coup de sabre.” Arch Dermatol. 1986,122:76-79. 12. Lakhani PJ, David TJ: Progressive hemifacial atrophy with scleroderma and ipsilateral limb wasting (Parry-Romberg syndrome). J R Soc Med. 1984;77: 138-139. 13. Cantwell AR Jr, Jones JE, Kelso DW: Pleomorphic, variably acid-fast bacteria in an adult patient with disabling pansclerotic morphea. Arch Dermatol. 1983;120:656-661. 14. Su WPD, Person JR: Morphea profunda: a new concept and a histopathologic study of 23 cases. Am J Dermatopathol. 1981;3:251-260. 15. Uitto J, Santz Cruz DJ, Bauer EA, Eisen AZ: Morphea and lichen sclerosus et atrophicus. J Am Acad Dermatol. 1980; 3:271-279.

CHAPTER 17 ■ ALTERATIONS OF COLLAGEN AND ELASTIN

HISTOPATHOLOGIC FEATURES Fragile X syndrome results in diminished dermal elastic tissue with fragmented and curled elastic fibers as well as diminished ground substance (mucopolysaccharides).

VARIABLE OR MINOR ELASTIC TISSUE CHANGES

HISTOPATHOLOGIC FEATURES Elastosis perforans serpiginosa and striae distensae occurring in patients with Marfan syndrome have characteristic features (described under Marfan Syndrome). Clinically uninvolved skin in patients with Marfan syndrome shows no apparent abnormalities.

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16. LeRoy EC, Black C, Fleischmajer R, et al: Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15:202-205. 17. Krieg T, Meurer M: Systemic scleroderma: Clinical and pathophysiologic aspects. J Am Acad Dermatol. 1988;18:457-481. 18. Haustein UF, Herrmann K, Bohme HJ: Pathogenesis of progressive systemic sclerosis. Int J Dermatol. 1986;25: 286-293. 19. Perlish JS, Lemlich G, Fleischmajer R: Identification of collagen fibrils in scleroderma skin. J Invest Dermatol. 1988;90: 48-54. 20. Kahari V-M, Sandberg M, Kalimo H, et al: Identification of fibroblasts responsible for increased collagen production in localized scleroderma by in situ hybridization. J Invest Dermatol. 1988;90: 664-670. 21. McCarty GA: Autoantibodies in scleroderma and polymyositis: an update. Semin Dermatol. 1991;10:206-216. 22. Silverstein JL, Steen VD, Medsger TA Jr, Falanga V: Cutaneous hypoxia in patients with systemic sclerosis (scleroderma). Arch Dermatol. 1988;128:1379-1382. 23. Velayos EE, Masi AT, Stevens MB, Shulman LE: The “CREST” syndrome: comparison with systemic sclerosis (scleroderma). Arch Intern Med. 1979;139: 1240-1244. 24. Rodnan GP, Myerowitz RL, Justh GO: Morphologic changes in the digital arteries of patients with progressive systemic sclerosis (scleroderma) and Raynaud phenomenon. Medicine. 1980; 59:393-408. 25. Sharp GC, Irvin WS, Tan EM, et al: Mixed connective tissue disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52:148-159. 26. Sharp GC, Anderson PC: Current concepts in the classification of connective tissue diseases: overlap syndromes and mixed connective tissue disease. J Am Acad Dermatol. 1980;2:269-279. 27. Chanda JJ, Callen JP, Taylor WB: Diffuse fasciitis with eosinophilia. Arch Dermatol. 1978;114:1522-1524. 28. Falanga V, Medsger TA Jr: Frequency, levels, and significance of blood eosinophilia in systemic sclerosis, localized scleroderma, and eosinophilic fasciitis. J Am Acad Dermatol. 1987;17: 648-656. 29. Dunger DB, Dicks-Mireaux C, O’Driscoll P, et al: Two cases of Winchester syndrome: with increased urinary oligosaccharide excretion. Eur J Pediatr. 1987;146:615-619. 30. Oikarinen A, Palatsi R, Kylmaniemi M, et al: Pachydermoperiostosis: analysis of the connective tissue abnormality in one family. J Am Acad Dermatol. 1994; 31:947-953. 31. Friedman SJ, Doyle JA: Sclerodermoid changes of porphyria cutanea tarda: possible relationship to urinary uroporphyrin levels. J Am Acad Dermatol. 1985; 13:70-74. 32. Parks DL, Perry HO, Muller SA: Cutaneous complications of pentazocine injections. Arch Dermatol. 1971;104:231-235. 33. Mountz JD, Downs Minor MB, Turner R, et al: Bleomycin-induced cutaneous toxicity in the rat: analysis of

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55. Zheng P, Lavker EM, Kligman AM: Anatomy of striae. Br J Dermatol. 1985; 112:185-193. 56. Tsuji T, Sawabe M: Elastic fibers in striae distensae. J Cutan Pathol. 1988; 15:215-222. 57. Lacour JPH, Maquart FX, Bellon G, et al: Fibroblastic rheumatism: clinical, histological, immunohistological, ultrastructural, and biochemical study of a case. Br J Dermatol. 1993;128:194-202. 58. Vignon-Pennamen M-D, Naveau B, Foldes C, et al: Fibroblastic rheumatism. J Am Acad Dermatol. 1986;14:1086-1088. 59. Lister DM, Graham-Brown RAC, Burns DA, et al: Collagenosis nuchae: a new entity? Clin Exp Dermatol. 1988;13: 263-264. 60. Frieden IJ: Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol. 1986;14: 646-660. 61. Harari Z, Pasmanik A, Dvoretzky I, et al: Aplasia cutis congenita with dystrophic nail changes. Dermatologica. 1976;153: 363-368. 62. Staughton RCD: Focal dermal hypoplasia (Goltz’s syndrome) in a male. Proc R Soc Med. 1976;69:232-233. 63. Goltz RW, Henderson RR, Hitch JM, Ort JE: Focal dermal hypoplasia syndrome: a review of the literature and report of two cases. Arch Dermatol. 1970; 101:1-11. 64. Howell JB, Freeman RG: Cutaneous defects of focal dermal hypoplasia: an ectomesodermal dysplasia syndrome. J Cutan Pathol. 1989;16:237-258. 65. Magid ML, Prendiville JS, Esterly NB: Focal facial dermal dysplasia: bitemporal lesions resembling aplasia cutis congenita. J Am Acad Dermatol. 1988;18:1203-1207. 66. Raque CJ, Stein KM, Lane JM, Reese EC Jr: Pseudoainhum constricting bands of the extremities. Arch Dermatol. 1972;105: 434-438. 67. Rivers JK, Duke EE, Justus DW: Etretinate: management of keratoma hereditaria mutilans in four family members. J Am Acad Dermatol. 1985;13: 43-49. 68. Rand R, Baden HP: Keratosis follicularis spinulosa decalvans: report of two cases and literature review. Arch Dermatol. 1983;119:22-26. 69. Stevanovic DV: Corticosteroid-induced atrophy of the skin with telangiectasia. Br J Dermatol. 1972;87:548-556. 70. Fritsch WC: Deep atrophy of the skin of the deltoid area. Arch Dermatol. 1970;101: 585-587. 71. Berman A, Berman GD, Winkelmann RK: Atrophoderma (Pasini-Pierini): findings on direct immunofluorescent, monoclonal antibody, and ultrastructural studies. Int J Dermatol. 1988;27:487-490. 72. Miller RF: Idiopathic atrophoderma: report of a case and nosologic study. Arch Dermatol. 1965;92:653-660. 73. Mehregan AH, Schwartz OD, Livingood CS: Reactive perforating collagenosis. Arch Dermatol. 1967;96:277-282. 74. Detlefs RL, Goette DK: Collagenome perforant verruciforme. Arch Dermatol. 1986;122:1044-1046. 75. Poliak SC, Lebwohl MG, Parris A, Prioleau PG: Reactive perforating collagenosis associated with diabetes mellitus. N Engl J Med. 1982;306:81-84. 76. Bank DE, Cohen PR, Kohn SR: Reactive perforating collagenosis in a setting of

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115. Disdier P, Harlé JR, Andrac L, et al: Primary anetoderma associated with the antiphospholipid syndrome. J Am Acad Dermatol. 1994;30:133-134. 116. Stephansson EA, Niemi KM: Antiphospholipid antibodies and anetoderma: are they associated? Dermatology. 1995;191:204-209. 117. Oikarinen AI, Palatsi R, Adomian GE, et al: Anetoderma: biochemical and ultrastructural demonstration of an elastin defect in the skin of three patients. J Am Acad Dermatol. 1984;11:64-72. 118. Schreiber MM, Tilley JC: Cutis laxa. Arch Dermatol. 1961;84:266-272. 119. Ledoux-Corbusier M: Cutis laxa, congenital form with pulmonary emphysema: an ultrastructural study. J Cutan Pathol. 1983;10:340-349. 120. Mehregan AH, Lee SC, Nabai H: Cutis laxa (generalized elastolysis): a report of four cases with autopsy findings. J Cutan Pathol. 1978;5:116-126. 121. Sephel GC, Byers PH, Holbrook KA, Davidson JM: Heterogeneity of elastin expression cutis laxa fibroblast strains. J Invest Dermatol. 1989;93:147-153. 122. Kitano Y, Nishida K, Okada N, et al: Cutis laxa with ultrastructural abnormalities of elastic fiber. J Am Acad Dermatol. 1989;21:378-380. 123. Menkes JH, Alter M, Steigleder GK, et al: A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics. 1962;29:764-779. 124. Hart DB: Menke’s syndrome: an updated review. J Am Acad Dermatol. 1983;9:145-152. 125. Waldstein G, Mierau G, Ahmad R, et al: Fragile X syndrome: skin elastin abnormalities. Birth Defects. 1987;23:103-114. 126. Convit J, Kerdel F, Goihman M, et al: Progressive, atrophying, chronic granulomatous dermohypodermitis. Arch Dermatol. 1973;107:271-274. 127. LeBoit PE, Beckstead JH, Bond B, et al: Granulomatous slack skin: clonal rearrangement of the T-cell receptor B gene is evidence for the lymphoproliferative nature of a cutaneous elastolytic disorder. J Invest Dermatol. 1987;89:183-186. 128. Matsuoka LY, Wortsman J, Uitto J, et al: Altered skin elastic fibers in hypothyroid myxedema and pretibial myxedema. Arch Intern Med. 1985;145:117-121. 129. Roth SI, Schedewie HK, Herzberg VK, et al: Cutaneous manifestations of leprechaunism. Arch Dermatol. 1981;117:531-535. 130. Shabana WM, Cohan RH, Ellis JH, et al: Nephrogenic Systemic Fibrosis: A Report of 29 Cases AJR. Am J Roentgenol. 2008; 90:736-41. 131. Deng A, Bilu Martin D, Spillane A, et al: Nephrogenic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling. J Cutan Pathol. 2009;3.

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double disaster: acquired immunodeficiency syndrome and end-stage renal disease. J Am Acad Dermatol.1989;21:371-374. Faver IR, Daoud MS, Su WP: Acquired reactive perforating collagenosis. Report of six cases and review of the literature. J Am Acad Dermatol. 1994;30:575-580. Kawakami T, Saito R: Acquired reactive perforating collagenosis associated with diabetes mellitus: eight cases that meet Faver’s criteria. Br J Dermatol. 1999; 140: 521-524. Burns DA, Calnan CD: Chondrodermatitis nodularis antihelicis. Clin Exp Dermatol. 1978;3:207-208. Hurwitz RM: Painful papule of the ear: a follicular disorder. J Dermatol Surg Oncol. 1987;13:270-274. Sidhu-Malik NK, Wenstrup RJ: The Ehlers-Danlos syndrome and Marfan syndrome: inherited diseases of connective tissue with overlapping clinical features. Semin Dermatol. 1995;14:40-46. Pope FM, Nicholls AC, McPheat J, et al: Collagen genes and proteins in osteogenesis imperfecta. J Med Genet. 1985; 22: 466-478. Dietz HC, McIntosh I, Sakai LY, et al: Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics. 1993;17:468-475. Beauregard S, Gilchrest BA: Syndromes of premature aging. Dermatol Clin. 1987; 5:109-121. Muftuoglu M, Oshima J, von Kobbe C, Cheng WH, et al: The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet. 2008;24(4):369-377. Arakawa M, Hatamochi A, Takeda K, Ueki H: Increased collagen synthesis accompanying elevated mRNA levels in cultured Werner’s syndrome fibroblasts. J Invest Dermatol. 1990;94:187-190. Sephal GC, Sturrock A, Giro MG, Davidson JM: Increased elastin production by progeria skin fibroblasts is controlled by the steady-state levels of elastin mRNA. J Invest Dermatol. 1988; 90:643-647. Jimbow K, Kobayashi H, Ishii M, et al: Scar and keloidlike lesions in progeria. Arch Dermatol. 1988;124:1261-1266. De Groot WP, Tafelkruyer J, Woerdeman MJ: Familial acrogeria (Gottron). Br J Dermatol. 1980;103:213-223. Pope FM, Nicholls AC, Narcici P, et al: Type III collagen mutations in EhlersDanlos syndrome type IV and other related disorders. Clin Exp Dermatol. 1988;13:285-302. Uitto J, Olsen DR, Fazio MJ: Extracellular matrix of the skin: 50 years of progress. J Invest Dermatol. 1989;92(suppl):61S-77S. Uitto J, Fazio IM, Kahari V-M: Elastic fibers. In Lapiere CM, Kreig T (eds). Connective Tissue Diseases in the Skin (Clinical Dermatology Series No 9). New York: Marcel Dekker; 1993:31. Madri JA, Dise CA, LiVolsi VA, et al: Elastofibroma dorsi: an immunochemical study of collagen content. Hum Pathol. 1981;12:186-190. Schwarz T, Oppolzer G, Duschet P, et al: Ulcerating elastofibroma dorsi. J Am Acad Dermatol. 1989;21:1142-1144.

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CHAPTER 18 Ectopic Tissue

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Jacqueline M. Junkins-Hopkins

408

A specimen submitted to a dermatopathologist or pathologist with the clinical diagnosis of tag or nodule may, on occasion, have histologic features that may be normal or characteristic but not for a particular location. Such a lesion could be considered ectopic (ektopos is Greek for “out of place”) and may be benign and of no systemic consequence, or it may be associated with an extracutaneous and potentially serious condition. Various types of ectopic tissue and their characteristic locations are listed in Table 18-1.

Table 18-1 Classification of Accessory Mammary Tissue

Traditional Classification 1. Complete breast with nipple, areola, and glandular tissue (polymastia) 2. Nipple and glandular tissue only 3. Areola and glandular tissue only 4. Glandular tissue only (ectopic breast tissue) 5. Nipple and areola with gland replaced by fat (pseudomamma) 6. Nipple only (polythelia) 7. Areola only (polythelia areolaris) 8. Tuft of hair only (polythelia pilosis) Modern Classification Type 1: Accessory mammary tissue with glandular parenchyma Type 2: Accessory mammary tissue without evidence of glandular parenchyma Subtype 2a: Polythelia (nipple only) Subtype 2b: Supernumerary areola (areola only) Subtype 2c: Mixed (nipple with areola) Proposed Addition to Modern Classification Type 3: Intra-areolar polythelia* Subtype 3a: AMT arising from the areola (“paired or dysplastic divided nipple.”) Subtype 3b: AMT arising from the primary nipple (“nipple nevus”) *Embryogenesis is considered to result from in utero division (dichotomy) of the developing nipple as opposed to failure of regression along the milk line. AMT = accessory mammary tissue. SOURCE: Adapted from Lewis, et al.11

ACCESSORY TRAGUS Synonyms: Preauricular tag, polyotia, accessory auricle anomaly, rudimentary ear, supernumery pinna, ear tag, wattle The tragus is the portion of the external ear derived from the first branchial arch. This, together with the second branchial arch, moves dorsally, forming the auricle. An accessory tragus may develop at any point along the migratory line that extends from the tragus to the angle of the mouth or along the anterior margin of the sternocleidomastoid muscle.1 Some synonyms for this anomaly, such as accessory auricle, are less appropriate because the rest of the external ear is derived from the second branchial arch. CLINICAL FEATURES Accessory tragi are located most commonly in the preauricular region, slightly above or below the level of the tragus. They may present more anteriorly on the cheek or along the line of the mandible, on the neck between the sternocleidomastoid muscle and the suprasternoclavicular region, or (rarely) on the glabella or suprasternal region.1,2 Lesions arising on the neck are referred to by some as wattles.3 Others consider wattles to be cutaneous cartilaginous rests.1 Accessory tragi typically

present as pedunculated soft to cartilagenous papules; they may be solitary or multiple, unilateral or bilateral, and are often diagnosed clinically as skin tags or fibromas. Vellus hairs may cover the surface. The lesions are asymptomatic unless they become infected or ulcerated. Associated developmental abnormalities of the pharyngeal arch may be seen in at least 5% of patients with accessory tragi.2 Accessory tragi are a consistent feature in individuals with Goldenhar syndrome, which also includes epibulbar dermoids and vertebral defects. Less consistently, accessory tragi may be seen with TownesBrocks syndrome, Treacher-Collins syndrome, VACTERL (vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, esophageal atresia, renal or radial anomalies, and limb anomalies) association, and WolfHirschhorn syndrome. 4 In addition, patients have an associated risk of diminished auditory acuity.1 HISTOPATHOLOGIC FEATURES Histologically, the features are similar to those of the fetal external ear. At scanning magnification, accessory tragi are easily recognized by their polypoid appearance and central core of elastic cartilage present in most specimens (Fig. 18-1). The surface may be

 FIGURE 18-1 Accessory tragus. The structure is polypoid with a central core of elastic cartilage. Vellus hairs and adipose tissue are present between the epidermis and cartilage.

smooth or slightly rugated with a thin, compact or basket-weave stratum corneum. The papillary dermis consists of collagen intermingled with adipose tissue and dilated vessels. Vellus hair follicles are scattered throughout the papillary dermis (see Fig. 18-1). The associated sebaceous glands are hormonally responsive and vary in prominence depending on the age of the patient. Eccrine glands and ducts are often present, but apocrine glands are rarely seen.2 Skeletal muscle may be present.1

ACCESSORY NIPPLE Synonyms: Polythelia, supernumerary nipple Supranumerary nipples or areolas without fully developed nipples have been detected in up to 5.6% of children. Supernumerary nipples occur less frequently with breast tissue.7 The occurrence of accessory breast tissue depends on the population studied. Supranumerary nipples occur more often in males, with a male-to-female ratio of up to 2.5:1.7 Polymastia and polythelia are more common in black and white Americans, Native Americans, Japanese, Israeli Jews, and Arabs. There is a low frequency (.22%) in white Europeans children. Familial cases have been reported in up to 10% of cases.8 The modes of inheritance are heterogeneous and may be autosomal

CLINICAL FEATURES Supernumerary nipples may be solitary or multiple. A case of six accessory nipples and accessory breast glandular tissue has been reported in a girl with a three-generation family history of polythelia.9 The most common site is the left thoracic region inferior to the normal nipple.7,10 However, they may be found anywhere along the milk line (ie, the anterior axillary fold to the inner inguinal fold). Unusual sites outside the milk line include the perineum,15 scapula, posterior aspect of the thigh, face, neck, and labia majora.8,16 A rare variant is termed nipple nevus, which presents as a nevoid nodule surmounting a normal primary nipple. This is thought to have resulted from in utero nipple dichotomy as opposed to failure of regression along the embryonic milk line.11 In infancy, these nipples may be pigmented to pearl-colored macules that may be wrinkled or concave and exhibit a crease when the area is folded between two fingers.7 In adulthood, if not associated with ectopic breast tissue, they may remain macular. However, they may become pigmented or raised, simulating nevi, dermatofibroma, and skin tags. Dermatoscopy may show features that

overlap with dermatofibroma, including a white central scar-like tissue with a peripheral fine pigment network, but it is differentiated by a central cleft.17 If no overlying nipple or areola is present, the clinical differential diagnosis should include entities such as lipoma, cyst, and lymph node. Polythelia pilosa presents as a tuft of hair, and it may be more apparent in hirsuitism.12 There may be cyclical variation in size with menstruation and pregnancy. There may be tenderness or lactation. Polythelia has been associated with and has arisen within Becker nevus, with or without associated renal abnormalities.18 Erosive adenosis and Paget disease may occur within accessory nipples19 and polymastia or ectopic breast tissue and are subject to the same benign and malignant processes experienced by normal breast tissue.10 Rare reports of primary ectopic breast carcinoma include ductal carcinoma, medullary breast carcinoma, and cystosarcoma phylloides and papillary carcinoma.20 Malignant melanoma has rarely been reported in an accessory nipple.21 The main concern related to supernumerary nipples is the possible association with urologenital and less frequently other developmental anomalies.22,23 Kidney and renal abnormalities diagnosed by ultrasonography have been reported to occur in 14.5% of patients with accessory breast tissue, in contrast to the 1% to 2% occurrence of urogenital anomalies in the general population.8 A statistically significant incidence of supranumerary nipples was found in children with kidney and urinary tract anomalies, but this was less significant in children with functional urinary disorders.24 Others have not found this same association.25 The association of renal anomalies may be more common in familial polythelia.22 Renal carcinoma may been associated with polymastia.26 Polythelia is a component of the Simpson-Golabi-Behmel syndrome, which also includes postaxial polydactyly and heart malformations.24 Accessory breast tissue has also been associated with other cardiovascular disorders, including heart block, although this is controversial. HISTOPATHOLOGIC FEATURES Histologically, accessory nipples closely resemble their anatomic counterpart. These lesions have a characteristic low-power silhouette that is dome shaped and, if sectioned centrally, umbilicated (Fig. 18-2). In the nonelevated areolar portion, the epidermis shows a slight corrugated pattern of papillomatosis and various degrees of uniform

CHAPTER 18 ■ ECTOPIC TISSUE

DIFFERENTIAL DIAGNOSIS Accessory tragi should be differentiated from a macrotragus, which is a single enlarged tragus, with the cartilage in continuity with the tragal cartilage. It may be displaced anteriorly.5 Histologically, macrotragi and accessory tragi show identical histologic features, and the two conditions may coexist. An accessory tragus may be confused with a fibroepithelial polyp or a soft fibroma if cartilage is not present and a chondroma if cartilage is included. These lesions would not be present from birth, and the multiple vellus hairs and other associated adenexal structures support the diagnosis of an accessory tragus. A congenital midline hamartoma may have overlapping clinicopathologic features but is differentiated by a midline location near the chin, absence of elastic cartilage, and the presence of prominent striated muscle.1 Hair follicle nevi and accessory tragi also show common histologic features, differing only in the amount of associated adipose tissue. It has been proposed that hair follicle nevi represent incomplete accessory tragi with scant fat cells.6

dominant with incomplete penetrance, X-linked dominant, and recessive.9 Embryologically, the breasts develop from mammary ridges (milk lines), which are thickened areas of ectoderm extending ventrally from the base of the forelimb to the base of the hindlimb. Normally, the breast develops in the pectoral region of the ridge, and the remainder regresses. A number of anomalies may result from failure of this regression, including complete (polymastia) or incomplete supernumerary breasts; complete supernumerary nipples with nipple areola and glandular breast tissue (polymastia); a supernumerary nipple only (polythelia), which is the most common, representing 60% to 70% of cases; a nipple and areola with the gland replaced by fat (pseudomamma); a nipple and glandular tissue without a nipple; an areola and glandular tissue without a nipple; an areola alone (polythelia areolaris); glandular tissue alone; and a patch of hair (polythelia pilosis).8,10 Clinical and morphologic classification schemes have been proposed.8,11,12 Ectopic breast tissue, in particular that arising outside the milk line, may represent a continuum that includes cutaneous mammary-like sweat glands. These have been referred to as mixed sweat glands or apoepocrine glands.13,14

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

chemical stains can reliably distinguish between these two entities.20 Anogenital mammary-like glands have been separated out from ectopic breast tissue and designated as a cutaneous adnexal gland localized to the anogenital region. These have features of modified eccrine and apocrine glands and may be indistinguishable from normal breast tissue. Apocrine adenomas arising from these glands are in the differential diagnosis of fibroadenoma arising from ectopic breast tissue. The anatomic site favors the former.14

410

SUPERNUMERARY DIGIT

 FIGURE 18-2 Accessory nipple. The lesion is domeshaped and shows central invagination. The central invagination exhibits some papillomatosis and slight epithelial hyperplasia.

hyperpigmentation. Depending on the plane of sections, the center of the nipple may show a dome-shaped elevation or an invagination, from which atrichial or vellus-associated sebaceous glands mammary ducts, or both open into the epidermis. The dermis immediately beneath the central portion of the nipple consists of fine bundles of collagen with thin and diminished elastic fibers and prominent vascularity. The adjacent areolar portion exhibits collagen that is similar to normal dermis.26 Scattered smooth muscle bundles are characteristic, which are admixed with multiple vessels and nerves.27 Mammary ducts at various levels of the dermis may open into the epidermis or pilosebaceous structures. In most cases, scattered mammary glands surrounded by a fibrous connective tissue stroma are located in the deep dermis. Toker cells, found in approximately 10% of normal nipples have also been documented in 65% of accessory nipples with CK7. These also stain with epithelial membrane antigen (EMA).28 The dermis may show changes reminiscent of sclerotic fibroma.29 DIFFERENTIAL DIAGNOSIS When all of the features are present, the diagnosis is straightforward, with the only possible

exception being a normal nipple. If only a portion of the specimen is available for study, the differential diagnosis includes normal skin, a benign keratosis, epidermal nevus, Becker nevus, lentigo, fibroepithelial polyp, and soft fibroma. In the absence of mammary tissue, the presence of multiple smooth muscle bundles helps confirm the diagnosis. Atrichial sebaceous glands are also helpful supportive microscopic features. Clinical information differentiates an accessory nipple from a Becker nevus or smooth muscle hamartoma, both of which are characterized by epidermal hyperpigmentation and elongation of epidermal rete ridges overlying smooth muscle proliferation. The latter lesions have been reported rarely in association with an accessory nipple.30 Polythelia pilosa is differentiated from anatomic follicles by the identification of apocrine glands, hypertrophic sebaceous glands or atrichial sebaceous lobules, and areolar rete hyperplasia.7 Primary ectopic axillary breast carcinoma must be differentiated from primary adnexal carcinoma. This presentation is often diagnosed at TNM stage III to IV, and it has been reported to have a higher incidence of lymph node involvement due to delayed diagnosis. Unfotunately, no perfect immunohisto-

Synonyms: Polydactyly, rudimentary digit, rudimentary polydactyly, accessory digit. Polydactyly is a relatively common congenital deformity that probably results from the duplication of a single embryologic bud.31 This deformity has been classified according to the extent of normal components of the digit present.31 Type I polydactyly is an extra soft tissue mass unattached to the underlying skeletal structure that variably may contain nail, bone, cartilage, or tendons. In type II, some portion of the digit is duplicated with its normal components. Type III consists of a complete digit, including the metacarpal and associated soft tissues. This discussion will be limited to type I polydactyly, which is the type encountered most frequently by dermatopathologists. Rudimentary polydactyly is a probable amputation stump of a supernumerary digit resulting from intrauterine trauma.32 These lesions may also result from purposeful strangulation during the neonatal period. CLINICAL FEATURES Supernumerary digits may occur in a medial (preaxial) or lateral (postaxial) location and may involve the hands or feet. Postaxial polydactyly, which may be autosomal dominantly inherited, is seen frequently in blacks, with an incidence of approximately 1 in 300 versus 1 in 3000 in whites. 31 Polydactyly is often associated with other anomalies or syndromes,31,33 including a syndrome associated with segmental basaloid follicular hamartomas,34 and it has also been reported in individuals with hypertension.35 The most common site of duplication is the fifth digit, and bilaterality is common.15 The gross morphology varies depending on the structural composition of the lesion. Rudimentary digits occur most often at the ulnar base of the fifth digit or radial base of the thumb.18

Some consider rudimentary digits to represent traumatic neuromas rather than an abortive attempt of polydactyly. This is a common sequela of surgical ligation or in utero amputation of accessory digits and may be differentiated from polydactyly by the presence of localized nerve pain.36 When the digit is not fully developed, as with the rudimentary digit, the clinical differential diagnosis may include a skin tag, wart, fibroma, digital fibrokeratoma, or other similar flesh-colored papule.

 FIGURE 18-4 Supernumerary digit with focal nail formation.

and the dermis contains numerous nerve bundles associated with mucin and surrounded by perineural sheaths. The histologic features are similar to those seen in traumatic neuromas. Numerous Meissner corpuscles are seen in nearly

every other dermal papilla.37 Cartilage is not typically present. DIFFERENTIAL DIAGNOSIS If cartilage or bone is present, the diagnosis of a supernumerary digit is not difficult. A skin tag or wart does not contain the adnexal structures or nerve bundles characteristic of a supernumerary digit. An acquired digital fibrokeratoma contains thick, vertically oriented collagen bundles devoid of adnexal structures and elastic tissue. The rudimentary digit may be difficult to differentiate from common traumatic neuromas without appropriate clinical history.

CHAPTER 18 ■ ECTOPIC TISSUE

HISTOPATHOLOGIC FEATURES The histologic features correspond to the digital components present. There is compact keratin similar to that of normal acral skin. The epidermis shows elongation of rete ridges and numerous acrosyringeal structures (Fig. 18-3). The usual components of the dermis are present along with numerous eccrine apparati. Nerve bundles may be present at the base. A central core of cartilage with or without joint or osteoid formation and abrupt keratinization (see Fig. 18-3), consistent with nail formation, may be present (Fig. 18-4). In what has been referred to as rudimentary digit, compact hyperkeratosis and rete elongation, similar to polydactyly (Fig. 18-5), is present. Only a few eccrine glands may be present,

ENDOMETRIOSIS

 FIGURE 18-3 Supernumerary digit. This bulbous structure contains a central core of cartilage with the presence of a joint and osteoid formation.

Synonyms: Endometrioma, menstruating tumor, Villar nodule Endometriosis, defined as the presence of endometrial tissue outside the uterine cavity, affects approximately 10% of women of childbearing age.38 Men taking estrogen therapy and postmenopausal women may be affected rarely.39 Endometriosis may occur in conjunction with hormonal replacement.40 Extrapelvic endometriosis may occur in the intestines, skin and subcutaneous tissue, and lungs, among other less common sites.38 Possible mechanisms for endometriosis include (1) transportation, via tubal regurgitation, surgical manipulation, or hematogenous or lymphatic dissemination and (2) local dedifferentiation or metaplasia of embryonic

411

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

scars.45 The interval between benign and malignant transformation ranges from 3 to 39 years, with a mean of 17 years.

412

 FIGURE 18-5 Rudimentary digit. The epidermis shows elongated rete ridges with compact hyperkeratosis. An eccrine coil and Meissner corpuscle can be observed in the dermis.

HISTOPATHOLOGIC FEATURES Ectopic endometrial tissue variably responds to the same hormonal fluctuations as eutopic endometrial tissue, and the microscopic features vary accordingly, demonstrating proliferative, secretory, and menstrual changes. Different glandular morphology may be seen within the same specimen.46 Within the dermis, subcutaneous tissue or muscle is irregular glandular lumina embedded within a cellular and vascular stroma (Fig. 18-6). A broad spectrum of metaplastic changes occur that may involve the epithelial or the stromal components.47 The glands are typically lined by columnar, cuboidal, or flat cells, and cystic dilatation may be seen. Whereas decapitation secretion characterizes the secretory phase, interluminal erythrocytes and degenerative epithelial cells suggest menstrual changes. Numerous epithelial mitoses may be found in the proliferative phase.48 Metaplastic changes of Müllerian epithelium that may be seen include tubal, oxyphilic, hopnail, mucinous, and papillary syncytial metaplasia.47 The stroma consists of spindled cells admixed with vessels; lymphocytes; histiocytes; and a variable admixture of neutrophils, plasma cells, and mast cells. In the secretory phase, two stromal cell types may be present: a large cell and a small clear cell.48 Erythrocyte extravasation and scattered hemosiderin deposits, highlighted with

celomic mesothelium into endometrial tissue.41 Identification of intralymphatic embolic endometrial cells in a patient with umbilical endometriosis supports the transplantation theory.42 Ectopic implantation of other structures of the female reproductive system, such as cutaneous endosalpingiosis after tubal ligation, may occur rarely. Cutaneous deciduosis refers to hormonally transformed endometrial tissue.

pain is characteristic. A menstruating tumor refers to the rare occurrence of bleeding or secretion from an endometrioma during menses.33 Cutaneous endometriosis is often an isolated event, but occasionally, dysmenorrhea, infertility, and other conditions associated with pelvic endometriosis may be seen. Malignant degeneration of cutaneous endometriosis is rare,39,40,45 occurring in 0.3% to 1.0% of episiotomy

CLINICAL FEATURES Common locations for cutaneous endometriosis include gynecologically induced abdominal or pelvic scars, including episiotomy and laparoscopy scars,38,39 and the umbilicus, which is involved in up to 1% of patients41 but represent 40% of patients with extrapelvic endometriosis.43 Non–surgeryrelated sites of endometriosis include the vulva, perineum, groin, and extremities.38 Involvement of thoracic skin in a patient with an ovarian granulosa cell tumor has also been reported.44 Clinical presentations vary. A painful swelling is one of the most common presentations of scar endometriosis.41 Endometriomas, which are distinct masses of endometrial tissue, occur in scars and other sites. They appear as a firm nodule ranging from a few millimeters to several centimeters in size and may be fleshcolored or various shades of red, blue, or purple depending on the amount of blood present, the depth of the lesion, and the duration. Waxing and waning

 FIGURE 18-6 Endometriosis. Glandular lumina are embedded in a cellular and vascular stroma.

DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of cutaneous endometriosis includes ectopic cutaneous endosalpingiosis, which lacks the cellular stroma, hemorrhage, and hemosiderin noted in endometriosis.49 In addition, endometriosis has fewer ciliated cells.50 Omphalomesenteric duct remnants, which also have an umbilical location, contain glands lined by gastrointestinal (GI) epithelium. Endometrial carcinoma can usually be differentiated from endometriosis by its higher degree of nuclear atypia. Metaplastic changes, such as those described above, and mucinous metaplasia, may occur in cutaneous endometriosis, possibly suggesting other metastatic neoplasms. Atypical glandular mitoses and vessel and perineural invasion may be seen, further complicating the assessment.49 Catamenial symptoms and characteristic stromal changes are helpful in supporting a diagnosis of endometriosis. Rarely, massively decidualized tissue may be present. Cutaneous deciduosis may be variable histologically, and the presence of enlarged polygonal cells with abundant and often vacuolated cytoplasm floating in pools of mucin and lacking glandular components may mimic carcinoma, atypical fibroxanthoma, or epithelioid sarcoma. The presence of PASnegative, sulfated mucopolysaccaride– positive signet ring–type cells and vimentin-positive, CD30-positive, keratin-negative and CD68-negative decidual cells, and the absence of significant nuclear atypia and mitoses support the

diagnosis of myxoid change in decidualized endometriosis over carcinoma and sarcoma.51,52

ECTOPIC CUTANEOUS ENDOSALPINGIOSIS Ectopic endosalpingiosis, or ectopic growth of fallopian tube epithelium, may arise in the pelvic cavity after salpingectomy. Only a few cases of cutaneous endosalpingiosis have been reported.49, 53 CLINICAL FEATURES Most of the reported cases of ectopic fallopian tube epithelium have occurred as papules or swellings in the umbilical or periumbilical region. There may be a long interval between surgical pelvic manipulation and the onset of the lesion. Cyclical discomfort is not typically reported. HISTOLOGIC FEATURES Cutaneous endosalpingiosis shows a cystic dermal proliferation with fallopian tube epithelium differentiation. Three cell types—ciliated columnar cells; nonciliated columnar, secretory, and mucinous cells; and intercalary dark cells intercalated between the two—may be present. Papillary projections into the lumen may be observed. The surrounding dermis shows fibrosis with chronic inflammation and vascular proliferation.49 DIFFERENTIAL DIAGNOSIS Cutaneous endometriosis is differentiated from endosalpingiosis by the presence of a cellular stroma with hemorrhage and hemosiderin. Endosalpingiosis may be difficult to differentiate from cutaneous ciliated cysts. The latter does not have columnar or secretory mucous-type cells found in endosalpingiosis and are typically occur on the lower extremities.49

OMPHALOMESENTERIC DUCT REMNANTS Synonyms: Vitello-intestinal anomaly, umbilical granuloma, umbilical polyp, enteroteratoma, raspberry tumor The omphalomesenteric duct is an embryonic structure that joins the midgut to the yolk sac. Around the fifth week of gestation, this duct becomes incorporated into the umbilical cord, and by the ninth week of gestation, it detaches from the midgut and is obliterated.54,55 Disturbances of this process may result in a variety of anomalies, determined by the portion of the duct that remains (Table 18-2). A combination of these

anomalies may coexist. Cutaneous presentation of omphalomesenteric duct remnant is less common than intestinal complications, but because there may be fatal consequences from the latter, identification and complete removal of this tissue has been advocated.56 CLINICAL FEATURES Omphalomesenteric duct anomalies occur in approximately 2% of the population. The age of presentation ranges from infancy to adulthood. Male predominance has been noted.55,57 This is particularly true with patent omphalomesenteric duct anomalies, which may also be associated with prematurity and other congenital anomalies. The clinical features of the various anomalies are outlined in Table 18-2. The umbilical lesions tend to be polypoid and range from a few millimeters to a few centimeters in size. Local symptoms include irritation of the overlying or adjacent skin, drainage if a sinus or fistula is present, and (on rare occasions) pain. The clinical differential diagnosis for umbilical lesions includes pyogenic granuloma, foreign body granuloma, granulation tissue, fibroepithelial polyp, and epithelial inclusion cysts. Except for patent ducts, umbilical omphalomesenteric remnants are generally of minimal consequence. The main concern is to rule out a coexisting intestinal or intraabdominal remnant, which may be associated with fatal consequences.

CHAPTER 18 ■ ECTOPIC TISSUE

Perl stain, are important diagnostic features. Pseudoxanthoma cells, which are histiocytic cells containing fine browngray pigment representing blood degradation products, are also characteristic. These demonstrate periodic acid–Schiff (PAS) and oil red O positivity characteristic of ceroid (lipofuscin).46 Stromal changes may also include smooth muscle metaplasia, proliferation of spiral vessels, stromal endometriosis, and elastosis. There may be reactive changes involving the surrounding sweat glands, including periglandular myxoid stroma, branching lumina, pagetoid-like growth, cystic dilation, solid compaction, and pseudocarcinomatous hyperplasia. The surrounding fat and muscle may also show atypical features, including lipoblast-like cells simulating liposarcoma and atypical myocytes. Other unusual histologic features include necrotic pseudoxanthomatous nodule formation, intranuclear adipocyte inclusions, and CD56+ large granular lymphocytes.47

HISTOPATHOLOGIC FEATURES The capacity of the omphalomesenteric remnants to differentiate into all types of enteric epithelium is reflected in the histologic features. Demonstration of ectopic epithelium from any portion of the GI tract within an umbilical polyp or lining a cyst, sinus tract, or fistula from this site is sufficient for the diagnosis (Fig. 18-7). Gastric mucosa is recognized by columnar epithelium and the presence of chief, zymogenic, and parietal cells. Brunner glands and changes of intestinal metaplasia may be seen occasionally. Small intestinal mucosa may be admixed with gastric mucosa and, in addition, contains goblet cells and submucosal lymphoid follicles. Colonic mucosa contains glandular crypts lined by goblet cells interspersed with columnar cells. Muscularis layers are present in all mucosal types. Rarely, pancreatic tissue may be observed.55 The surrounding skin may show various inflammatory and reparative changes due to irritation. DIFFERENTIAL DIAGNOSIS These lesions need to be differentiated from GI

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Table 18-2 Omphalomesenteric Duct Anomalies ANOMALY

REMNANT

CLINICAL

Patent OM duct

Entire portion, patent

OM band

May be entire portion, nonpatent

Meckel diverticulum

Proximal portion: Diverticulum in small bowel +/− attachment to abdominal wall

OM polyp

Distal, umbilical portion

OM sinus

Distal portion

OM cyst

Midportion, any site

Umbilical–intestinal fistula with feculant, serous, mucous, purulent, or bilious drainage Small bowel umbilical herniation +/− intussusception Volvulus Intussusception (if with Meckel diverticulum) Asymptomatic Intussusception Ulceration (especially if ectopic gastric mucosa present) Volvulus Bright red, sticky, umbilicated nodule or polyp May be a/w OM sinus Sinus of varying depth +/− drainage Often a/w OM polyp Subcutaneous cyst or nodule Intraabdominal cyst +/− attachment to abdominal wall and intestine GI complications as in Meckel and OM band

GI, gastrointestinal; OM, omphalomesenteric; a/w, associated with.

carcinoma metastatic to the umbilicus. Endometriosis, which may also occur in the umbilicus, also contains glandular structures. However, ciliated columnar cells do not predominate, and goblet cells and gastric enzymatic cells are not present. Cutaneous ectopic GI mucosa is a rare occurrence58 and can usually be differentiated by a non-umbilical location because this is usually associated with accidental implantation during a surgical bowel procedure.

ECTOPIC SALIVARY GLANDS Heterotopic islands of salivary gland tissue may occur at various head and neck sites, including the neck, oral cavity, external ear, mastoid or mandible bone, thyroid tissue, sternoclavicular joint, lymph nodes, and pituitary gland.59 Heterotopic salivary glands may be unilateral or bilateral and commonly involve the middle and lower parts of the neck near the border of the sternocleidomas-

toid muscle or are located suprasternally.60 There may be a predilection for the right neck near the anterior sternocleidomastoid muscle.61 Orifices may be localized to the lower neck. Ectopic salivary glands may present as asymptomatic papules or nodules, but often, especially in the posterior triangle of the neck, these typically present as a sinus that discharges clear fluid, simulating a branchial sinus.59 A sinogram reveals a tubular structure that may have small side branches. Histologically, features typical of mucinous and serous salivary glandular tissue are present (Fig. 18-8). The duct may be dilated, collapsed, or cystic, and the ductal epithelium ranges from simple squamous to pseudostratified columnar with cilia and goblet cells. Apocrine secretion may be seen. There is often associated acute or chronic inflammation (or both).61 A sinus tract lined by pseudostratified cylindrical epithelium with serous and mucous acini typical of anatomic salivary glands is present in the adjacent connective tissue.59

MISCELLANEOUS ECTOPIC TISSUE

414

 FIGURE 18-7 Omphalomesenteric duct remnant. This remnant shows ulceration and gastrointestinal mucosa beneath the area of ulceration.

Ectopic tissue from multiple different organs other than those already described may be seen, although much less frequently, but should be recognized as ectopic to avoid misdiagnosis of metastatic disease.

Table 18-3 Benign Neoplasms of the Umbilicus

SOURCE: Adapted with permission from Powell and Su.68

 FIGURE 18-8 Ectopic salivary glandular tissue. Lobules of mucinous and serous salivary glandular tissue are present in the subcutis of the neck associated with a fibrous stroma and surrounding skeletal muscle. (Reproduced, with permission, from Haemel A, Gnepp DR, Carlstein J, et al: Heterotopic salivary gland tissue in the neck, J Am Acad Dermatol. 2008;58(2):251-256).

Ectopic Thyroid Tissue Ectopic thyroid tissue, also referred to as aherrant thyroid tissue, is rare and may occur witnin or outside the migration path of normal thyroid, beginning at the cecum and passing through the muscular tongue to the hypoid bone and ending at the isthmus. This may occur in mediastinal; intracardiac; GI; intraperitoneal; and rarely, in cutaneous locations, such as the posterior neck.62 Ectopic thyroid may be present at birth or infancy as a dermal papule or nodule but may not be detected until adolescence or at pregnancy, when it is associated with an increased thyroid-stimulating hormone level or hyperplasia. The tissue is usually hypoactive. Complications include rare hyperactivity, compression of normal structures, and malignant transformation. HISTOLOGIC FEATURES The histologic features are similar to those of the normal thyroid. In the dermis, subcutis, or both, a circumscribed nodular epithelial lesion can be seen composed of variably sized glandular structures lined by a single layer of follicular cells. These cells range from flattened to low columnar and have pale acidophilic- to amphophilic-stining cytoplasm. The lumen is lined by microvilli and contains pale-stining material. Ectopic thyroid tissue should be differentiated from metastatic malignant

thyroid tissue and thyroid tissue associated with brancial cleft cyst. The latter may have associated cystic epithelium and lymphoid tissue.

Glial Heterotopia Heterotopic glial tissue, or gliomatosis, is the presence of glial tissue outside the craniospinal axis and is most often found on the head and neck, where a common dermatologic presentation is as a nasal glioma. These presentions often contain leptomeningeal tissue or have a fibrous attachment to the dura and have various causes, including sequestration of encephalocele, dysraphism, or as a part of germ cell neoplams. Isolated soft tissue gliomatosis has rarely been reported on other sites, such as spine and chest63 and scalp.64 In these cases, a herniation or communication with the central nervous system could not be established. These ectopic presentations occurred in children aged 2 years and younger without other neurologic associations. Cutaneous histologic findings of gliomatosis have been reviewed63,64 and include a reticular dermal-based or subcutaneous nodule composed of irregularly shaped cells with abundant cytoplasm, bland nuclei, and indistinct cellular margins associated with a fibromucinous stroma. This glial tissue has an immunohistochemical profile that is positive for S-100, Vimentin,

GFAP, NSE, and CD57 and negative for cytokeratin, neurofilament protein, EMA, CD34, and Ki-67.63 This immunohistochemical profile helps differentiate glial tissue from ependymal rests, ependymomas, and chordomas. EMA staining of pseudovascular spaces suggests a meningeal component.

CHAPTER 18 ■ ECTOPIC TISSUE

Melanocytic nevi Seborrheic keratosis Epidermal nevus Endometriosis Pyogenic granuloma Epithelial inclusion cyst Hemangioma Dermatofibroma Neurofibroma Condyloma accuminatum Granular cell tumor Teratoma Keloid Desmoid tumor Lipoma

Umbilical Lesions The anatomy of the umbilicus makes it vulnerable to numerous inflammatory, anomalous, and malignant conditions. Its crevasse-like nature predisposes it to intertrigo, psoriasis, seborrheic dermatitis, foreign body granulomas, pilonidal sinus, omphaliths, and infections such as candidiasis and, in neonates, beta-hemolytic Streptococcus spp. and Staphylococcus aureus infections. Other dermatoses that have a predilection for the umbilicus include Fabry disease and herpes gestationis. Numerous benign and malignant neoplasms can also be found in this location65 (Tables 18-3 and 18-4). In infants, pyogenic granulomas are common. In adulthood,

Table 18-4 Primary Malignant Tumors of the Umbilicus Basal cell carcinoma Squamous cell carcinoma Malignant melanoma Adenocarcinoma of urachal remnants Adenocarcinoma of omphalomesenteric duct remnants Primary papillary psammomatous adenocarcinoma

415

melanocytic nevi are seen frequently. The histologic features of these conditions are described elsewhere in this text. The base of the umbilicus consists of the stump of the umbilical cord, which may include remnants of embryologic structures that may give rise to various anomalies. The umbilicus is also richly vascularized with an extensive venous drainage system,66 and lymphatic channels from the axillary, external and deep inguinal, and paraaortic lymph nodes pass through the umbilical region,66-68 allowing exposure to metastatic disease.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Urachal Remnants The urachus is a tube that extends from the umbilicus to the urinary bladder in the developing fetus. By the fourth or fifth gestational month, it atrophies to a fibromuscular cord called the medial umbilical ligament.69 This cord is contained in a pre-peritoneal fascial space.70 The anatomy and embryologic aspects of the urachus have been reviewed recently.71 Persistence of any portion of the urachal duct may result in a variety of anomalies (Table 18-5). CLINICAL FEATURES In newborns, the most common urachal anomaly is the patent urachal duct, which classically presents with umbilical micturition. Enlargement of the umbilicus or erythema of the umbilical region may also occur.72 In adulthood, urachal cysts predominate. These frequently become infected and present as an infraumbilical midline mass associated with fever; abdominal pain; and occasionally, urinary symptoms.72 A reopening of the canal may then result in purulent umbilical or bladder drainage (alternating sinus).73 Other less common cutaneous presentations of urachal remnants include umbilical retraction during micturition72 and a suprapubic sinus.74,75 The clinical relevance of urachal remnants pertains to the potential urologic and infectious complications with which they are associated.69 In addition, malignant

degeneration of these remnants may occur.69,76-79 HISTOPATHOLOGIC FEATURES Urachal remnants are diagnosed most readily radiologically and rarely present to the dermatopathologist. Occasionally, portions of a remnant may be present at the base of other lesions involving the umbilicus.80,81 Histologically, the urachus is characterized by three layers: luminal cuboidal or transitional epithelium, submucosal connective tissue, and an outer smooth muscle layer.82 In most cases, uroepithelium (cuboidal or transitional cells) is present, but columnar epithelium may occur adjacent to the uroepithelium or alone, at times with papillary projections.76 Rarely, malignant degeneration occurs, with the most common neoplasm being adenocarcinoma, but signet ring, transitional, neuroendocrine, and sarcomatous tumors have also been reported.69,76-79 DIFFERENTIAL DIAGNOSIS With the appropriate clinical information, the diagnosis is straightforward. An omphalomesenteric duct remnant, which frequently has a similar clinical presentation, can be differentiated from urachal processes by the presence of GI epithelium rather than uroepithelium. The glands of endometriosis, although they occasionally contain cuboidal epithelium, are distinguished by the associated cellular stroma with scattered areas of hemorrhage and hemosiderin deposition.

Omphalith An omphalith is an accumulation of compacted keratin and sebaceous material within the umbilicus. CLINICAL FEATURES The umbilical anatomy and poor hygiene are predisposing factors for the development of omphaliths. They typically present as long-standing asymptomatic, black, firm nodules attached to the base of the umbilicus. Discomfort may

Table 18-5 Urachal Duct Remnants

416

REMNANT

ANOMALY

Entire tubular duct Superior portion Inferior portion Mid portion Mid portion

Patent urachal duct connecting urinary bladder and umbilicus Urachal sinus with drainage to inferior umbilicus Vesicourachal diverticulum Urachal cyst, usually lower third portion Alternating sinus, usually with urachal cyst with intermittent umbilical or bladder drainage

arise from secondary inflammation or infection of the surrounding skin.76 Because many clinicians may be unfamiliar with this condition, this lesion may be biopsied to rule out a seborrheic keratosis, epithelial or melanocytic nevus, malignant melanoma, and metastatic carcinoma (Sister Joseph nodule). HISTOPATHOLOGIC FEATURES Dense laminated keratin is intermingled with sebum, interspersed hair fragments, and clusters of gram-positive cocci and pleomorphic gram-positive rods. Although the pigment observed clinically is thought to be due, in part, to oxidation of lipids, Fontana-Masson positivity suggests the presence of melanin.80

Metastatic Disease As described earlier, the venous and lymphatic systems of the umbilicus make it subject to metastatic disease. Endometriosis and metastatic disease each account for approximately onethird of umbilical tumors.81 Metastasis to the umbilicus is an infrequent but unique and ominous condition. Commonly referred to as Sister (Mary) Joseph nodule, after the surgical assistant to Dr. William Mayo who first noted this sign of internal malignancy,82 these tumors are associated most frequently with stomach and other GI carcinomas, including pancreatic83 and gallbladder, and ovarian carcinoma. Less common neoplasms include other gynecologic malignancies; penile, breast, and renal carcinomas; myeloma82; leiomyosarcoma84; transitional bladder carcinoma85; mesothelioma86; vaginal squamous cell carcinoma87; liver carcinoma82; small cell carcinoma of the lung88; and Paget disease associated with prostate carcinoma.89,90 CLINICAL FEATURES Tumors metastatic to the umbilicus typically present as a firm vascular plaque or nodule that may be be ulcerated or fissured and exhibit a mucous or purulent discharge.79 In some instances, the process may resemble cellulitis.66 Such tumors may be the first sign of malignancy and usually portend a poor prognosis. HISTOPATHOLOGIC FEATURES The histology varies with the malignancy. In up to 20% of patients, the histologic features may be nonspecific.84

Pilonidal Sinus and Foreign Body Granuloma The pathophysiology of the pilonidal (nest of hair) sinus remains controversial.91

In most cases, it is an acquired condition in men characterized by a hair shaft that becomes embedded within the skin and elicits an inflammatory reaction. Factors contributing to this situation include hirsutism and obesity.87 Hairs are often found perpendicular to the skin surface with the distal end pointing outward and the cuticle scales oriented in a direction that resists outward movement. Negative subcutaneous pressure and a pit or a deep umbilical cleft may promote penetration of the hair.91-93

HISTOPATHOLOGIC FEATURES Microscopically, within the dermis, there is a sinus lined by slightly acanthotic keratinizing epithelium and surrounded by dense acute and chronic inflammatory cells, occasional multinucleated giant cells, and a stroma with fibrosis and granulation tissue–type vascular proliferation. The sinus cavity contains hair shafts, keratin, and other debris. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes a ruptured epidermoid cyst or pilosebaceous unit. In contrast to the latter entities, pilonidal sinuses contain longer hairs unassociated with hair follicles and longer, noncystic sinus tracts. Other foreign body reactions should be differentiated from the pilonidal sinus, especially the talc granuloma, a condition now observed rarely in infants after the now-obsolete application of talc-containing hexachlorophane powders to the umbilical stump. These granulomas present clinically as a nodule or polyp with a denuded granulating surface that is indistinguishable from a pyogenic granuloma. Histologically, there is dense fibrous tissue with numerous foreign body giant cells, many of which contain the doubly refractile crystals of talc. Vascular proliferation, similar to that of a pyogenic granuloma, may be seen in association with the foreign body reaction.95

REFERENCES 1. Jansen T, Romiti R, Altmeyer P: Accessory tragus: report of two cases and review of the literature. Pediatr Dermatol. 2000;17: 391-394. 2. Brownstein MH, Wanger N, Helwig EB: Accessory tragi. Arch Dermatol. 1971;104: 625-631.

25. Grotto I, Browner-Elhanan K, Mimouni D, et al. Occurrence of supernumerary nipple in children with kidney and urinary malformations. Pediatr Dermatol. 2001;18:291-294. 26. Goeddert JJ, McKeen EA, Fraumeni JF: Polymastia and renal adenocarcinoma. Ann Int Med. 1981;95:182-184. 27. Mehregan AH: Supernumerary nipple: a histologic study. J Cutan Pathol. 1981;8: 96-104. 28. Willman JH, Golitz LE, Fitzpatrick JE: Clear cells of Toker in accessory nipples. J Cutan Pathol. 2003;30(4):256-260. 29. High WA, Stewart D, Essary LR, et al: Sclerotic fibroma-like change in various neoplastic and inflammatory skin lesions: is sclerotic fibroma a distinct entity? J Cutan Pathol. 2004;31:373-378. 30. Urbani CE, Betti R: Olythelia within Becker’s naevus. Dermatology. 1998;196: 251-252. 31. Dobyns JH, Wood VE, Bayne LG, Frykman GK: Congenital hand deformities, in Green DP (ed). Operative Hand Surgery. New York: Churchill-Livingstone; 1982:213-450. 32. Chung J, Nam IW, Ahn SK, et al: Rudimentary polydactyly. J Dermatol. 1994; 21:54-55. 33. Coppolelli BG, Ready JE, Awbrey BJ, Smith LS: Polydactyly of the foot in adults: literature review and unusual case presentation with diagnostic and treatment recommendations. J Foot Surg. 1991;30(1):12-18. 34. Happle R, Tinschert S: Segmentally arranged basaloid follicular hamartomas with osseous, dental, and cerebral anomalies: a distinct syndrome. Acta Derm Venereol. 2008;88:382-387. 35. Isik D, Bulut O, Sunay M, Bekerecioglu M: Polydactyly and hypertension. Ann Plast Surg. 2008;61:511-512. 36. Leber GE, Gosain AK: Surgical excision of pedunculated supernumerary digits prevents traumatic amputation neuroms. Pediatr Dermatol. 2003;20:108-112. 37. Ban M, Kitajima Y: The number and distribution of Merkel cells in rudimentary polydactyly. Dermatology. 2001;202:31-34. 38. Albrecht LE, Tron V, Rivers JK: Cutaneous endometriosis. Int J Dermatol. 1995;34(4): 261-262. 39. Firilas A, Soi A, Max M: Abdominal incision endometriomas. Am Surg. 1994; 60:259-261. 40. Choi SW, Lee HN, Kang SJ, Kim HO: A case of cutaneous endometriosis developed in postmenopausal woman receiving hormonal replacement. J Am Acad Dermatol. 1999;41:327-329. 41. Igawa HH, Ohura T, Sugihara T, et al: Umbilical endometriosis. Ann Plast Surg. 1992;29:266-268. 42. Ichimiya M, Hirota T: Intralymphatic embolic cells with cutaneous endometriosis in the umbilicus. J Dermatol. 1998; 25:333-336. 43. Vivtory R, Diamond MP, Johns DA: Villar’s nodule: a case report and systematic literature review of endometriosis externa of the umbilicus. J Minim Invasive Gynecol. 2007;14: 23-32. 44. Ferrara G, Giordano G, Longo M, Magri M: Primary cutaneous endometriosis of thoracic skin with ovarian granulosa cell tumor. Acta Obstet Gynaecol Scand. 1993;72:225-227.

CHAPTER 18 ■ ECTOPIC TISSUE

CLINICAL FEATURES The umbilicus is a rare site of involvement by a pilonidal sinus, which classically occurs in the sacrococcygeal region. Symptoms may include intermittent pain and purulent drainage. Rarely, malignant degeneration to squamous cell carcinoma may occur.94

3. Christensen P, Barr RJ: Wattle: An unusual congenital anomaly. Arch Dermatol. 1985; 121:22-23. 4. Hodges FR, Sahouria JJ, Wood AJ: Accessory tragus: a report of 2 cases. J Dent Child. 2006;73 (1): 42-44. 5. Demirseren ME, Afandiyev K, Durgun M, et al: An Unusual auricular malformation accompanied by acessory tragus: macrotragus. Eur Arch Otorhinolaryngol 2008;265:639-641. 6. Ban M, Kamiya H, Yamada T, Kitajima Y: Hair follicle nevi and accessory tragi: Variable quantity of adipose tissue in connective tissue framework. Pediatr Dermatol. 1997;4:433-436. 7. Schmidt H: Supranumery nipples: prevalence, size, sex and site predilection. A prospective clinical study. Eur J Pediatr. 1998;157:821-823. 8. Loukas M, Clarke P, Tubbs RS: Accessory breasts: a historical and current perspective. Am Surgeon. 2007;73:525-528. 9. Galli-Tsinopoulou A, Krohn C, Schmidt H: Familial polythelia over three generations with polymastia in the youngest girl. Eur Pediatr. 2001;160: 375-377. 10. Velanovich V: Ectopic breast tissue, supernumerary breasts, and supernumerary nipples. South Med J. 1995;88:903-906. 11. Lewis EJ, Crutchfield CE, Ebertz MJ, Prawer SE: Report of a nipple nevus and an overview of accessory mammary tissue. Cutis. 1998;62:243-246. 12. Camacho F, González-Cámpora R: Polythelia pilosa: a particular form of accessory mammary tissue. Dermatology. 1998; 196:295-298. 13. Pfeifer JD, Barr RJ, Wick MR: Ectopic breast tissue and breast-like sweat gland metaplasias: an overlapping spectrum of lesions. J Cutan Pathol. 1999;26:190-196. 14. Ahmed S, Campbell RM, Hong JH, et al: Adenoma of anogenital mammary-like glands. J Am Acad Dermatol. 2007;57:896-898. 15. Basu S, Bag T, Saha SK, Biswas PC: Accessory breast tissue in the perineum. Tropical Doctor. 2003;33:245. 16. Cellini A, Offidani A: Familial supernumerary nipples and breasts. Dermatology. 1992;185:56-58. 17. Oztas MO, Gurer MA: Dermatoscopic features of accessory nipples. Int J Dermatol. 2007;46:1067-1068. 18. Urbani CE, Betti R: Polythelia within Becker’s naevus. Dermatology. 1998;196: 251-252. 19. Martin VG, Pellettiere EV, Gress D, Miller AW: Paget’s disease in an adolescent arising in a supernumerary nipple. J Cutan Pathol. 1994;21:283-286. 20. Gutermuth J, Audring H, Voit C, Haas N: Primary carcinoma of ectopic axillary breast tissue. J Eur Acad Dermatol Venereol. 2006;20: 217-221. 21. Carmichael AR, McIntyre M, Chetty U: Malignant melanoma in accessory nipple in a male. J Coll Physicians Surg Pak. 2006; 16:799-800. 22. Leung AK, Robson WL: Renal anomalies in familial polythelia [letter, comment]. Am J Dis Child. 1990;144:619-620. 23. Leung AK, Robson WL: Accessory nipples and urinary tract malformation [letter]. Pediatr Dermatol. 1993;10(3):300-301. 24. Ferrara P, Giorgio V, Vitelli O, et al: Polythelia: still a marker of urinary tract anomalies in children? Scand J Urol Neprol. 2009;43(1):47-50.

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS 418

45. Chene G, Darcha C, Dechelotte P, et al: Malignant degeneration of perineal endometriosis in episiotomy scar, case report and review of the literature. Int J Gynecol Cancer. 2007; 17:705-734. 46. Clement PB: Pathology of endometriosis. Pathol Ann. 1990;25:245-295. 47. Kazakov DV, Ondic O, Zamecnik M, et al: Morphologic variations of scar-related and spontaneous endometriosis of the skin and superficial soft tissue: a study of 71 cases with emphasis on atypical features and types of Müllerian differentiations. J Am Acad Dermatol. 2007;57:134-146. 48. Tidman MJ, MacDonald DM: Cutaneous endometriosis: a histopathologic study. J Am Acad Dermatol. 1998;18:373-377. 49. Redondo P, Idoate M, Corella C: Cutaneous umbilical endosalpingiosis with severe abdominal pain. J Euro Acad Dermatol Venerol. 2001;15:179-180. 50. Dore N, Landry M, Cadotte M, Schurch W: Cutaneous endosalpingiosis. Arch Dermatol. 1980;116:909-912. 51. Nogales FF, Martin F, Linares J, et al: Myxoid change in decidualized scar endometriosis mimicking malignancy. J Cutan Pathol. 1993;20:87-91. 52. Fair KP, Patterson JW, Murphy RJ, Rudd RJ: Cutaneous deciduosis. J Am Acad Dermatol. 2000;43:102-107. 53. Perera GK, Watson KM, Salisbury J, Vivier DU: Two cases of cutaneous umbilical endosalpingiosis. Br J Dermatol. 2004;151:924-925. 54. Kamii Y, Zaki AM, Honna T, Tsuchida Y: Spontaneous regression of patient omphalomesenteric duct: from a fistula to Meckel’s diverticulum. J Pediatr Surg 1992;27:115-116. 55. Steck WD, Helwig EB: Cutaneous remnants of the omphalomesenteric duct. Arch Dermatol. 1964;90:463-470. 56. Notman RA, Dewberry CT: Dermatologic presentation of omphalomesenteric duct remnant. Skinmed. 2006;5:154-155. 57. Benson JM, Sparnon AL: Double intussusception of ileum through a patent vitellointestinal duct: Report of a case and literature review [review]. Aust NZ J Surg. 1992;62(5):411-413. 58. Francis EP, Sandahl L, Reed MJ, Miller FO: Cutaneous presentation of ectopic small bowel mucosa. J Am Acad Dermatol. 2004;51:476-477. 59. Sevilla A, Morell A, Navas J, et al: Orifices at the lower neck: heterotopic salivary glands. Dermatology. 1997;194: 360-361. 60. Marshell JN, Soo G, Coakley FV: Ectopic salivary gland in the posterior triangle of the neck. J Laryngol Otol. 1995;109:669670.

61. Haemel A, Gnepp DR, Carlsten DR, Robinson-Bostom L: Heterotopic salivary gland tissue in the neck. J Am Acad Dermatol. 2008;58:251-256. 62. Maino K, Skelton H, Yeager J, Smith KJ: Benign ectopic thyroid tissue in a cutaneous location: a case report and review. J Cutan Pathol. 2004;31:195-198. 63. Skelton HG, Smith KJ: Glial heterotopia in the subcutaneous tissue overly T-12. J Cutan Pathol. 1999;26:523-527. 64. McDermott MB, Glasner SD, Nielson PL, Dehner LP: Soft tissue gliomatosis: morphologic unity and histogenentic diversity. Am J Surg Pathol. 1996;20:148-155. 65. Hernandez N, Medina V, AlvarezArguelles H, et al: Primary papillary psammomatous adenocarcinoma of the umbilicus. Histol Histopathol. 1993;8:593-598. 66. Raymond PL: The ubiquitous umbilicus: what it can reveal about intra-abdominal disease. Postgrad Med. 1990;87:175-181. 67. Majmudar B, Wiskind AK, Croft BN, Dudley AG: The Sister (Mary) Joseph nodule: its significance in gynecology. Gynecol Oncol. 1991;40:152-159. 68. Powell FC, Su WPD: Dermatoses of the umbilicus. Int J Dermatol. 1988;27(3): 150-156. 69. Binkovitz LA: Case of the month. Urachal carcinoma. Mayo Clin Proc. 1993; 68:393-394. 70. Ward TT, Saltzman E, Chiang S: Infected urachal remnants in the adult: case report and review. Clin Infect Dis. 1993;16:26-29. 71. Cappele O, Sibert L, Descargues J, et al: A study of the anatomic features of the duct of the urachus. Surg Radiol Anat. 2001;23:229-235. 72. Rowe PC, Gearhart JP: Retraction of the umbilicus during voiding as an initial sign of a urachal anomaly. Pediatrics. 1993; 91:153-154. 73. MacNeily AE, Koleilat N, Kiruluta HG, Homsy YL: Urachal abscesses: protean manifestations, their recognition, and management. Urology. 1992;40:530-535. 74. Groff DB: Suprapubic dermoid sinus. J Pediatr Surg. 1993;28:242-243. 75. Lawson A, Corkery JJ: Prepubic sinus: an unusual urachal remnant. Br J Surg. 1992; 79:573. 76. Munichor M, Szvalb S, Cohen H, Bitterman W: Mixed adenocarcinoma and neuroendocrine carcinoma arising in the urachus: a case report and review of the literature. Eur Urol. 1995;28:345-347. 77. Chen KT, Workman RD, Rainwater G: Urachal signet-ring cell carcinoma. Urology. 1990;36:339-340. 78. Lyth DR, Booth CM: Transitional cell carcinoma of the urachus. Br J Urol. 1990;65:544-545.

79. Ravi R: Signet-ring cell carcinoma of urachus: a case report and review of literature. Arch Esp Urol. 1990;43:927-929. 80. Swanson SL, Woosley JT, Fleischer AB Jr, Crosby DL: Umbilical mass: omphalith. Arch Dermatol. 1992;128:1267-1270. 81. Patel KS, Watkins RM: Recurrent endometrial adenocarcinoma presenting as an umbilical metastasis (Sister Mary Joseph’s nodule). Br J Clin Pract. 1992;46:69-70. 82. Shetty MR: Metastatic tumors of the umbilicus: a review 1830-1989. J Surg Oncol. 1990;45:212-215. 83. Yendluri V, Centeno B, Springett GM: Pancreatic cancer presenting as a Sister Mary Joseph’s nodule. Case report and update of the literature. Pancreas. 2007; 34:161-164. 84. Powell FC, Cooper AJ, Massa MC, et al: Sister Mary Joseph’s nodule: a clinical and histologic study. J Am Acad Dermatol. 1984;10:610-615. 85. Edoute Y, Ben-Haim SA, Malberger E: Umbilical metastasis from urinary bladder carcinoma. J Am Acad Dermatol. 1992; 26(4):656-657. 86. Chen KT: Malignant mesothelioma presenting as Sister Joseph’s nodule. Am J Dermatopathol. 1991;13:300-303. 87. Bakri YN, Subhi J, Hashim E, Senoussi M: Umbilical metastasis (Sister Joseph’s nodule) from carcinoma of the vagina. Acta Obstet Gynaecol Scand. 1991;70:509-510. 88. Saito H, Shimokata K, Yamada Y, et al: Umbilical metastasis from small cell carcinoma of the lung. Chest. 1992;101(1): 288-289. 89. Remond B, Aractingi S, Blanc F, et al: Umbilical Paget’s disease and prostatic carcinoma. Br J Dermatol. 1993;128(4): 448-450. 90. Sina B, Deng A: Umbilical metastasis from prostate carcinoma (Sister Mary Joseph’s nodule): a case report and review of literature. J Cutan Pathol. 2007;34:581-583. 91. Sondenaa K, Pollard ML: Histology of chronic pilonidal sinus. APMIS. 1995; 103(4):267-272. 92. Eby CS, Jetton RL: Umbilical pilonidal sinus. Arch Dermatol. 1972;106:893. 93. Ohtsuka H, Arashiro K, Watanabe T: Pilonidal sinus of the axilla: report of five patients and review of the literature. Ann Plast Surg. 1994;33(3):322-325. 94. Davis KA, Mock CN, Versaci A, Lentrichia P: Malignant degeneration of pilonidal cysts (review). Am Surg. 1994;60(3): 200-204. 95. McCallum DI, Hall GF: Umbilical granulomata—with particular reference to talc granuloma. Br J Dermatol. 1970;83:151-156.

3 PART Infections

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CHAPTER 19 Bacterial Infections Ronald P. Rapini

or plasma cells may not be numerous, one or both are usually present in most bacterial infections. The only exception is that infections caused by bacteria, such as Lyme disease, exhibit a predominance of lymphocytes. Even in most cases of Lyme disease, a few scattered plasma cells are often found among the lymphocytes. The presence of tissue plasma cells is considered historically to be a marker for secondary syphilis and other spirochetal infections. It is less often appreciated that scattered plasma cells may be a clue to the recognition of subtle foamy infiltrates of lepromatous leprosy. Some bacterial diseases are granulomatous, that is, an infiltrate characterized by a predominance of macrophages, also known as true histiocytes, with or without multinucleated giant cells. Even bacterial diseases that are considered granulomatous (see Table 19-1) may be suppurative (neutrophils prominent) in their early stages. Thus bacterial diseases evolve over time, as with other skin conditions, and their stereotypical histologic presentations emphasized in textbooks such as this one vary according to the age of the lesion.9

IMPETIGO This common superficial bacterial infection occurs most often in children, especially around the mouth, nose, and groin (Table 19-2). It may occur after trauma to the skin, such as abrasions or insect bites. Poor hygiene; warm, humid weather; and occlusion of the skin contribute to impetigo. The etiologic agents are Staphylococcus aureus and Streptococcus pyogenes, either bacterium detected alone or in combination.10 Streptococcus spp. is isolated much less commonly at present than Staphylococcus spp. Bullous impetigo is an infrequent variant of impetigo that is usually related to infection with the phage group II of S. aureus. Exfoliative toxins A and B, produced by these strains of S. aureus, have been shown to target desmoglein 1 and not desmoglein 3.1,11 Desmoglein 1 is the same target antigen seen in pemphigus foliaceus. This explains the acantholysis found in some patients. In rare instances, glomerulonephritis or cellulitis may complicate impetigo. Impetigo is often diagnosed on clinical grounds, with or without culture, and consequently biopsies are frequently not performed. Cultures of the bullous lesions are more likely to be positive than in staphylococcal scalded-skin syndrome (SSSS), in which the organisms tend to reside in a remote site.12

CHAPTER 19 ■ BACTERIAL INFECTIONS

Definitive diagnosis of most bacterial diseases depends on specific identification of the pathogenic organisms. This must often be accomplished by appropriate cultures or molecular techniques because special bacterial stains frequently fail to detect sparse numbers of bacteria. Studies of infectious cellulitis show that even cultures yield organisms in less than 10% of cases. Cultures from actual biopsies have a higher yield than cultures originating from injected saline aspirates. Swab cultures from pustules, ulcers, or crusted lesions are suitable for only the most superficial infections, such as impetigo. An ideal method for deeper infections is to send half of the biopsy for culture and the other half for hematoxylin and eosin (H&E) and special stains. Before biopsy, excess antiseptic, such as chlorhexidine or povidoneiodine, which may inhibit the culture, should be wiped off the skin. Cultures are best performed on tissue that is rushed to the laboratory before it desiccates. It should be minced and added immediately to the culture medium. If there is a chance that a biopsy might dry during transport, the biopsy should be placed on sterile gauze soaked in normal saline (without preservatives such as benzyl alcohol). Even if the organisms are stained, it may be impossible to distinguish similar pathogens from normal flora. The location of the bacteria is important to note. Gram-positive cocci and coccobacilli, such as staphylococci and corynebacteria, are normal flora within the follicles or secondarily on the surface of crusted, eroded, or ulcerated conditions.1 In contrast, gram-positive cocci in the dermis or deeper tissue indicate a significant infectious process such as infectious cellulitis (dermis), panniculitis (fat), or fasciitis (fascia). If the follicles are disrupted and infiltrated by neutrophils, then bacteria in the follicles may be pathogenic. They can also be secondary invaders in cases of fungal folliculitis and noninfectious folliculitis; therefore, in such cases, it is important for pathologists finding bacteria to consider looking for other etiologic agents and to

remember that the primary condition may not be infectious. In immunosuppressed patients, particularly those with acquired AIDS, it is well known that a single biopsy specimen may contain more than one pathogen; consequently the pathologist should not stop after identifying one organism.2,3 Smears or touch preparations from tissue may improve the chances of detecting organisms. This is particularly true for acid-fast bacillus (AFB) infections, chancroid, and granuloma inguinale, in which stains of tissue sections have a lower yield. The Fite modification of the AFB stain may be better than the more routine Ziehl-Neelson method because the Fite stain has an enhanced ability to stain Mycobacterium leprae and some atypical mycobacteria. The Fite stain also stains the organisms identified by the other AFB methods. The auramine fluorescent method also may enhance the ability to find AFB.4 Modifications of the tissue Gram stain, such as Brown-Brenn and Brown-Hopps stains, are modestly satisfactory for staining gram-positive organisms in tissue sections but are poor for demonstrating gram-negative organisms. Immunohistochemical methods are available for the detection of some pathogens, such as certain Rickettsia.5 Reliance on cultures and staining techniques probably results in many infections being missed. Usually fewer than 1% of known bacteria can be cultured successfully from the environment, for example.6 Molecular genetic techniques, such as the polymerase chain reaction (PCR) and in situ hybridization, are clearly more sensitive and are increasingly commercially available for some organisms; however, many of these applications are available only in research laboratories or in special facilities, such as the Centers for Disease Control and Prevention in Atlanta, Georgia.7 These methods are becoming very important because of their exquisite sensitivity, but occasionally, there can be false-positive results if careful techniques are not followed in the laboratory. A limited number of histologic patterns are seen with bacterial infections in the skin (Table 19-1), and none of these reaction patterns are specific for bacterial infections or for any particular pathogens.8 Bacterial infections with a predominance of neutrophils producing subcorneal pustules have been termed pyodermas (pyo- referring to “pus”), a generic term with limited utility. Most bacterial infections exhibit at least a few neutrophils or plasma cells as valuable etiologic clues. Even though neutrophils

421

PART III ■ INFECTIONS

Table 19-1 Histologic Patterns Seen With Bacterial Infections and Their Differential Diagnosis Subcorneal pustules Impetigo Tinea and Candida SPP Scabies Psoriasis and subcorneal pustular dermatosis Drug eruptions Neonatal pustular melanosis Acropustulosis of infancy Pemphigus (various types) Gonococcemia Mucha-Habermann disease Late stages of intraepidermal blistering diseases Pseudoepitheliomatous diseases listed herein Dermal neutrophils Infectious cellulitis (bacterial or fungal) Infectious vasculitis (especially Rickettsia, gonococcemia, meningococcemia) Noninfectious vasculitis Dermatitis herpetiformis Bullous lupus erythematosus Pemphigoid (sometimes) Areas of necrosis attract neutrophils Inflamed cysts or follicles Granuloma faciale Urticaria Neutrophilic eccrine hidradenitis “Neutrophilic dermatoses” (must exclude infection) Sweet syndrome Behçet syndrome Pyoderma gangrenosum Erythema elevatum diutinum Rheumatoid neutrophilic dermatitis Bowel bypass syndrome Plasma cells in inflammatory conditions Syphilis, yaws, pinta Granuloma inguinale

Table 19-2 Impetigo and Ecthyma

Clinical Features “Honey-colored” crusted lesions, usually of acute onset Bullae in “bullous impetigo” Ulceration in “ecthyma” Children are more commonly affected Paranasal, axilla, groin are common sites Histopathologic Features Subcorneal pustule filled with neutrophils and sometimes occasional acantholytic cells Subcorneal bullae in bullous form, with few inflammatory cells Ulceration in ecthyma Sometime gram-positive cocci found in the pustule or on the surface of crusts or ulcers Variable dermal infiltrate (usually sparse)

422

Lyme disease Lupus erythematosus Rhinoscleroma Leprosy Necrobiosis lipoidica Folliculitis of many types HIV infection Inflammatory conditions of mucous membranes and genitals Many other infections as minor component Granulomatous dermatitis Noninfectious granulomas (see Chapter 6) AFB infections (atypical, tuberculosis, leprosy) Deep fungal infections Syphilis and yaws Granuloma inguinale and lymphogranuloma venereum Tularemia and brucellosis Leishmaniasis Granulomatous dermatitis with pseudoepitheliomatous hyperplasia and intraepithelial microabscesses Botryomycosis AFB infections Deep fungal infections Halogenodermas (bromoderma, iododerma) Pyoderma vegetans Pemphigus vegetans Foamy infiltrates Leprosy Leishmaniasis Atypical mycobacteria Xanthomas of many types Histiocytosis X Panniculitis Granular cell tumor (more granular than foamy) Some neoplasms (such as atypical fibroxanthoma, hibernoma, liposarcoma, balloon cell nevus and melanoma, sebaceous cell tumors)

Differential Diagnosis Other diseases with subcorneal pustules (see Table 19-1) Pemphigus foliaceus and erythematosus

CLINICAL FEATURES Lesions are characteristically “honey-color crusts” of acute onset.13 The lesions seen in patients with bullous impetigo are nonpustular and may be 1 to 2 cm in diameter (Fig. 19-2A).14 Common areas of involvement are on the face, particularly below the nose, and the groin. When eczema is secondarily “impetiginized,” the extremities are often involved. Mild infections may be self-limited. The usual treatment involves topical mupirocin or oral antibiotics such as cephalexin, erythromycin, or dicloxacillin.

HISTOPATHOLOGIC FEATURES Subcorneal pustules containing, by definition, neutrophils are present in the subcorneal zone15 (Figs. 19-1 and 19-2; see also Table 19-2). As with any subcorneal pustule, occasional acantholytic keratinocytes may be found. Sometimes gram-positive cocci may be identified. Older lesions have a crust with neutrophils and parakeratosis rather than clearly delineated pustules. The epidermis may be spongiotic. The dermal infiltrate is usually composed of lymphocytes and neutrophils in a pervascular distribution. Lesions of bullous impetigo exhibit a histology identical to that of SSSS. DIFFERENTIAL DIAGNOSIS Other conditions that may produce subcorneal pustules are listed in Table 19-1. Most of the latter entities can be distinguished from impetigo based on the clinical

characteristics, but in some cases, cultures or fungal stains may be needed. If acantholytic cells are prominent, pemphigus foliaceus or erythematosus may cause confusion and can be identified with direct immunofluorescence. Occasional cases of impetigo have been reported with a confusing positive immunofluorescence pattern similar to pemphigus. Positive identification of organisms by histology or culture does not exclude the possibility of secondary impetiginization of another dermatologic condition.

ECTHYMA

HISTOPATHOLOGIC FEATURES A crust is present within the ulceration. Grampositive cocci may be present in the ulcer bed. Neutrophils are usually found diffusely throughout the dermis. DIFFERENTIAL DIAGNOSIS Ecthyma may be confused with any secondarily impetiginized ulceration.

CHAPTER 19 ■ BACTERIAL INFECTIONS

 FIGURE 19-1 Impetigo. Subcorneal pustule containing neutrophils and occasional acantholytic keratinocytes.

CLINICAL FEATURES In this uncommon variant of impetigo, patients, usually children, present with punched-out, crusted excavations of the skin (see Table 19-2), usually caused by S. pyogenes. Lesions may occur after trauma and often involve the extremities. They are more likely to scar than common impetigo.

ECTHYMA GANGRENOSUM The adjective gangrenosum appended to ecthyma generally refers to severe, disseminated, ulcerative lesions in very ill patients owing to sepsis with Pseudomonas aeruginosa.16,17 This type of sepsis often occurs in those who are immunosuppressed from a wide variety of causes, and the condition often is fatal. A CLINICAL FEATURES The ulcers may start as red macules, bullae, or pustules, but eventually they become covered with black eschars. Patients are very ill owing to sepsis.

B  FIGURE 19-2 Bullous impetigo. (A) Intact bulla on the wrist. (B) Subcorneal blister containing a few neutrophils and acantholytic keratinocytes. Prominent papillary dermal edema.

HISTOPATHOLOGIC FEATURES In most cases, the most striking change is extensive necrosis or ulceration of the epidermis and infarction of the dermis (Fig. 19-3). The inflammatory infiltrate is usually composed of sparse lymphocytes or neutrophils, sometimes with vessel wall changes compatible with vasculitis. Gram-negative bacilli may sometimes be seen in the dermis in huge numbers as subtle light blue rods with routine H&E staining (even though staining with Gram stain shows a red color).

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 FIGURE 19-3 Ecthyma gangrenosum in a patient who died of disseminated intravascular coagulation. Epidermis and dermis are pale because of necrosis and infarction. There are numerous thrombi and only sparse inflammation.

DIFFERENTIAL DIAGNOSIS Cultures or special stains allow a definitive diagnosis. Extensive necrosis of the epidermis may occur in toxic epidermal necrolysis (TEN) and herpes simplex. Extensive dermal infarction is common with pyoderma gangrenosum and certain deep fungal infections, such as from Mucor, Rhizopus, Aspergillus, and Fusarium infection, but hyphae are demonstrated with special stains.

STAPHYLOCOCCAL SCALDED-SKIN SYNDROME SSSS, also known as Ritter disease, is a generalized systemic illness caused by strains of S. aureus (phage group II, especially type 71) that produce an exfoliative exotoxin A or B.18 The target of the toxin as in SSSS and bullous impetigo, and the IgG antibodies in pemphigus foliaceus is desmoglein 1.11 Bullous impetigo can be considered to be a localized form of SSSS. The exfoliative toxins are superantigens that stimulate T-cell proliferation19 (see explanation of superantigens under Toxic Shock Syndrome).

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CLINICAL FEATURES The disease most commonly affects children younger than

5 years of age (Table 19-3). It is rare in adults, and most adults with the disease are immunosuppressed or have renal insufficiency, probably lacking an ability to excrete the toxin.20,21 Some apparently

Table 19-3 Staphylococcal Scalded-Skin Syndrome

Clinical Features Superficial peeling of bright red skin Head and neck most common Children usually Constitutional symptoms, usually of acute onset Occult source of staphylococci in nonlesional sites (eg, conjunctiva, nares, groin, blood) Histopathologic Features Pauci-inflammatory subcorneal blister that may contain few acantholytic keratinocytes Minimal perivascular inflammatory infiltrate Bacteria not present in lesional skin Differential Diagnosis Pemphigus erythematosus or foliaceous Toxic epidermal necrolysis (clinical) Kawasaki disease

healthy adults have developed SSSS.22 Patients develop mild constitutional symptoms while the skin of the face and neck becomes red, as in scarlet fever, and eventually superficially blistered.23 The trunk, axilla, groin, and extremities are usually involved later. Conjunctivitis is common. Flaccid bullae with fragile roofs develop, leaving denuded skin after friction causes expansion of the blisters (Nikolsky sign). SSSS may occur after an upper respiratory infection of a different etiology, such as varicella, measles, or other viruses. SSSS can be self-limited, resolving in a few weeks without scarring, but it is usually treated with antibiotics. Mortality in children beyond the neonatal period is low, and long-term complications are rare. In neonates and adults, mortality is up to 60% even with aggressive treatment, usually because of comorbidities.24,25 A variant known as staphylococcal scarlet fever differs from SSSS because the bright red erythroderma becomes desquamative instead of producing the blistering observed in SSSS. Because these patients are more likely to have enterotoxins or toxic shock syndrome toxin rather than exfoliative toxins, it probably represents an abortive form of toxic shock syndrome rather than a milder form of SSSS.26 HISTOPATHOLOGIC FEATURES The level of blistering is in the subcorneal zone through the granular layer (Fig. 19-4). There is often very little inflammation, and epidermal necrosis generally is not seen. Acantholytic keratinocytes and dermal edema may be present. DIFFERENTIAL DIAGNOSIS TEN (Lyell disease) is usually drug induced, is more common in adults, and is characterized by full-thickness epidermal necrosis instead of the more superficial subcorneal peeling seen with SSSS. TEN is more likely to involve the mucous membranes and is more serious. The distinction is usually apparent clinically, but sometimes this can be an indication for rapid frozen section analysis of the blistering process. An invasive biopsy is not necessary because a frozen section can be prepared easily by rolling up some of the sloughed skin to determine the depth of separation. A new rapid serologic test for the toxin of SSSS may provide rapid distinction from TEN.18 Bullous impetigo differs because whereas the site of the proliferation of the bacteria is in the skin, in SSSS, it is generally at remote sites such as the nose, conjunctiva, groin, or

syndrome is mainly defined by clinical features and the culture of the bacteria. Skin biopsies may show nonspecific changes observed with any “toxic erythema” such as spongiosis; exocytosis of lymphocytes and neutrophils; necrotic keratinocytes; intraepithelial microabscesses; papillary dermal edema; and perivascular dermal inflammation with lymphocytes, neutrophils, and extravasated erythrocytes. DIFFERENTIAL DIAGNOSIS Toxic shock syndrome may resemble streptococcal scarlet fever, Rocky Mountain spotted fever, meningococcemia, TEN, Kawasaki syndrome, SSSS, and drug eruptions.

 FIGURE 19-4 Staphylococcal scalded-skin syndrome. Sloughing of the stratum corneum with acantholytic keratinocytes and a sparse lymphocytic dermal infiltrate are seen.

even the blood of very sick patients. Kawasaki disease and toxic shock syndrome are principally distinguished from SSSS by their clinical presentations.

TOXIC SHOCK SYNDROME This rare syndrome was first described in the late 1970s as an acute illness owing to S. aureus (phage group I) toxin. Most cases at that time were caused by intravaginal growth of the bacteria in tampons.27,28 At present, about 45% of cases are nonmenstrual, and the sites of growth of bacteria in those patients include abscesses, empyema, osteomyelitis, and surgical wound infections.29 Certain strains of S. pyogenes also cause a toxic shock syndrome and the closely related scarlet fever.10,30,31 Many of the toxic effects of toxic shock syndrome appear related to enterotoxins or toxic shock syndrome toxin (versus the exfoliative toxins that cause SSSS). These toxins serve as superantigens that activate superantigen genes that are usually dormant in normal hosts.32,33 Instead of presenting antigens in the normal way, superantigens activate class II major histocompatability complex molecules on antigen-presenting cells.34 They also bind to specific variable regions on the beta chain of T-cell antigen receptors. The result is a massive release of cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor, far beyond the magnitude seen with ordinary antigen-specific activation. The use of intravenous immunoglobulin as part of treatment is thought to decrease the cytokine release caused by superantigen activity.

CLINICAL FEATURES Patients are usually acutely ill with high fever, a generalized sunburn-like rash that eventually desquamates (especially on the palms and soles), hypotension, vomiting, diarrhea, and involvement of at least three or more organ systems (Table 19-4). HISTOPATHOLOGIC FEATURES Histology is not crucial to the diagnosis because the

Table 19-4 Toxic Shock Syndrome

Clinical Features Acute onset of systemic illness Toxin-producing staphylococci or streptococci at remote sites eg, (tampons, surgical wound) Fever, hypotension, involvement of other organs Bright red diffuse patches that later desquamate Histopathologic Features Spongiosis, necrotic keratinocytes Perivascular inflammation Differential Diagnosis Cellulitis Exfoliative erythroderma Erythema multiforme and toxic epidermal necrolysis Drug eruption Streptococcal scarlet fever and toxic shock–like syndrome Kawasaki disease Meningococcemia Rocky Mountain spotted fever Staphylococcal scalded-skin syndrome

CLINICAL FEATURES Erysipelas is a special type of infectious cellulitis that occurs most commonly on the face, with a welldemarcated, rapidly advancing, red, elevated margin.35,36 Vesicles and bullae may develop because of prominent dermal edema. S. pyogenes and rarely other streptococci or S. aureus are responsible for erysipelas. As with other forms of cellulitis, the organisms may be difficult to demonstrate or culture. Skin biopsy cultures have a low yield (about 13%).35 Elevated serologic titers to antistreptolysin O (ASO) and antideoxyribonuclease B (anti-DNAase B) are often helpful diagnostically. Constitutional symptoms, such as fever, malaise, headache, and vomiting, may occur. Bacteremia is noted in 5% of patients. Erysipelas is prone to recurrence but otherwise is far more innocuous than SSSS in adults or toxic shock syndrome. Diabetes mellitus can be a predisposing factor.

CHAPTER 19 ■ BACTERIAL INFECTIONS

ERYSIPELAS

HISTOPATHOLOGIC FEATURES The histology is similar to other examples of cellulitis, but dermal edema and lymphatic dilatation are often exceptionally prominent, even to the point of subepidermal blister formation. Fibrosis may occur in recurrent cases. The gram-positive cocci are very difficult to demonstrate with routine Gram stain. Direct immunofluorescence has been used to demonstrate the organisms but is not used routinely in most laboratories. DIFFERENTIAL DIAGNOSIS Erysipelas may clinically resemble many other inflammatory conditions, such as lupus erythematosus, seborrheic dermatitis, rosacea, photodrug reactions, and contact dermatitis. Most of the latter entities do not cause fever or diffuse infiltration of the dermis by neutrophils. Other causes of infectious cellulitis may be similar

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histologically, but the difference depends on demonstration of the offending agent by various methods described in the introduction to this chapter. The difference between erysipelas and other forms of infectious cellulitis may be more historical than real. Authorities claiming that erysipelas is most common on the legs in areas of lymphedema or peripheral vascular disease are including examples of what others would call ordinary cellulitis. Other diseases with diffuse infiltration of the dermis by neutrophils are listed in Table 19-1.

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ERYSIPELOID The name derives from the clinical resemblance to erysipelas (hence the suffix -oid). This is a relatively rare cellulitis owing to the gram-positive bacillus Erysipelothrix rhusiopathiae, which is found in decaying animal matter. Although it grows in routine culture media, definitive identification depends on the clinician alerting the laboratory about the detection of this organism, which otherwise may resemble streptococci and diphtheroids. Cultures are best accomplished by skin biopsy taken from the advancing edge of the cellulitis. CLINICAL FEATURES Erysipeloid usually develops on the hands and fingers of those who are injured after handling fish or other animal products. A purplish macule may arise at the site of injury. The lesions are otherwise erythematous macules or slightly elevated plaques, as with other forms of cellulitis, but there tends to be a central pallor or clearing and a slowly advancing edge. Constitutional symptoms are less common than with cellulitis secondary to streptococci and staphylococci. Lymphangitis and lymphadenitis are rare. In unusual cases, endocarditis may ensue.37 If untreated, erysipeloid tends to resolve spontaneously within 3 weeks, although relapses may occur. HISTOPATHOLOGIC FEATURES Biopsies of erysipeloid are similar to other forms of infectious cellulitis. Edema of the dermis may be prominent, and the diffuse inflammatory cells tend to be polymorphous, with superficial and deep perivascular lymphocytes and plasma cells as well as neutrophils. Organisms generally cannot be demonstrated with the Gram stain.

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DIFFERENTIAL DIAGNOSIS Staphylococcal and streptococcal infections are more common and are histologically similar to erysipeloid. Cultures may allow a distinction, but the treatment is often the same.

Other hand infections may be worth considering. Brucellosis typically presents as erythema, papules, or pustules on the hands of veterinarians or other animal workers who handle infected placentas. Hand infections with tularemia usually manifest ulcerated lesions after contact with infected rabbits; ticks; or occasionally, other animals. Because cultures are hazardous, the diagnosis of brucellosis or tularemia is often made serologically. Both brucellosis and tularemia eventually become more granulomatous than erysipeloid. Anthrax is also more likely to ulcerate; the histology may resemble erysipeloid, but the exceptionally large gram-positive rods are usually numerous and easily demonstrated. Early lesions of orf, milker’s nodule, and erythema multiforme may cause some confusion with erysipeloid, but later the clinical and histological manifestations are quite different. Herpetic whitlow also may present initially as erythema, but vesicles form later. The biopsy would show herpetic cytopathic changes, and direct fluorescence antibody staining of smears, viral cultures, or Tzanck smears may be positive.

BLISTERING DISTAL DACTYLITIS This is a superficial S. pyogenes or S. aureus infection of the anterior fat pad on the volar surface, usually of one distal finger. CLINICAL FEATURES Patients present with acute swelling, redness, crusting, and blistering of the finger.38,39 The condition is most common in children and adolescents, some of whom have an upper respiratory infection as well. HISTOPATHOLOGIC FEATURES The patients are often not subjected to skin biopsy because the clinical presentation is distinctive or confirmed by cultures and Gram stains or smears. The histology shows overlapping features of impetigo and cellulitis depending on the stage of the lesion biopsied. A diffuse dermal neutrophilic infiltrate may extend into the adipose tissue. Edema may be prominent enough to produce blistering or pustule formation. Epidermal necrosis may be present.

CELLULITIS Although cellulitis is rigidly defined as inflammation of cellular tissue (without reference to infection), in common usage, the term refers to infectious cellulitis, indicating a diffusely spreading infection of the dermis or underlying soft tissues,

usually by bacteria. Infections by other agents such as fungi have occasionally been designated cellulitis when they present with the clinical features described in the following section. As stated in the introduction to this chapter, the causative organisms may be difficult to identify in many cases despite special stains and cultures of biopsies.40 Group A streptococci and S. aureus rank among the more common offenders. In immunosuppressed patients, a myriad of different organisms may be pathogenic. Perianal cellulitis presents as a distinct bright red, tender erythema thought to be related to Streptococcus, but it is rarely biopsied. Haemophilus influenzae type B causes an uncommon but distinct form of cellulitis in children between 6 months and 3 years of age, generally on the face or periorbital area. Marine vibrios may cause a fulminant form of cellulitis or necrotizing fasciitis after a wound or laceration while swimming, especially on the extremities (see Necrotizing Fasciitis). Pasteurella multocida is well known to be present in some animal bite wounds. CLINICAL FEATURES The most common presentation is a warm and tender, bright red macule or indurated plaque (Table 19-5). Epidermal changes such as scaling, pustules, and ulcers are not present in most patients but may occur in the later stages. Fever, chills, lymphangitis, and regional lymphadenopathy may develop. HISTOPATHOLOGIC FEATURES Biopsies are often not necessary unless an unusual (such as nonbacterial) pathogen or clinical

Table 19-5 Infectious Cellulitis

Clinical Features Bright red erythematous patches or plaques without epidermal change Low yield of positive cultures after biopsy Sharply demarcated raised edge on the facial “erysipelas” variant Histopathologic Features Diffuse dermal interstitial neutrophils Dermal edema Gram stain uncommonly demonstrates bacteria in dermis Possible epidermal necrosis in later stages if severe Differential Diagnosis Other diseases with dermal neutrophils (see Table 19-1)

mimic of cellulitis (such as malignancy) is suspected. Histologic features are often not specific, and demonstration of bacteria is rare. Biopsies usually show diffuse infiltration of the dermis or underlying soft tissue by lymphocytes or neutrophils (Figs. 19-5 and 19-6). Edema and extravasation of erythrocytes may be present. The epidermis is unremarkable except in the later stages, when intraepidermal pustules or necrotic foci may be present. Necrosis in the dermis and secondary vasculitis may be found in late lesions. Special stains for AFB or fungi may be needed.

NECROTIZING FASCIITIS This is an acute, rapidly progressive deep infection of the fascia and soft tissue. Initially, it tends to largely spare the skin and underlying muscle. It usually occurs as a result of an injury, diabetes, alcoholism, peripheral vascular disease, malignancy, drug abuse, or immunosuppression.41 The origin of some cases is idiopathic because it can appear suddenly in young, healthy individuals. However necrotizing fasciitis (NF) is more common in children than in adults. Predisposing factors include varicella, intramuscular injections, penetrant gluteal trauma, dental abscess, and streptococcal toxic shock syndrome. The administration of nonsteroidal anti-inflammatory drugs also may contribute to the progression NF in children, especially when associated with varicella.42a A number of different organisms have been implicated, often growing synergistically. Streptococci, enterococci, S. aureus, Proteus spp., and anaerobes such as Peptostreptococcus, Bacteroides, and Clostridium spp. are common.42 When a mixed infection is present, the term type I necrotizing fasciitis has been used.40,43 Meleney synergistic gangrene and Meleney ulcer are terms used for a similar type of mixed infection when it occurs in surgical wounds. Fournier gangrene is a related condition involving the genital area idiopathically or after trauma, surgery, urinary infection, appendicitis, or pancreatitis. Type II necrotizing fasciitis infections are caused by group A streptococci or sometimes S. aureus.30,40,43 Some authors

 FIGURE 19-5 Infectious cellulitis. Perivascular and interstitial infiltrate of neutrophils and lymphocytes.

 FIGURE 19-6 Staphylococcal furuncle. As in cellulitis, neutrophils are predominant in the dermis, but here they are dense and form a dermal abscess. Most are centered on follicles, which largely have been destroyed here.

CHAPTER 19 ■ BACTERIAL INFECTIONS

DIFFERENTIAL DIAGNOSIS Erysipelas is considered to be a variant of cellulitis with a more sharply demarcated, elevated advancing edge. Erysipeloid, also described earlier, is another special type of cellulitis. Other diseases with diffuse dermal infiltration by neutrophils are described in Table 19-1. The neutrophilic dermatoses are primarily distinguished by the clinical presentation and negative cultures and special stains.

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have more strictly defined necrotizing fasciitis as this type only. The lay press has recently coined the term flesh-eating bacteria (usually referring to Streptococcus) for some of these rapidly progressive infections.44 A third type of necrotizing fasciitis is the fulminant form caused by marine organisms, such as Vibrio vulnificans, Vibrio parahemolyticus, and Vibrio alginolyticus, either spontaneously or after a puncture wound.40 Early antibiotic therapy, aggressive surgical debridement of necrotic tissue, and fasciotomy are important for successful treatment of necrotizing fasciitis.45 Magnetic resonance imaging and computed tomography scanning may help determine the depth of tissue necrosis for surgical management.46,47 The mortality rate is as high as 50%. CLINICAL FEATURES Necrotizing fasciitis presents as a rapidly advancing, painful, indurated erythema that progresses to necrosis, blistering, and ulceration. The abdominal wall, perineum, and extremities are involved most commonly. Anaerobic infections may be foul-smelling. HISTOPATHOLOGIC FEATURES There is diffuse infiltration of the soft tissue and fascia with neutrophils and lymphocytes, with areas of necrosis, hemorrhage, and thrombosis (Figs. 19-7 and 19-8). Secondary vasculitic changes may occur. In the late stages, only a few inflammatory cells may be present. Special stains may reveal organisms. DIFFERENTIAL DIAGNOSIS Necrotizing fasciitis may be confused initially with any type of panniculitis or deep inflammatory condition, but the rapidly aggressive course makes the diagnosis more obvious. Lupus panniculitis and eosinophilic fasciitis are seldom mistaken for very long. Special stains and cultures are key to the latter distinction.

 FIGURE 19-7 Necrotizing fasciitis. Epidermal necrosis and perivascular dermal infiltrate. The most striking changes are the fibrosis and diffuse inflammation in the adipose septa and the fascia.

it is often difficult to determine whether it is the primary agent causing the vegetating epithelial proliferation or a secondary colonizer. Pseudomonas and Proteus spp. have also been isolated in some patients. CLINICAL FEATURES Verrucous or vegetating plaques with pustules or sinus tracts

are present. This process may occur anywhere, but the intertriginous areas, face, and legs are involved most commonly. Lesions have been reported at the edges of tattoos. A variant known as coral reef granuloma (based on its elevated verrucous appearance, not etiology) is most common on the forearms. Another

PYODERMA VEGETANS (“BLASTOMYCOSIS-LIKE” PYODERMA)

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The terminology used for this condition has been confusing. Hallopeau used the term pyoderma vegetans to refer to what is now called pemphigus vegetans, but this is a different disease. Pyoderma vegetans is now used to refer to a vegetating pustular skin reaction to a bacterial infection or as a variant of pyoderma gangrenosum.48-50 Patients may have some of the same underlying diseases implicated with pyoderma gangrenosum, such as inflammatory bowel disease. Some patients have decreased immunologic function. The most common organism isolated is S. aureus, and

 FIGURE 19-8 Necrotizing fasciitis. Higher power view of Fig. 19-7 showing diffuse hemorrhage and mixed inflammatory infiltrate in the fibrosing adipose septa and fascia.

variant termed actinic comedonal plaque has a cribriform clinical appearance and appears on sun-damaged skin.

DIFFERENTIAL DIAGNOSIS Other diseases with pseudoepitheliomatous hyperplasia and intraepithelial microabscesses are listed in Table 19-1. Pemphigus vegetans ordinarily shows positive direct immunofluorescent staining, unlike pyoderma vegetans.

HISTOPATHOLOGIC FEATURES Ulcerations contain a prominent amount of fibrin, necrotic material, and neutrophils on the surface. There may be evidence of an underlying skin disease such as scabies or eczema. Special stains may reveal the gram-positive bacilli.

DIPHTHERIA Diphtheria is a localized infection of the skin or mucous membranes by the grampositive rod Corynebacterium diphtheriae.51-53 Because of widespread immunization in the United States, the disease is rare, except for imported cases and those in older Americans who have lost their immunity. Because 25% to 50% of older adults are susceptible, local outbreaks in the United States have resulted in several hundred to 1000 cases in recent years. The diagnosis is made by alerting the laboratory to use special media to ensure isolation of the organism.

DIFFERENTIAL DIAGNOSIS Because diphtheria may resemble many cutaneous infections and other dermatoses, a high index of suspicion is necessary so the appropriate cultures can be obtained.

ERYTHRASMA This is a superficial infection caused by the gram-positive coccobacillus Corynebacterium minutissimum and possibly other corynebacteria.54 Corynebacteria are difficult to speciate; many species are normal flora, and collectively, they have been known as diphtheroids or coryneforms. Besides this condition, they are

Table 19-6 Erythrasma

Clinical Features Red or brownish-red patches in moist intertriginous areas Characteristic coral-red fluorescence with Wood lamp Histopathologic Features Filamentous gram-positive rods in stratum corneum seen with H&E, PAS, or Giemsa stains Minimal inflammation Differential Diagnosis Nonspecific intertrigo Tinea, Candida spp. Contact dermatitis

implicated in pitted keratolysis and trichomycosis. CLINICAL FEATURES Erythematous or brownish-red patches are found in moist intertriginous areas, such as the groin, axillae, inframammary areas, and interdigital spaces between the toes (Table 19-6). A slight amount of scale may be present. Most lesions are asymptomatic. A coralred fluorescence is seen with Wood light examination (ultraviolet A).

CHAPTER 19 ■ BACTERIAL INFECTIONS

HISTOPATHOLOGIC FEATURES Pseudoepitheliomatous hyperplasia and intraepithelial and dermal microabscesses are the principal findings (Fig. 19-9). Sometimes focal areas of granuloma formation are present. As in pemphigus vegetans, eosinophils may be prominent in the abscesses. Variants such as coral reef granuloma and actinic comedonal plaque contain areas of solar elastosis.

CLINICAL FEATURES Infection of the tonsils and pharynx results in a characteristic thick, gray pseudomembrane. Systemic effects are mostly owing to toxin elaborated by the bacteria. Skin infection is more common in the tropics but has also been seen rarely in the United States. It is usually a result of secondary infection complicating other skin diseases such as scabies or impetiginized eczema. It can occur almost anywhere on the skin. Punched-out ulcers are a common presentation, often covered with necrotic membranes.

HISTOPATHOLOGIC FEATURES Pathologic changes are restricted primarily to the stratum corneum, in which the organisms proliferate without significant host inflammatory response. The coccobacilli and thin bacterial filaments may be barely visible with H&E stain but are seen more easily with the Gram, periodic acid–Schiff (PAS), Gomori methenamine silver (GMS), and Giemsa stains or with electron microscopy.55 DIFFERENTIAL DIAGNOSIS Erythrasma may resemble contact dermatitis, nonspecific intertrigo, tinea, or Candida or other superficial fungal infections. Some of these diseases may occur concomitantly with erythrasma. None of these conditions is characterized by the thin bacterial filaments in the stratum corneum and the coral-red color with the Wood lamp. The organisms of tinea and Candida are larger.

TRICHOMYCOSIS

 FIGURE 19-9 Blastomycosis-like pyoderma. Pseudoepitheliomatous hyperplasia, intraepithelial microabscesses, and diffuse mixed dermal infiltrate.

This uncommon condition is thought to be due to Corynebacterium tenuis, but other members of this genus may be involved as well. The identification of

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specific species of this genus is not well delineated and is not done routinely; thus, the diagnosis generally is made clinically without culture or biopsy.

PART III ■ INFECTIONS

CLINICAL FEATURES Asymptomatic nodular concretions form on the axillary or pubic hair shafts. These are most commonly yellow but may be black or reddish.56 It has been debated whether the concretions form on the basis of some sort of gluelike substance produced by the organisms or whether apocrine sweat causes adherence to the hair shaft. There may be an associated odor. HISTOPATHOLOGIC FEATURES The diagnosis is made clinically, and microscopic examination generally is not performed unless there is serious consideration of one of the related conditions discussed in the differential diagnosis. Corynebacteria (coccobacilli and filaments) are seen within the concretion stuck to the hair. They stain weakly with H&E and are better seen with Giemsa stain or electron microscopy. DIFFERENTIAL DIAGNOSIS Concretions on the hairs are also seen with white piedra (Trichosporon cutaneum) on the scalp, mustache, or groin hairs. In black piedra (Piedraia hortae), concretions form on the scalp. Both of these fungi are larger than corynebacteria and can be distinguished microscopically or by culture. Both white and black piedra mainly occur in South America. Tinea also most commonly involves scalp hair rather than axillary or groin hair; the endothrix hyphae or spores tend to invade the hair shaft and are not present on the outside in concretions in the more common species.

 FIGURE 19-10 Pitted keratolysis. Coccobacilli and bacterial filaments are infiltrating the superficial stratum corneum.

They may be seen with H&E stain but are seen more clearly with Gram stain, as well as PAS, GMS, and Giemsa stains. There is no significant inflammatory reaction. DIFFERENTIAL DIAGNOSIS The diagnosis is usually clinically straightforward and should not be confused with other causes of pits on the palms and soles, such as Darier disease and basal cell nevus syndrome. The hyphae of tinea pedis are larger. Cultures for fungus may be done if necessary. Most laboratories are not prepared to routinely identify the various causative agents of pitted keratolysis and will report “normal skin flora” or “diphtheroids.”

MENINGOCOCCAL INFECTIONS PITTED KERATOLYSIS This is a superficial skin infection caused by various Corynebacterium spp., Micrococcus sedentarius, Dermatophilus congolensis, or Actinomyces.57,58 It is due to excessive heat and moisture and prolonged occlusion of the feet. The organisms apparently elaborate a proteinase that produces hundreds of tiny pits in the skin. CLINICAL FEATURES Numerous 1- to 2-mm or larger asymptomatic pits occur in the whitish macerated stratum corneum of the soles, especially over pressure points. The feet may have a strong odor.

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HISTOPATHOLOGIC FEATURES Coccobacilli and filaments are seen within the stratum corneum in the pits (Fig. 19-10).

Neisseria meningitidis occurs naturally in the throats of a minority of the population who serve as asymptomatic carriers. Infection is spread through the respiratory route. Sporadic epidemics of bacteremia and meningitis occur. Meningitis is more common in children. CLINICAL FEATURES Clinical disease varies from severe meningitis and disseminated severe septicemia (meningococcemia) to occult bacteremia.59 Patients with acute meningococcemia, with or without meningitis, are febrile and acutely ill, and develop red macules, nodules, pustules, petechiae, or ecchymoses60,61 (Table 19-7). Purpura becomes predominant after disseminated intravascular coagulation (DIC) ensues. The early skin lesions may be the first

sign that leads to the diagnosis. The Waterhouse-Friderichsen syndrome is a fulminant form of the disease with adrenocortical insufficiency, vasomotor collapse, and shock. In a recent study, cultures were positive from the blood, cerebrospinal fluid, and skin in 56%, 50%, and 36% of patients, respectively.62 Cultures from the pharynx may also be positive in a minority of patients. In the rare chronic meningococcemia, fever and arthritis appear along with a recurring vesiculopustular, maculopapular, or petechial eruption.63 HISTOPATHOLOGIC FEATURES The petechiae and ecchymoses exhibit microthrombi in the dermal blood vessels, with dermal hemorrhage. In cases of DIC, very little inflammation may be present. Sometimes frank vasculitis is found, with necrosis of

Table 19-7 Meningococcemia

Clinical Features Febrile multisystem illness Acute onset of petechiae or ecchymoses Histopathologic Features Septic neutrophilic vasculitis Gram-negative diplococci are sometimes demonstrated Differential Diagnosis Neutrophilic (leukocytoclastic) vasculitis Viral exanthems Gonococcemia Rocky Mountain spotted fever Other septicemias

DIFFERENTIAL DIAGNOSIS Meningococcemia may clinically resemble viral exanthems, gonococcemia, Rocky Mountain spotted fever, other forms of septicemia, and other purpuric eruptions. The histologic differential diagnosis includes other infectionrelated small vessel vasculitides associated with fibrin thrombi and neutrophil-rich infiltrates, pustular vasculitis, septic or sterile thrombi, and leukocytoclastic vasculitis from any cause.64 The chronic form of meningococcemia without vasculitis exhibits nonspecific features, suggesting infection in general, connective tissue disease, Still disease, or a neutrophilic dermatosis.

Table 19-8 Gonococcemia

Clinical Features Acute onset of necrotic pustules, usually sparse in number, especially acral Acute septic arthritis Histopathologic Features Neutrophilic (leukocytoclastic) vasculitis Gram-negative diplococci are rarely demonstrated Pustules vary in site of formation (subcorneal, intraepidermal, subepidermal) Differential Diagnosis Meningococcemia and other causes of septic and nonseptic vasculitis Rickettsial infections Other pustular conditions (see Table 19-1) Pustular vasculitis

HISTOPATHOLOGIC FEATURES Biopsies of disseminated skin lesions show neutrophilic (leukocytoclastic) vasculitis (Fig. 19-11). There often are hemorrhage, thrombosis, focal epidermal necrosis, intraepidermal or subepidermal pustules, and pustular vasculitis. The gram-negative diplococci are seldom found. The nondisseminated primary skin pustules or ulcers contain a diffuse infiltrate of neutrophils, forming an abscess. Organisms are easier to demonstrate than in gonococcemia but are best seen

using smears of the pustular discharge instead of biopsies. DIFFERENTIAL DIAGNOSIS Reiter syndrome, meningococcemia, and other bacteremias may resemble gonococcemia. Other causes of pustules are listed in Table 19-1.

TUBERCULOSIS Mycobacterium tuberculosis primarily affects the lungs, but many other organs, including the skin, may also be involved. Tuberculosis (TB) was decreasing in incidence in North America and Europe until the advent of AIDS. It has been estimated that 50% of the earth’s population is infected with this bacterium, and it is responsible for 6% of all deaths worldwide. Bacterial resistance to antibiotics is a growing concern. In the United States, 95% of individuals who are infected recover completely from their primary TB in the lung, with no further evidence of disease. With any worsening in health status or immunosuppression, the quiescent bacteria persisting within macrophages may proliferate and cause clinical disease. In some parts of the world, immunity results from vaccination with bacille Calmette-Guérin (BCG). Skin testing with tuberculin purified-protein derivative is used commonly in patients who have not been vaccinated with BCG as a reliable means of confirming previous mycobacterial

CHAPTER 19 ■ BACTERIAL INFECTIONS

vessel walls, and neutrophils in and around vessels, with nuclear dust. Meningococcal infection, as with many other bacterial infections, may present as pustular vasculitis. The gram-negative diplococci can sometimes be found in and around vessels. Intraepidermal and subepidermal pustules and epidermal necrosis sometimes occur. In chronic meningococcemia, a nonspecific perivascular infiltrate of lymphocytes and a few neutrophils is found more commonly, and organisms are discovered less frequently. Petechial or pustular lesions may show neutrophilic (leukocytoclastic) vasculitis, sometimes with intraepidermal or subepidermal aggregates of neutrophils.

GONOCOCCAL INFECTIONS Gonorrhea is a common venereal disease caused by Neisseria gonorrhoeae.65 Males usually develop acute purulent urethritis and, less commonly, proctitis or oropharyngitis. Females most often develop endocervicitis. CLINICAL FEATURES Gonococcemia (gonococcal septicemia) sometimes has been called the dermatitis–arthritis syndrome, although meningococcemia and other bacteremias can produce a similar picture (Table 19-8). Patients develop fever, oligoarthritis, and skin lesions.66,67 The skin lesions most commonly are sparse acral necrotic hemorrhagic pustules, but red macules, papules, furuncles, ulcers, cellulitis, and bullae also have been described. The presence of skin lesions usually indicates disseminated disease (gonococcemia) because Neisseria species are not able to invade intact skin. Localized pustular or ulcerated primary skin infections may occur in genital glandular tissue and have also been reported on the fingers.

 FIGURE 19-11 Gonococcemia. Vasculitic picture with necrosis, fibrin, and neutrophils in the vessel walls, nuclear dust, extravasated erythrocytes, and microthrombi.

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LEPROSY (HANSEN DISEASE)

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Hansen disease, caused by M. leprae, affects millions of people worldwide. In the United States, it occurs mainly in immigrants from endemic areas, but some cases originate in Texas and Louisiana, perhaps from armadillo exposure. Leprosy affects multiple organs of the body, but clinical disease is most apparent in the skin, eyes, and peripheral nerves. Neuropathies may result in deformities of the distal extremities.

 FIGURE 19-12 Primary inoculation tuberculosis. Caseating granuloma in the dermis.

infection. Cultures and acid-fast stains of biopsies, sputum, or other fluids are required to make a diagnosis of active disease. When these results are negative, PCR testing may be helpful.68,69 CLINICAL FEATURES TB of the skin almost always means long-standing active disease elsewhere, with the rare exception of primary-inoculation TB (Fig. 19-12).70-73 There are many different types, as outlined in Table 19-9.74,75 HISTOPATHOLOGIC FEATURES TB classically causes caseating granulomas, but in some forms, the granulomas do not caseate, and suppuration or purulence may be prominent, depending on the patient’s immune status76 (Figs. 19-12 to 19-14). Different patterns are described in Table 19-9. DIFFERENTIAL DIAGNOSIS Other granulomatous conditions listed in Table 19-1 should be considered. Cultures and acidfast stains are definitive.

ATYPICAL MYCOBACTERIA

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There are many different Mycobacterium species that may infect humans besides M. tuberculosis and M. leprae77-79 (Table 19-10). The Runyon classification into four groups of atypical mycobacteria is not as useful as it once was. Common organisms include Mycobacterium marinum (common “swimming pool granuloma”), Mycobacterium ulcerans (Buruli ulcer in Central Africa), Mycobacterium avium-intracellulare (MAI,

especially with AIDS), and Mycobacterium fortuitum and Mycobacterium chelonei (rapid growers). CLINICAL FEATURES Clinical lesions include solitary or multiple erythematous nodules, abscesses, ulcers, verrucous plaques, or sinus tracts (see Table 19-10). Sometimes lesions spread in a sporotrichoid pattern. In most cases, an infection is apparent clinically, but some cases of prurigo nodularis and other chronic skin disorders have been found to be related to mycobacterial infection when tested by culture, biopsy, or molecular techniques.80,81 HISTOPATHOLOGIC FEATURES Typical biopsies show suppurative granulomatous inflammation with or without caseation or coagulative necrosis in the case of mycobacterium ulcerans (Figs. 19-15 and 19-16). The epidermis may be hyperplastic or ulcerated. Fibrosis and granulation tissue may be prominent. Various modifications of the ZiehlNeelson acid-fast stain or Fite stain may reveal the AFB.3 The AFB are most frequently found in microabscesses or within vacuoles in the sections rather than within multinucleated giant cells (Fig. 19-17). Fluorescent antibodies or PCR may be used for detection of the organism.80 DIFFERENTIAL DIAGNOSIS Other diseases associated with granulomas or neutrophilic infiltrates in the dermis are listed in Table 19-1.

CLINICAL FEATURES Leprosy is divided into several types in the Ridley-Jopling classification based on the immune status of the patient81,82 (Table 19-11). The tuberculoid form occurs in those with intact immunity, and patients tend to develop one or a few lesions with prominent hypoesthesia and palpable peripheral nerves. The lesions may be annular or scaly or macular and hypopigmented. Patients with lepromatous leprosy are anergic, and they tend to develop widespread cutaneous lesions. Although they are less likely to have hypoesthesia in the lesions, the peripheral nerves may still be enlarged with consequent neuropathies. Lepromatous lesions include hypopigmented or erythematous macules, infiltrated erythematous nodules or plaques, leonine (lionlike) facies with a loss of eyebrows and eyelashes, and diffuse macular involvement of the skin resulting in a smooth surface. In borderline leprosy, combined features of tuberculoid and lepromatous disease are seen. Indeterminant leprosy represents early disease in patients living in populations where leprosy is prevalent; it is difficult to establish a definite diagnosis in some of these patients. They tend to have only a single or few hypopigmented or erythematous macules with or without hypoesthesia. The disease may heal spontaneously or may evolve into one of the other forms. Histoid leprosy refers to dermatofibroma-like nodules of leprosy. There are three types of reactional leprosy, and they occur with or without treatment, usually as a result of a change in the patient’s immune status. The type I reaction (Lepra reaction) is called a reversal reaction when the patient is under treatment and has shifted toward the tuberculoid spectrum with greater immunity.83 It is called a downgrading reaction when untreated patients shift toward the lepromatous pole. Type I reactions involve swelling of previously existing cutaneous and neural lesions with associated constitutional symptoms.

Table 19-9 Tuberculosis

Type II reactions (erythema nodosum leprosum) occur in lepromatous and borderline lepromatous leprosy patients. Tender new red plaques and nodules develop on normal skin, accompanied by constitutional symptoms. This type of reaction involves immune complexes. Type III reactions (Lucio phenomenon) occur only in patients with the

diffuse form of lepromatous leprosy. Hemorrhagic plaques occur on the legs, arms, or buttocks. These may ulcerate eventually. There are usually no constitutional symptoms. HISTOPATHOLOGIC FEATURES The histologic findings are summarized in Table 19-1184,85 (Figs. 19-18 to 19-22).

DIFFERENTIAL DIAGNOSIS Other diseases with granulomatous infiltrates or foamy infiltrates are listed in Table 19-1.

ANTHRAX Anthrax is an acute infection caused by Bacillus anthracis.88-95 About 95% of natural human infections occur 1 to 7 days after primary inoculation of the skin by contact with infected animals, such as goats, sheep, or other herbivores. About 5% of cases are inhalation anthrax (woolsorter’s disease) or gastrointestinal (GI) disease from eating infected meat. Since September 2001, the organism has been used as a biological weapon by treating spores chemically to prevent agglutination and suspending them in powder. Mail in the United States has been intentionally contaminated with white powder containing anthrax spores. Before 2001, the United States typically averaged less than one case per year, but naturally occurring disease is more common in some parts of the world. The bacteria grow readily in culture, but if the laboratory is not alerted to the suspicion of anthrax, the organisms may not be identified correctly. Confirmatory cultures and serologic and PCR testing are available through the public health network. Further information is available from Web sites such as the Centers for Disease Control and Prevention (CDC)’s Emergency Preparedness and Response Site (http://www.bt.cdc.gov). CLINICAL FEATURES In cutaneous anthrax, the exposed skin is typically involved. Whereas adults tend to have more involvement of the hands, children younger than 5 years of age often acquire head and neck infections after being bitten by flies that carry the organism. The initial lesion is a red macule, sometimes pruritic, evolving through papular and vesicular stages and eventually ulcerating, often with a black eschar (the name anthrax comes from the Greek word for “coal”). The clinical appearance has been called the malignant pustule, but this is a misnomer because the typical lesion is not purulent and is asymptomatic.

CHAPTER 19 ■ BACTERIAL INFECTIONS

Clinical Features Miliary: Rare papulopustular eruption as a result of widespread hematogenous dissemination owing to poor immunity (PPD-negative) or steroid treatment Primary inoculation: Rare crusted ulcer with regional adenopathy following infection of the skin by laboratory accidents, performance of autopsies, or tatooing TB cutis orificialis: Mucosal ulcers in patients with poor immunity Scrofuloderma (TB colliquativa cutis): Nodular swelling or ulceration resulting from direct extension of underlying bone or lymph node TB TB verrucosa cutis: Solitary purulent verrucous plaque seen in patients with high immunity Lupus vulgaris: Reddish brown apple jelly patches or plaques, usually on the head or neck, resulting from reactivation in a patient with good immunity Tuberculids (hypersensitivity reactions to active TB elsewhere; lesions improve after treatment of the TB): Papulonecrotic tuberculid: Multiple crusted papules Lichen scrofulosorum: Lichenoid papules, sometimes follicular or annular, mostly on the trunk Erythema induratum (Bazin disease): Indurated nodules on the calves. Questionable whether this is related to TB (see Chap. 11) Histopathologic Features Miliary TB, primary inoculation TB, TB cutis orificialis, scrofuloderma Variable epidermal ulceration Diffuse mixed infiltrate with many neutrophils Variable granulomatous component Acid-fast bacilli often present Tuberculosis verrucosa cutis Hyperkeratosis, papillomatosis, acanthosis Sometimes neutrophilic microabscesses in the epidermis Diffuse mixed infiltrate in the dermis, neutrophils prominent Tuberculoid granulomas, sometimes with caseation Acid-fast bacilli sometimes present Lupus vulgaris Epidermal atrophy, hyperplasia, or ulceration Tuberculoid granulomas in the superficial dermis Minimal or no caseation Predominance of Langhans-type giant cells Acid-fast bacilli usually cannot be demonstrated Papulonecrotic tuberculid Lymphocytic or neutrophilic vasculitis Microthrombi frequent Wedge of dermal necrosis Lichen scrofulosorum Granulomatous inflammation with or without caseation Often around follicles Differential Diagnosis Leprosy Atypical mycobacterial infection Lymphoma Tertiary syphilis Other granulomatous diseases (see Table 19-1)

The Fite stain or modifications of it are recommended because the ZiehlNeelson method used for other AFBs does not work as well.3 Immunostaining for AFBs can enhance the ability to diagnose lesions containing few bacilli.86 In situ hybridization and PCR analysis of specimens are more sensitive and are available through the Hansen’s Disease Center in Baton Rouge, Louisiana.87

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A

B

 FIGURE 19-13 Tuberculosis verrucosa cutis. (A) Discrete verrucoid lesion involving the fifth digit of the hand. (B) Pseudoepitheliomatous hyperplasia with granulomatous inflammation.

The eschar is usually surrounded by striking edema, which usually is more extensive on the head or neck than on the trunk or extremities. Malignant edema occurs rarely, consisting of severe edema, bullae, or shock. Patients usually are afebrile, with mild or no constitutional symptoms, but tender regional lymphadenopathy, fatigue, fever, or chills may develop (ulceroglandular disease). The lesions heal spontaneously in 1 to

2 weeks in 80% to 90% of cutaneous cases, leaving very little scarring. Death from untreated cutaneous infection ranges up to 20% but is near 0% with appropriate early treatment. Inhalation or GI anthrax has a mortality rate of 50% to 90% unless early antibiotic treatment is started. GI anthrax begins with a severe sore throat, fever, or dysphagia, with oral or esophageal ulceration, progressing to

vomiting, malaise, bloody diarrhea, acute abdomen, and sepsis. Inhalation anthrax is biphasic, beginning with fever, malaise, myalgia, cough, and chest and abdominal pain. Patients later rapidly develop acute dyspnea, cyanosis, subcutaneous edema, and a characteristic mediastinal widening with adenopathy. HISTOPATHOLOGIC FEATURES Biopsies and cultures should be obtained from the edges of vesicles or eschars. Direct contact with the exudate should be avoided, but the risk of health care workers acquiring pulmonary anthrax from this material is thought to be minimal. Biopsies generally show edema, necrosis, hemorrhage, and scattered diffuse dermal lymphocytes more than neutrophils. The exceptionally large grampositive rods (≤μm long) are usually

Table 19-10 Atypical Mycobacteria

434

 FIGURE 19-14 Lupus vulgaris. Noncaseating granulomas in the dermis with prominent Langhans giant cells.

Clinical Features Ulcers, cysts, sinus tracts, or purulent nodules Multiple or solitary, systemic or cutaneous only May be sporotrichoid Histopathologic Features Epidermis hyperplastic or ulcerated Suppurative granulomatous inflammation with or without necrosis Acid-fast bacilli may be present Sometimes prominent fibrosis or granulation tissue Differential Diagnosis Other granulomatous conditions (or others with dermal neutrophils); see Table 19-1

BRUCELLOSIS Four species of Brucella may cause infection in humans (Brucella mellitensis, Brucella suis, Brucella abortus, and Brucella canis).96,97 The organism is a gram-negative coccobacillus. Human infection occurs after contact with infected milk or animal products. The diagnosis of brucellosis is usually made serologically because cultures are hazardous and may take 6 weeks to grow. The antibodies may cross-react with those of Vibrio cholerae, Francisella tularensis, and Yersinia enterocolitica. A vaccine is available for animals but not for humans.

numerous and easily demonstrated (Fig 19-23). They have a characteristic capsule. They may also be seen on smears from vesicular fluid, eschars, or other body fluids. Immunohistochemistry may facilitate more definitive identification of the organisms. DIFFERENTIAL DIAGNOSIS Clinical lesions of anthrax may resemble staphylococcal

A

infections, sporotrichosis, orf, arthropod bites, or tularemia. Painful pustules are more typical of staphylococcal infections because cutaneous anthrax is usually not pustular or symptomatic. Spider bites also are more likely to be painful. Insect bites are more likely to contain eosinophils. Other hand infections (discussed under Erysipeloid) might also be considered.

CHAPTER 19 ■ BACTERIAL INFECTIONS

 FIGURE 19-15 Atypical mycobacterial infection. Caseating granuloma in the dermis.

CLINICAL FEATURES Brucellosis is usually an acute multisystemic influenza-like febrile condition occurring after the ingestion of food or inhalation of the organisms. The incubation period is 5 to 60 days (usually 30 to 60 days). Symptoms include headache, profound weakness, nausea, vomiting, diarrhea, constipation, or arthritis. About 10% of patients develop nonspecific erythematous macular, morbilliform, or eczematous eruptions or erythema multiforme, ulcers, bullae, or petechiae along with systemic infection. Brucellosis results in death in only 5% of humans, even if untreated. Primary inoculation of Brucella spp. into the skin may present as erythema, papules, or pustules on the hands or arms of veterinarians and other animal workers who handle infected placentas or other

B

 FIGURE 19-16 Mycobacterium ulcerans. (A) Buruli ulcer on the foot. (B) Extensive coagulative necrosis throughout the dermis and subcutaneous fat.

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manifestations of systemic infection range from generalized macular erythema to petechiae and purpura. Y. enterocolitica and Y. pseudotuberculosis mostly cause fever and GI disease, and 10% to 30% of patients develop reactive polyarthritis. About 30% of patients develop skin lesions, usually involving the trunk or legs, and often resembling erythema nodosum.100-102 HISTOPATHOLOGIC FEATURES Histologic changes in the skin are generally not diagnostic and vary according to the type of lesion biopsied. The purpuric and petechial lesions may show microthrombi, hemorrhage, and other signs of DIC. DIFFERENTIAL DIAGNOSIS Yersiniosis can mimic many infectious diseases, and only definitive serology or cultures allow a specific diagnosis.  FIGURE 19-17 Mycobacterium ulcerans. Acid-fast bacilli (Ziehl-Neelsen stain)

GRANULOMA INGUINALE

infected animal products. The latter exposure often results in a contact hypersensitivity reaction to Brucella antigens. HISTOPATHOLOGIC FEATURES The histology of skin lesions has seldom been described in the literature. Superficial and deep lymphohistiocytic perivascular dermatitis and septal or lobular panniculitis have been reported. Necrotic foci are common, and suppurative granulomatous inflammation with plasma cells may be present. DIFFERENTIAL DIAGNOSIS The differential diagnosis of similar infections acquired from animals is discussed under Erysipeloid.

YERSINIOSIS AND PLAGUE

436

There are three species in the gramnegative genus Yersinia, all of which are zoonotic and are acquired in humans from various rodents, farm animals, and birds. The term yersiniosis is usually used for infections by Yersinia enterocolitica and Yersinia pseudotuberculosis, and Yersinia pestis causes plague. Wild rodents and their fleas are the normal hosts for plague, and involvement in humans is incidental and has caused epidemics. In the Middle Ages, this disease resulted in the death of 25% of the population of Europe. It still exists today, with about 16,000 cases and 1700 deaths worldwide over the past 15 years, including a

few cases in the United States.98 Plague is almost 100% lethal if untreated. Mortality decreases to 20%-60% if treatment is started within 24 hours of the onset of symptoms. The potential use of plague as a biological weapon has been of recent interest.99 Suspected infections should be reported to local health authorities. Further information is available on government sites such as the CDC’s Emergency Preparedness and Response Site (http://www.bt.cdc.gov). A live vaccine is under study. Infection is by direct inoculation of flea bites or by oropharyngeal or pulmonary routes. The incubation period is usually about 2 to 3 days. Veterinarians may acquire infection when they treat plague abscesses of domestic cats. Diagnosis is made by culturing the blood, stools, pharynx, sputum, or aspirates from the buboes or by serology. A Gram stain of lymph node aspirates or aspirates from other sites may reveal the organisms. A specific fluorescent antibody test for use on smears is available. Detection by Y. pestis DNA is also possible. CLINICAL FEATURES Plague infections in humans vary from mild to severe. Patients may develop fever, malaise, regional adenopathy (bubonic plague), pneumonia (pneumonic plague), septicemia, meningitis, pharyngitis, cyanosis, and shock. Pustules or carbuncles may form at the site of bites or near buboes, sometimes with centrifugal vesicles. Dermatologic

Granuloma inguinale (GI, donovanosis) is an uncommon venereal disease caused by the gram-negative Calymmatobacterium (formerly Donovania) granulomatis.103-105 The diagnosis is usually made from smears rather than biopsies or cultures. Culture is possible but is generally not available as a routine test in most laboratories.106 PCR has been used to distinguish the organism from Klebsiella species, with which it shares a high degree of molecular homology. CLINICAL FEATURES Asymptomatic genital or perianal ulcers tend to develop abundant friable granulation tissue, spreading in a serpiginous pattern (Table 19-12). When these ulcers become large, considerable local destruction may occur. Fibrotic vegetating ulcers may cause considerable destruction (esthiomene). Adenopathy is usually not prominent. Dissemination beyond the genital and inguinal regions to the liver and other organs eventually may occur in neglected cases. HISTOPATHOLOGIC FEATURES The ulcerations show considerable granulation tissue, with a suppurative granulomatous infiltrate of macrophages (histiocytes), plasma cells, and neutrophils. Lymphocytes are few in number. The borders of the ulcers may exhibit acanthosis or pseudoepitheliomatous hyperplasia. Very large macrophages, up to 20 μm in diameter, may contain the 1- to 2-μm organisms (Donovan bodies), which have a safety-pin appearance when stained with WarthinStarry or Giemsa stain (bipolar staining

Table 19-11 Leprosy (Hansen Disease)

surrounded by a vacuole). Smears made from crushed biopsies stained with Wright or Giemsa stain are better for demonstrating the organisms than tissue sections. Semithin 1-μm sections prepared for electron microscopy and stained with toluidine blue may also be used to identify the organisms.

DIFFERENTIAL DIAGNOSIS Chancroid, syphilis, herpes simplex, and lymphogranuloma venereum also commonly produce genital ulcerations (see the discussion that follows for the differential diagnosis of chancroid below). Pseudoepitheliomatous hyperplasia seen with GI may cause confusion with squamous cell carcinoma.

CHANCROID Chancroid is a venereal disease caused by Hemophilus ducreyi.103 It is the most common cause of genital ulceration in Africa and has been implicated in the transmission of HIV.107 In the United States, the disease is uncommon, occurring in clustered outbreaks, usually in large cities. CLINICAL FEATURES The typical presentation is solitary, painful, nonindurated ulcers (soft chancre) on the genitals 2 to 5 days after sexual contact (Table 19-13). Small satellite ulcers are sometimes present. Lesions are more commonly seen in males. Prominent regional lymphadenopathy may be present. HISTOPATHOLOGIC FEATURES Ulcers may have acanthosis at the edge. The literature has stressed the three characteristic zones of inflammation, but this is not as specific as often implied.108 Classically, the ulcers have a surface of fibrin, neutrophils, and red blood cells. The middle zone consists of granulation tissue, swollen endothelial cells, and vessels that may contain thrombi. The deepest dermis contains a dense infiltrate of plasma cells and lymphocytes. The coccobacilli (1.5-0.2 μm) are demonstrated more readily on smears than in tissue sections. On smears, they sometimes line up in a pattern known as a “school of fish” or “railroad tracks.” If seen in the skin biopsy, organisms are more common in the more superficial neutrophilic zone. They stain with Giemsa and are gram-negative. DIFFERENTIAL DIAGNOSIS Ulcers of secondary syphilis are clinically less painful and tend to be more indurated. The diagnosis rests on positive serology (rapid plasma regain [RPR] or Venereal Disease Research Laboratory [VDRL], which may be negative initially), positive darkfield examination for spirochetes, or positive Warthin-Starry stains. Syphilis, like any ulcer on mucous membranes or genital skin, also tends to exhibit plasma cells, but the three zones of inflammation tend to be more distinct in chancroid. Granuloma inguinale also tends to lack the three zones. Plasma cells and granulation tissue are often prominent.

CHAPTER 19 ■ BACTERIAL INFECTIONS

Clinical Features Lepromatous: Multiple erythematous or hypopigmented smooth patches, plaques, or nodules, sometimes leonine facies Tuberculoid: Hypopigmented scaly or annular patches or plaques, smaller in number than lepromatous, more hypoesthesia in the lesions Borderline: Features intermediate between lepromatous and tuberculoid Indeterminant: Early hypopigmented or erythematous macules Lepra reaction (type I reaction): Acute redness or pain in previously existing lesions Erythema nodosum leprosum (type II reaction): Acute onset of erythematous nodules in new sites not previously involved Lucio phenomenon (type III or variant of II): Acute onset of hemorrhagic plaques or ulcers Histopathologic Features Lepromatous Diffuse dermal infiltrate of foamy macrophages Grenz zone separating the macrophages from the epidermis Numerous AFB, often in clumps called globi Tuberculoid Tuberculoid (epithelioid) granulomas without grenz zone Granulomas often linear, following nerves AFB rare or absent Borderline Histology in between lepromatous and tuberculoid Indeterminant Perivascular and/or perineural lymphohistiocytic inflammation Few or no AFB Type I reaction Histology as in borderline leprosy Type II reaction Lepromatous leprosy plus leukocytoclastic vasculitis Type III reaction Similar to type II, with greater tendency to thrombosis, necrosis, and ulceration Differential Diagnosis Lepromatous (see Table 19-1) Leishmaniasis Atypical mycobacteria Histiocytic infiltrates Xanthomas Granular cell tumors Clear-cell neoplasms Tuberculoid Tuberculosis Atypical mycobacteria Secondary and tertiary syphilis Noninfectious sarcoidal granulomas Sarcoidosis Beryllium Reaction to foreign agents Zirconium Silica Keratin (e.g., rosacea) Cutaneous Crohn disease Granulomatous cheilitis

Parasitized macrophages are also noted with rhinoscleroma, histoplasmosis, and leishmaniasis, but the staining and culture characteristics, clinical presentation, and location of the lesions usually easily allow a distinction.

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most frequent site, the nose. It is caused by Klebsiella rhinoscleromatis, a gramnegative coccobacillus.109,110 The disease is mainly found in Central and South America, India, Indonesia, parts of the former Soviet Union, China, and Africa. Poor hygiene, malnutrition, and crowded living conditions contribute to the infection. The disease is spread by direct or indirect contact with an infected person, usually in the initial secretory “rhinorrheal” or “catarrhal” stage. The disease later evolves into a granulomatous stage, in which the lesions are more exuberant, with painless friable granulation tissue. During this stage, the organisms are easier to see on biopsy. Laryngeal involvement may cause hoarseness. Last, the lesions become fibrotic or sclerotic, sometimes resulting in life-threatening obstruction of the airway.  FIGURE 19-18 Tuberculoid leprosy. Linear granuloma following the course of a nerve.

Macrophages containing gram-negative and Giemsa- and Warthin-Starry–positive bacilli clumped into collections of 10 to 20 organisms (Donovan bodies) are found. Lymphogranuloma venereum tends to produce multiple small, painless ulcers. The histologic changes of lymphogranuloma venereum are nonspecific, and Chlamydia species are difficult to identify with Giemsa stain. The diagnosis usually rests on serology or cultures. Herpes simplex ulcers tend to

A

438

show the characteristic herpetic cytopathic epithelial changes (nuclear molding, steel-gray nuclei with margination of chromatin), multinucleated epithelial giant cell formation, and eosinophilic intranuclear inclusions.

RHINOSCLEROMA Rhinoscleroma is sometimes called scleroma because it may involve other portions of the respiratory tract besides the

CLINICAL FEATURES In the early stages, patients have nasal congestion, crusting, and discharge. Later, tremendous deforming tissue proliferation occurs, followed by indurated scarring. HISTOPATHOLOGIC FEATURES There is a dense, diffuse infiltration of the tissue by many macrophages and plasma cells. Some of the larger macrophages (parasitized histiocytes called Mikulicz cells) contain many of the Frisch bacilli. They are visible with H&E but are best seen with the Warthin-Starry stain. The Gram, Giemsa, and PAS stains may also be used. The prominent plasma cell

B

 FIGURE 19-19 Lepromatous leprosy. (A) Scattered erythematous plaques and nodules on the trunk. (B) Diffuse infiltration of the dermis by foamy macrophages separated from the dermis by a grenz zone.

TULAREMIA This rare zoonotic infection is caused by Francisella tularensis, a gram-negative coccobacillus.111,112 Infection usually occurs after skin contact with infected wild rabbits, deer flies, or tick feces, but infection may also be acquired after contact with a wide variety of other animals. The usual incubation period is 3 to 5 days. Because cultures are difficult and may be hazardous, the diagnosis is usually made serologically. Antibodies may cross-react with those of brucellosis. PCR may verify the diagnosis in patients with negative serology or culture.113

HISTOPATHOLOGIC FEATURES Biopsies typically reveal ulceration, extravasated erythrocytes, and necrosis surrounded by neutrophils. Suppurative granuloma formation eventually develops, sometimes with caseation. Organisms are rarely demonstrated with the Gram stain. The modified Dieterle silver stain and a fluorescent antibody stain are said to be more successful.

 FIGURE 19-21 Lepromatous leprosy. Fite stain of numerous acid-fast bacilli, often clumped into globi.

infiltrate may exhibit many Russell bodies, which are eosinophilic blobs resulting from considerable immunoglobulin synthesis. Russell bodies also can be seen in any plasma cell–rich infiltrate from any cause. DIFFERENTIAL DIAGNOSIS Parasitized histiocytes with organisms about the same size occur with leishmaniasis,

histoplasmosis, and granuloma inguinale. Rhinoscleroma exhibits more plasma cells and Russell bodies. (See Table 19-1 for a list of other diseases with many plasma cells.) Cultures or electron microscopy may be needed for definitive diagnosis of difficult cases. Rhinosporidiosis may also infect the nose, but it tends to be more polypoid clinically, and the histologic findings are much different.

CHAPTER 19 ■ BACTERIAL INFECTIONS

 FIGURE 19-20 Lepromatous leprosy. Nodular dermal aggregate of foamy macrophages and lymphocytes surrounding a nerve.

CLINICAL FEATURES About 80% of cases are ulceroglandular tularemia, occurring after direct inoculation of the skin, usually the finger or hand.114 An erythematous papule eventually ulcerates, often forming a black eschar. Prominent adenopathy usually develops. Other forms of tularemia of less interest in dermatopathology include oculoglandular, oropharyngeal, GI, pulmonary, and typhoidal. Mortality of pneumonic tularemia ranges from 30% to 60% if untreated.115

DIFFERENTIAL DIAGNOSIS The clinical history and physical findings usually easily point toward the diagnosis. Some other considerations for hand infections are discussed under Erysipeloid. Atypical mycobacterial infection and sporotrichosis may resemble tularemia clinically and histologically, except that the causative agents are different, as demonstrated by cultures and special stains. Prominent lymphadenitis also develops in cat-scratch disease, but the localized skin lesions are usually much less impressive.

CAT-SCRATCH DISEASE The etiologic agent of this disease is now thought to be a gram-negative bacillus identical to or similar to that of bacillary angiomatosis.98 Bartonella (formerly Rochalimaea) henselae most recently has been thought to be the cause in most patients. It is closely related to Bartonella

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Table 19-12 Granuloma Inguinale

 FIGURE 19-22 Erythema nodosum leprosum. Leukocytoclastic vasculitis combined with foamy infiltrates of macrophages in the dermis.

Clinical Features Genital ulcers with characteristic beefy red granulation tissue Prominent lymphadenopathy (buboes) common Histopathologic Features Ulceration, sometimes with epithelial hyperplasia at edge Dermal mixed infiltrate of histiocytes, plasma cells, and few lymphocytes, with small neutrophilic microabscesses Donovan bodies (1–2 μm gram-negative organisms, Giemsa- and Warthin-Starry-positive) best seen on smear rather than in tissue sections Differential Diagnosis Other venereal ulcers, such as Syphilis Chancroid Lymphogranuloma venereum Herpes

themselves are not ill. Many human infections are subclinical and perhaps unnoticed. About one-third of patients develop fever or constitutional symptoms. Rarely, various morbilliform rashes, other skin eruptions, or internal organ involvement occurs. The diagnosis usually becomes suspected when tender regional adenopathy develops several weeks later. This is usually the chief complaint. There usually is no lymphangitis extending from the primary lesion, but the node may eventually suppurate. Involvement of the conjunctiva

Table 19-13 Chancroid  FIGURE 19-23 Anthrax. Exceptionally large gram-positive bacilli.

440

quintana, the etiologic agent of louseborne trench fever. Afipia felis, an unrelated organism, has also been implicated in cat-scratch disease, but current thinking favors B. henselae.116,117 The diagnosis may be established by the cat-scratch skin test (Hanger-Rose test). Although it is not readily available and is unstandardized, the skin test is reliable when done 1 week after infection. The organism is extremely difficult to culture. PCR has been used to identify it.

CLINICAL FEATURES The primary lesion begins at the site of a cat scratch or bite, most commonly in children.118 Sometimes injuries from other animals or inanimate objects have also been implicated. The lesion resembles an insect bite but does not itch and may present as a macule, papule, vesicle, pustule, or erosion. The lesions may be solitary or multiple, usually smaller than 5 mm, and they most commonly occur on the hand or forearm, healing uneventfully within 2 weeks. The cats

Clinical Features Nonindurated painful solitary genital ulcer Histopathologic Features Ulcer with three typical zones Surface neutrophils, erythrocytes, fibrin Middle zone of granulation tissue Deepest zone of dense plasma cells and lymphocytes Gram-negative, Giemsa-positive bacilli in “school of fish” pattern, mainly in smears Differential Diagnosis Other venereal ulcers Syphilis Herpes simplex Lymphogranuloma venereum Granuloma inguinale

 FIGURE 19-24 Cat-scratch disease. Palisading granuloma in the dermis, surrounding a necrotic focus at the site of the scratch.

and preauricular lymphadenopathy is known as Parinaud oculoglandular syndrome. HISTOPATHOLOGIC FEATURES Biopsies of some skin lesions may show palisading granulomas around necrobiotic foci (Fig. 19-24). Lymphocytes and eosinophils may surround the macrophages and multinucleated giant cells. Sometimes ulceration or epithelial hyperplasia is present. Other skin lesions show only nonspecific perivascular or lichenoid lymphoplasmacytic or neutrophilic infiltrates. The Warthin-Starry stain occasionally demonstrates the thin 0.2- to 2.5-μm rods.4 The more commonly biopsied lymph nodes show characteristic stellate microabscesses around subcapsular foci of necrosis. The necrosis becomes more extensive in older lymph nodes, and this becomes surrounded by a more granulomatous infiltrate. The nodes have also yielded positive WarthinStarry stains in some cases. DIFFERENTIAL DIAGNOSIS The palisading granulomas in the skin lesions of patients with cat-scratch disease may be confused with granuloma annulare, necrobiosis lipoidica, rheumatoid nodules, rheumatic fever nodules, foreign body granuloma, and caseating granulomatous infections such as mycobacterial and deep fungal infections. However, the clinical presentation and a careful history usually allows distinction of cat-scratch disease from the latter conditions, even if the cultures and

special stain results are negative and the skin test is not available. The suppurative granulomatous inflammation in the nodes may be confused with a wide variety of infectious diseases, especially tularemia, brucellosis, mycobacterial infections, infectious mononucleosis, yersiniosis, lymphogranuloma venereum, streptococcal and staphylococcal infections, sporotrichosis, Kawasaki disease, and even lymphoma. Mononucleosis and lymphomas tend to be bilateral. Demonstration of the organisms with Warthin-Starry silver stains is critical.

BACILLARY ANGIOMATOSIS This is an infection due to a gram-negative bacillus, most recently designated Bartonella (formerly Rochalimaea) henselae.119-126 Some cases seem to involve Bartonella quintana. Most cases have occurred in immunocompromised patients. The majority have AIDS, and the prevalence rate has been estimated to be about 1.2 cases per 1000 HIV-infected patients.123 Some patients have had leukemia or organ transplants.126 Cases have been reported rarely in immunocompetent individuals.125 Knowledge about this condition is increasing rapidly, and the naming of the infectious agents is in a state of flux.98 The organisms are related to the bacilli that cause cat-scratch disease. Despite infection by apparently the same or similar organisms, the lesions of bacillary angiomatosis are quite different from

CLINICAL FEATURES Friable grouped nodules or papules resembling pyogenic granulomas develop on the skin, sometimes after a history of a cat scratch. Lesions are often pedunculated. Some patients have presented with subcutaneous nodules, fungating masses, and hyperpigmented indurated plaques.121 Patients with AIDS usually have low CD4 counts when the lesions appear, and fever and chills are often present. Systemic dissemination may occur, which may result in death. Patients with this disease usually respond well to erythromycin and other antibiotics if they are treated in the early stages. The cure rate in HIV-infected patients is about 65%.123

CHAPTER 19 ■ BACTERIAL INFECTIONS

those of cat-scratch disease. The cat flea (Ctenocephalides felis) has been implicated as a potential vector in bacillary angiomatosis. The term bacillary angiomatosis refers to pyogenic granuloma–like vasoproliferative papules and nodules of the skin, which contain colonies of numerous organisms. The term bacillary peliosis is used when the liver or spleen is involved. Liver and lymph node involvement is mostly related to infection by B. henselae. B. quintana has been responsible for most subcutaneous, soft tissue, or bone infections.126 The GI tract, respiratory tract, bone marrow, and other organs have also been involved in bacillary angiomatosis.

HISTOPATHOLOGIC FEATURES Nodules have the low-power appearance of a pyogenic granuloma or granulation tissue, with many blood vessels and plump endothelial cells proliferating in a pale edematous stroma119,122 (Figs. 19-25 and 19-26). There are dermal or subcutaneous diffuse infiltrates of neutrophils and pale, smudgy amphophilic areas that contain the organisms (sometimes visible with H&E). Pseudocarcinomatous hyperplasia may be present. The bacilli usually are numerous and seen most easily with the Warthin-Starry, Giemsa, or GMS stain. They may also be seen with PAS and Alcian blue stains or by electron microscopy.124 PCR has also been used to demonstrate it. DIFFERENTIAL DIAGNOSIS It is important to distinguish bacillary angiomatosis from Kaposi sarcoma, which may occur in the same immunosuppressed population. A valuable clue is that the H&E-stained sections of bacillary angiomatosis usually contain smudgy amphophilic areas that contain the organisms, which later are easily demonstrated by the WarthinStarry stain. Pyogenic granulomas,

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Malakoplakia (meaning “soft plaque”) affects the GI and urinary tracts and other organs more commonly than the skin.127-129 The disease results from an inability of macrophages to adequately phagocytize bacteria. Some of the patients are on immunosuppressive therapy for lymphomas or renal transplantation. Others have underlying cancer or rheumatologic diseases. Escherichia coli is the most common offending organism, but S. aureus, Pseudomonas spp., and others have also been cultured. CLINICAL FEATURES Patients present with furuncular, tender, red nodules or papules, fluctuant abscesses or sinus tracts, or ulcers, most commonly in the groin.  FIGURE 19-25 Bacillary angiomatosis. Ulcerated pyogenic granuloma–like nodule with amphophilic smudgy stroma containing the bacilli.

 FIGURE 19-26 Bacillary angiomatosis. Warthin-Starry stain of numerous black, clumped bacilli.

HISTOPATHOLOGIC FEATURES A diffuse infiltrate of macrophages contains fine eosinophilic granules in the cytoplasm (von Hansemann cells) and small eccentric nuclei. Larger (5-15 μm) basophilic, ovoid to round phagolysosomes are also present (Michaelis-Gutmann bodies). These inclusions are positive with PAS, von Kossa, and Perl stains because they contain calcium and iron. The Gram stain also may stain bacteria within the cytoplasm of the macrophages. Partially digested bacteria may also be found in the phagolysosomes and are seen best with electron microscopy. Neutrophils, lymphocytes, and plasma cells may also be present in the infiltrate. DIFFERENTIAL DIAGNOSIS The macrophages of malakoplakia may be confused with macrophages that are digesting any nonspecific material. Parasitized macrophages are also seen with rhinoscleroma, granuloma inguinale, and histoplasmosis. Malakoplakia also has been confused with lymphoma.

PSITTACOSIS

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ordinary granulation tissue, and other vascular neoplasms may cause some confusion, but these are excluded easily as long as the index of suspicion is high enough to do the stain for organisms. The lesions of bacillary angiomatosis have some clinical similarity to the nodules of verruga peruana, which are the chronic manifestation of infection in the Andes Mountains of South America by Bartonella bacilliformis. Infection by this organism is sometimes called bartonellosis (even though Bartonella species also

cause cat-scratch disease, trench fever, and bacillary angiomatosis). The acute febrile, hemolytic phase of bartonellosis comes about 3 weeks after a bite by the sandfly Phlebotomus verrucarum and is known as Carrion disease or Oroya fever. Patients have hepatosplenomegaly, and the bacteria may be found within the erythrocytes. The verrous nodules occur 3 to 6 months later and are similar histologically to bacillary angiomatosis except that the bacteria are usually quite sparse.

Psittacosis (ornithosis) is an infection of birds caused by Chlamydia psittaci.130-133 It affects parrots (psittacines) as well as other birds. Occasionally, it can be transmitted to humans by the respiratory route, usually resulting in a fever, pneumonitis, and systemic disease. About 85% of infected humans have a history of contact with birds, but the birds themselves may be asymptomatic. The diagnosis is difficult to make and is confirmed most often serologically because the organism is difficult to culture.

Bronchoalveolar lavage with PCR analysis has been used in some cases. CLINICAL FEATURES The severity of illness varies greatly from mild to severe and may result in death. Symptoms and signs include fever, severe headache, cough, chest pain, pleurisy, pericarditis, myocarditis, epistaxis, myalgia, malaise, and hepatosplenomegaly. Cutaneous lesions are faint red macules (Horder spots), similar to the rose spots of patients with typhoid fever. Other lesions may resemble urticaria, erythema multiforme, erythema nodosum, and purpura of DIC.

DIFFERENTIAL DIAGNOSIS A wide variety of infectious diseases that cause pulmonary disease might be considered, such as mycoplasma pneumonia, Q fever, legionellosis, coccidioidomycosis, TB, and the more common bacterial and viral pneumonias.

LYMPHOGRANULOMA VENEREUM Lymphogranuloma venereum (LGV) is an uncommon venereal disease caused by Chlamydia trachomatis.103,134,135 It is five times more common in blacks and is more common in warmer climates. The diagnosis may be made by culture, serology, or PCR. The Frei intradermal skin test is no longer in general use. CLINICAL FEATURES The primary genital lesions are 2- to 3-mm papules or small erosions, often becoming grouped herpetiform ulcers (Table 19-14). Nonspecific urethritis may occur. Subsequent spread through the lymphatics results in very prominent inguinal lymphadenopathy (buboes), producing the “groove sign” when the lymph nodes are enlarged on both sides of Poupart ligament, especially in men. These nodes may eventually suppurate and drain, often subsiding within 3 months. Fibrosis of the lymphatics may cause obstruction, resulting in genital elephantiasis, rectal strictures, or fibrotic vegetating ulcerations of the pudenda

Clinical Features Multiple herpetiform genital ulcers Prominent regional lymphadenopathy Histopathologic Features Epidermis normal or ulcerated Diffuse mixed suppurative granulomatous infiltrate Differential Diagnosis Other granulomatous diseases (see Table 19-1) Other genital ulcers Herpes simplex

(esthiomene, which is Greek for “eating away”). This may be the initial presentation in women, in whom the primary skin lesions and inguinal buboes are seen less commonly. Rectovaginal fistulas in women may cause a “watering can perineum.” HISTOPATHOLOGIC FEATURES Early skin papules are nonspecific. Cutaneous ulcers are granulomatous, with many plasma cells and endothelial swelling. Occasionally, Giemsa stain may reveal the Chlamydia spp., but it is usually difficult to interpret. The histology of the lymph nodes is more characteristic than the skin lesions. Stellate microabscesses are seen, later surrounded by granulomatous inflammation with many plasma cells. Similar changes can be seen in patients with catscratch disease, tularemia, and certain deep fungal diseases. However, these conditions are not as common in the genital area. They become granulomatous in later stages. DIFFERENTIAL DIAGNOSIS Chancroid usually results in larger, more painful ulcers, but buboes are common in both disorders. They may be distinguished by positive Chlamydia cultures or serology in LGV and positive cultures or smears for H. ducreyi in chancroid. Granuloma inguinale also results in larger ulcers, which tend to develop considerable granulation tissue, without inguinal adenitis. Esthiomene may also occur in patients with granuloma inguinale, but the demonstration of Donovan bodies with the Giemsa stain is the definitive test.

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HISTOPATHOLOGIC FEATURES The histology of skin biopsies has been poorly documented in the literature. Most likely, this varies depending greatly on the type of lesion biopsied, as described under Clinical Features. The rose spots apparently show perivascular lymphoid infiltrates, as with any reactive erythema. Skin biopsies generally have not been used to make this diagnosis.

Table 19-14 Lymphogranuloma Venereum

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gating mass in an HIV-positive man. J Am Acad Dermatol. 1996;35:285-287. Amsbaugh S, Huiras E, Wang N, et al: Bacillary angiomatosis associated with pseudoepitheliomatous hyperplasia. Am J Dermatopathol. 2006;28:32-35. Granter SR, Barnhill RL: Bacillary angiomatosis. Adv Pathol Lab Med. 1993;6:491-504. Plettenberg A, Lorenzen T, Burtsche BT, et al: Bacillary angiomatosis in HIVinfected patients: an epidemiological and clinical study. Dermatology. 2000; 201:326-331. Schwartz RA, Nychay SG, Janniger CK, Lambert WC: Bacillary angiomatosis: presentation of six patients, some with unusual features. Br J Dermatol. 1997; 136:60-65. Smith KJ, Skelton HG, Tuur S, et al: Bacillary angiomatosis in an immunocompetent child. Am J Dermatopathol. 1996;18:597-600. Hoffman CF, Papadopoulos D, Palmer DM, et al: A case report of bacillary angiomatosis in a patient infected with human immunodeficiency virus. Cutis. 2002;69:175-178. Kohl SK, Hans CP: Cutaneous malakoplakia. Arch Pathol Lab Med. 2008; 132:113-117. Wittenberg PG, Douglass MC, Azam M, et al: Cutaneous malacoplakia in a patient with the acquired immunodeficiency syndrome. Arch Dermatol. 1998; 134:244-245. Kogulan PK, Smith M, Seidman J, et al: Malakoplakia involving the abdominal wall, urinary bladder, vagina, and vulva: case report and discussion of malakoplakia-associated bacteria. Int J Gynecol Pathol. 2001;20:403-406. Verweij PE, Meis JF, Eijk R, et al: Severe human psittacosis requiring artificial ventilation: case report and review. Clin Infect Dis. 1995;20:440-442. Crosse BA: Psittacosis: a clinical review. J Infect. 1990;21:251-259. Grayston JT, Thom DH: The chlamydial pneumonias. Curr Clin Topics Infect Dis. 1991;11:1-18. Green ST, Hamlet NW, Willocks L, et al: Psittacosis presenting with erythema marginatum-like lesions: a case report and a historical review. Clin Exp Dermatol. 1990;15:225-227. Rampf J, Essig A, Hinrichs R, et al: Lymphogranuloma venereum: a rare cause of genital ulcers in central Europe. Dermatology. 2004;209:230-232. Chen CY, Chi KH, Alexander S, et al: The molecular diagnosis of lymphogranuloma venereum: evaluation of a real-time multiplex polymerase chain reaction test using rectal and urethral specimens. Sex Transm Dis. 2007;34:451-455.

CHAPTER 19 ■ BACTERIAL INFECTIONS

84. Kahawita IP, Lockwood DNJ: Towards understanding the pathology of erythema nodosum leprosum. Transactions Royal Soc Trop Med Hygiene. 2008;102: 329-337. 85. Pereyra SB, Danielo CA, Ponssa GJ: Wade’s histoid leprosy: three clinical presentations. Int J Dermatol. 2007;46: 944-946. 86. Natrajan M, Katoch K, Katoch VM: Histology and immunohistology of lesions clinically suspicious of leprosy. Acta Leprol. 1999;11:93-98. 87. Dayal R, Agarwal M, Natrajan M, et al: PCR and in-situ hybridization for diagnosis of leprosy. Indian J Pediatr. 2007;74: 645-648. 88. Singh S, Sridhar MS, Sekhar PC, Bhaskar CJ: Cutaneous anthrax: a report of ten cases. J Assoc Phys India. 1992;40: 46-49. 89. Guarner J, Zaki SR: Histopathology and immunohistochemistry in the diagnosis of bioterrorism agents. J Histochem Cytochem. 2006;54:3-11. 90. Swartz MN: Recognition and management of anthrax: an update [review]. New Engl J Med. 2001;345:1621-1626. 91. Dixon TC, Meselson M, Guillemin J, Hanna PC: Anthrax. New Engl J Med. 1999;341:815-826. 92. Tutrone WD, Scheinfeld NS, Weinberg JM: Cutaneous anthrax: a concise review. Cutis. 2002;69:27-33. 93. Gallagher TC, Strober BE: Cutaneous Bacillus anthracis infection. New Engl J Med. 2001;345:1646-1647. 94. Mallon E, McKee PH: Extraordinary case report: cutaneous anthrax. Am J Dermatopathol. 1997;19:79-82. 95. Stocker JT: Clinical and pathologic differential diagnosis of selected potential bioterrorism agents of interest to pediatric health care providers. Clin Lab Med. 2006;26:329-344. 96. Burnett JW: Brucellosis. Cutis. 1995; 56:28. 97. Akcali C, Savas L, Baba M, et al: Cutaneous manifestations in brucellosis: a prospective study. Adv Ther. 2007;24: 706-711. 98. Walker DH, Barbour AG, Oliver JH, et al: Emerging bacterial zoonotic and vector-borne diseases: ecological and epidemiological factors. JAMA. 1996; 275:463-469. 99. Inglesby TV, Dennis DT, Henderson DA, et al: Plague as a biological weapon: medical and public health management. JAMA. 2000;283:2281-2290. 100. Ikeya T, Mizuno E, Takama H: Three cases of erythema nodosum associated with Yersinia enterocolitica infection. J Dermatol. 1986;13:147. 101. Butler T: Yersinia infections: centennial of the discovery of the plague bacillus. Clin Infect Dis. 1994;19:655-661.

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CHAPTER 20 Treponemal and Rickettsial Diseases

PART III ■ INFECTIONS

A. Neil Crowson Cynthia M. Magro J. Stephen Dumler Grace F. Kao Raymond L. Barnhill

Infections with treponemes and rickettsial organisms can produce a broad array of clinical manifestations, ranging from seemingly trivial viral-like illnesses to fulminant progressive disease. Recognition of these infections often requires correlation of a comprehensive travel and medical history with a detailed knowledge of the clinical and pathologic features of each.

endemic syphilis, yaws, and pinta.2 The use of polymerase chain reaction (PCR) methodologies and restriction polymorphism analysis has allowed the identification of at least 27 distinct strains of pathogenic treponemal species by 1997; a single genetic signature in the 59 and 39 flanking regions of the 15-kDa lipoprotein gene tpp15 distinguished the venereal and nonvenereal treponematoses in one study.3 Other studies have shown an 87% sequence homology of an open reading frame gene (tprJ) between the treponemes causing syphilis and yaws.4 The evidence suggests that these organisms have evolved from a common ancestor to cause different diseases in the modern era.5 In addition to certain highly conserved domains, ample size and sequence heterogeneity are demonstrable in other treponeme genes such as those that control expression of the TprK antigen, a target of opsonizing antibodies and thus important to host immune protection; such variances may play a role in evasion of the host response.6 Recently, the role of oral treponemes in the causation of periodontitis has been explored.7-9

TREPONEMAL DISEASES Treponemal diseases are caused by bacteria of the family Spirochaetaceae. The pathogenic treponemes measure 6 to 20 by 0.10 to 0.18 μm, are coiled with regular periodicity, and react with silver stains in dark-field and biopsy material1 (Fig. 20-1). The nonvenereal treponematoses are

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Venereal Syphilis CLINICAL FEATURES Venereal syphilis, caused by Treponema pallidum, was a significant cause of morbidity and mortality in the early twentieth century, although its incidence in the developed world has so diminished that many physicians are

 FIGURE 20-1 Primary syphilitic chancre. A silver stain (Steiner) reveals elongated coiled spirochetes from 8 to 12 μm in length in a perivascular distribution.

now unfamiliar with its manifestations.1 The incidence of acquired syphilis increased in the 1980s to 20 per 100,000 in North America.1 New diagnoses of syphilis increased eightfold in the United Kingdom between 1997 and 2002.10 By 2003, more than 60% of all reported cases of syphilis were believed to occur in men who have had sex with men.11 Spread of T. pallidum usually occurs by contact between an infectious lesion and disrupted epithelium, either at sites of trauma incurred during sexual intercourse or at sites of concurrent chancroid and other genital sores.12-18 Coinfection with human immunodeficiency virus (HIV) is common,12,16 particularly in parts of Africa, where the incidence is up to 360 per 100,000,12,17,18 and the transmission rate is up to 60%. The initial lesion of primary syphilis, the chancre, presents approximately 21 days after exposure at the inoculation site, as a painless, brown-red, indurated papule, nodule, or plaque up to 2 cm in diameter, in which organisms are identifiable. Multiple lesions or regional lymph node enlargement may be seen. After hematogenous dissemination of organisms, secondary syphilis occurs, resulting in widespread disease, with constitutional symptoms such as fever and malaise1,17; generalized lymphadenopathy1,19; and a disseminated eruption of red-brown macules, papules, papulosquamous lesions resembling guttate psoriasis, and rarely, pustules.20 Follicular-based annular or serpiginous lesions may be seen, particularly in recurrent attacks. Alopecia, condyloma lata comprising confluent gray papules in anogenital areas, pitted hyperkeratotic palmoplantar papules (syphilis cornee), or in severe cases, ulcerative lesions of lues maligna, may develop. Shallow, painless ulcers sometimes are seen in mucosal surfaces. Primary- and secondary-stage lesions that resolve without therapy may herald evolution into a latent phase, consisting of an early and late stage, and defined by an infection of less than or more than 1 year’s duration.17 After a variable latent period, the patient enters the tertiary stage. Tertiary syphilis encompasses gummatous skin and mucosal lesions, termed benign tertiary syphilis as well as cardiovascular and neurologic manifestations. Skin lesions are solitary or multiple and consist of superficial nodular and deep gummatous subtypes, the former having smooth, atrophic centers with raised, serpiginous borders, and the latter manifesting as ulcerative subcutaneous swellings21 (Tables 20-1 and 20-2).

Table 20-1 Primary Syphilis

Congenital syphilis arises through transplacental infection and affects more than 50% of infants born to mothers with primary or secondary syphilis.22 The diagnosis is made when organisms are seen by dark-field, fluorescent antibody, or conventional histochemical

Table 20-2 Secondary and Tertiary Syphilis

Clinical Features Secondary Fever Generalized lymphadenopathy Disseminated macular or papulosquamous eruption Occasionally alopecia, pustules, hyperkeratotic palmoplantar pits, ulcers Tertiary Gummatous skin and mucosal lesions Solitary or multiple nodules Ulcerative subcutaneous lesions Cardiovascular disease Syphilitic large-vessel aneurysms Neurologic disease Tabes dorsalis Meningoencephalitis Histopathologic Features Psoriasiform hyperplasia Rare spongiform pustulation Vacuolar or lichenoid interface injury pattern Mixed lymphohistiocytic and plasmacellular infiltrate Granulomata Obliterative endovasculopathy Differential Diagnosis Lichenoid dermatitides Psoriasiform dermatitides Tuberculoid leprosy Sarcoidal granulomatous dermatitides

HISTOPATHOLOGIC FEATURES Cutaneous syphilis manifests as a perivascular infiltrate composed of lymphoid cells and often plasma cells. The late secondary and tertiary stages also show infiltrates of epithelioid histiocytes and giant cells. In all stages, endothelial swelling and proliferation are apparent. Autopsy studies on newborns with congenital syphilis show multiorgan involvement by an angioinvasive CD68-+ve mononuclear cell infiltrate that imparts an “onion skin” morphology to involved vessels. Numerous spirochetes are usually detectable.24 Most HIV-infected patients exhibit a normal serologic response to T. pallidum infection; however, in some HIV-positive patients with biopsy-proven secondary syphilis, both treponemal (FTA-ABS,

MHA-TP, HATTS) and nontreponemal (VDRL, RPR) test results for syphilis have been reported as negative.25 The diagnosis of syphilis in seronegative HIV-infected patients depends on darkfield microscopy and histopathology of lesional biopsy tissue, with demonstration of spirochetes by silver stains (WarthinStarry, Steiner) or direct fluorescent antibody for T. pallidum (DFA-TP).26

Primary Syphilis The primary syphilitic chancre manifests a variable histopathology, depending on whether the center or edge is biopsied; the center is often ulcerated, and the edges show acanthosis, spongiosis, and exocytosis of lymphocytes and neutrophils (Fig. 20-2). The papillary dermis is edematous, and a dense dermal perivascular and interstitial lymphohistiocytic and plasmacellular infiltrate is present, often accompanied by neutrophils. An obliterative endarteritis, characterized by endothelial swelling and mural edema (Fig. 20-3), completes the picture. With silver stains or immunofluorescent techniques, spirochetes are usually seen within and around blood vessels and along the dermal–epidermal junction.26 In their full length, the spirochetes show 8 to 12 spiral convolutions, each roughly 1 μm in length (see Fig. 20-1). In evaluating biopsy specimens, histochemical stains, Warthin-Starry silver stains, and Steiner silver stains must be interpreted with caution because in addition to spirochetes,

 FIGURE 20-2 Primary syphilitic chancre. The epithelium is eroded, with a neutrophilic infiltrate centrally and psoriasiform hyperplasia laterally. The corium contains a dense plasma cell–rich infiltrate.

CHAPTER 20 ■ TREPONEMAL AND RICKETTSIAL DISEASES

Clinical Features Painless papulonodular lesion Develops 21 days after exposure Lymphadenopathy in some cases Histopathologic Features Frequent central ulceration Lateral psoriasiform hyperplasia Dense lymphoplasmacellular infiltrate Obliterative endovasculopathy Differential Diagnosis Chancroid Zoon balanitis Insect-bite reaction Granuloma inguinale

methods.22 A presumptive case includes any infant born to a mother whose syphilis was inadequately treated or untreated at the time of birth or when an infant or child with a reactive treponemal test has any evidence of congenital syphilis, including physical signs, longbone involvement radiologically, a reactive cerebrospinal fluid (CSF) Venereal Disease Research Laboratories (VDRL) test, an elevated CSF protein or white blood cell count, or quantitative treponemal titers four times higher than the mother’s.22-24 Clinical signs include rhinitis, chancres, or a desquamative maculopapular rash.22-24

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PART III ■ INFECTIONS

 FIGURE 20-3 Primary syphilitic chancre. Endarteritis obliterans appears as endothelial cell swelling, endothelial hyperplasia and expansion of vessel walls by edema, and a lymphohistiocytic infiltrate with luminal attenuation. Plasma cells are present.

other structures and artifacts may be mistaken as T. pallidum. Silver stains also decorate melanin and reticulin fibers, which must be differentiated based on recognition that melanin in the dendritic processes of melanocytes has a granular appearance27 and that reticulin fibers, although wavy, do not have a spiral architecture. Correlation with serology is prudent.

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DIFFERENTIAL DIAGNOSIS Chancroid, due to infection with Haemophilus ducreyi, is difficult to distinguish clinically from the syphilitic chancre. Chancroid lesions show dense lymphohistiocytic infiltrates with a paucity of plasma cells, granulomatous vasculitis, and an epidermal reaction pattern similar to the syphilitic chancre, consisting of psoriasiform epidermal hyperplasia and spongiform pustulation.12 A Giemsa, Alcian blue, or periodic acid-Schiff stain reveals coccobacillary forms between keratinocytes and along the dermal–epidermal junction. Spirochetes may coinfect chancroid lesions.12 Whereas Zoon balanitis may mimic those chancres, manifesting a lichenoid pattern of plasma cell-rich inflammation, and an insect bite reaction may resemble the ulcerative lesions of primary syphilis; neither lesion will show spirochetes. Granuloma inguinale is distinctive by virtue of manifesting Donovan bodies.

Secondary Syphilis In secondary syphilis, skin biopsies generally reveal variable epithelial alterations in the macular, papular, and papulosquamous eruptions, the latter showing the most pronounced psoriasiform epidermal hyperplasia. All may show spongiosis and basilar vacuolar alteration, sometimes with colloid body formation, exocytosis of lymphocytes, spongiform pustulation, and parakeratosis.27,28 Patchy or confluent parakeratosis may be present, sometimes accompanied by intracorneal neutrophilic abscesses, the latter mimicking psoriasis but lacking attenuation of the suprapapillary plates. Ulceration is not a feature, except in patients with lues maligna. Dermal changes include papillary dermal edema and perivascular and periadnexal lymphocyte- or histiocytepredominant infiltrates that may be frankly granulomatous in lesions older than 4 months of age. Infiltrates show greatest density in the papillary dermis and diminish in the reticular dermis. The papillary dermal infiltration may be lichenoid in character (Fig. 20-4), obscuring the superficial vasculature; or a cell-poor injury pattern may predominate. Atypical lymphoid forms, representing a type of lymphomatoid hypersensitivity, may suggest the possibility of mycosis fungoides29 or non-Hodgkin lymphoma.

A neutrophilic eccrine hidradenitis may be seen.27 Plasma cells are inconspicuous or absent in 25% of patients.28 Eosinophils are usually absent. Endothelial cell swelling and mural edema are seen in only 50% of patients,28 and mural necrosis is rare. Silver stains show spirochetes in only one-third of patients30 and are best visualized within the epidermis and around the superficial blood vessels; with immunofluorescent microscopy, however, all patients are positive. Histologic variants of secondary syphilis include condylomata lata, lues maligna, syphilis cornee, syphilitic alopecia, and pustular and bullous lesions.17 Condylomata lata show the aforementioned features of secondary syphilis; although epithelial hyperplasia is more pronounced, intraepithelial microabscesses are observed,20,31 and treponemes are more numerous.30 Lues maligna is an ulcerative form consisting of endarteritis obliterans of deep vessels at the dermal–subcutaneous junction, with attendant ischemic necrosis and a dense plasmacellular and histiocytic infiltrate. Defective cell-mediated immunity may play an integral role,32,33 as suggested by the occurrence of lues maligna in the setting of HIV infection, in which oral involvement may be a prominent feature.17 The histopathology of syphilis cornee and keratoderma punctatum includes epidermal invagination with a plug of laminated parakeratin, loss of the adjacent granular cell layer, thinning of the stratum spinosum,34 and a moderately dense perivascular plasma cell infiltrate with capillary wall thickening. Syphilitic alopecia shows a superficial and deep perivascular and perifollicular lymphocytic and plasma cell infiltrate, with permeation of outer root sheath epithelium; perifollicular fibrosis27; an involutional tendency with increased numbers of telogen hairs; and in some cases, a necrotizing pustular follicular reaction,20 as also characterizes the rare entity of pustular secondary syphilis.20 A bullous variant of secondary syphilis has also been described.35 There is considerable overlap between cases of secondary and tertiary syphilis because small sarcoidal granulomata in papular lesions of secondary syphilis may progress to extensive lymphoplasmacellular and histiocytic infiltrates resembling nodular tertiary syphilis; lesions of early tertiary syphilis may lack granulomata.36-38 DIFFERENTIAL DIAGNOSIS Other causes of lichenoid dermatitis—namely, lichen planus, lichenoid hypersensitivity reactions, pityriasis lichenoides, connective tissue disease, sarcoidosis, psoriasis, and

infiltrates are often noted in patients with lichenoid hypersensitivity reactions and psoriasiform drug reactions.

Tertiary Syphilis

A

NONVENEREAL TREPONEMATOSES

Yaws (Frambesia Tropica)

B  FIGURE 20-4 Secondary syphilis. (A) Multiple papulosquamous lesions on the soles. (B) Psoriasiform epidermal hyperplasia is accompanied by edema and exocytosis of lymphocytes. A bandlike lymphoplasmacellular dermal infiltrate is present.

psoriasiform drug eruptions27—may all resemble syphilis. Prominent spongiosis, suprabasilar dyskeratosis, deep perivascular inflammation, and plasma cells are not characteristic of lichen planus or psoriasis. A mid-dermal perivascular

infiltrate, keratinocyte necrosis, and pronounced lymphocytic exocytosis characterize pityriasis lichenoides, but the infiltrate is purely lymphocytic, and spongiform pustulation is not seen. Tissue eosinophilia and plasma cell

Yaws, which is caused by T. pallidum pertenue, is spread by casual contact between primary or secondary lesions and abraded skin; yaws classically affects the buttocks, legs, and feet of children and is most prevalent in warm, moist tropical climates. Seropositivity rates of up to 95% are seen in areas of Ecuador.39 T. pallidum pertenue is indistinguishable microscopically from T. pallidum pallidum but is distinctive by Southern blot analysis40 and by other molecular methods, as discussed earlier.4,5 Despite only minor sequence variation between the organisms, there are distinct differences between disease expressions of yaws and syphilis. For example, infants born to mothers with yaws do not produce IgM antibodies, and their organs, when examined by PCR methods and by animal inoculation studies, do not contain the spirochete.5 These findings emphasize the dermotropic, as opposed to organotropic, character of T. pallidum pertenue.5

CHAPTER 20 ■ TREPONEMAL AND RICKETTSIAL DISEASES

Tertiary syphilis includes nodular tertiary syphilis confined to the skin; benign gummatous syphilis principally affecting skin, bone, and liver; cardiovascular syphilis; neurosyphilis; and syphilitic hepatic cirrhosis. In nodular tertiary syphilis, granulomas are small and limited to the dermis, in which scattered, nested epithelioid cells are intermingled with a few multinucleated giant cells and lymphoid and plasma cells. Granulomata may be absent,38 and necrosis is not conspicuous. The vessels may show endothelial swelling.33 Benign gummatous syphilis shows granulomatous inflammation with central zones of acellular necrosis in involved organs; in the skin, blood vessels throughout the dermis and subcutis manifest endarteritis obliterans, with variable angiocentric plasma cell infiltrates.17

Primary Yaws An erythematous papule, or mother yaw, is seen roughly 21 days after inoculation and enlarges peripherally to form a 1- to 5-cm nodule, with an amber crust and adjacent satellite pustules. Lesions heal as pitted,

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hypopigmented scars. Fever, arthralgia, or lymphadenopathy may coexist.41

PART III ■ INFECTIONS

Secondary Yaws Progression to the secondary stage is characterized by involvement of skin, bones, joints, and cerebrospinal fluid. Skin lesions, or daughter yaws, resemble the mother yaw but are smaller and more numerous. Although periorificial lesions may resemble venereal syphilis, a circinate appearance may mimic fungal infection, hence the designation Tinea yaws. A morbilliform eruption may occur, as may condylomatous vegetations involving the axillae and groin. Macular, hyperkeratotic, and papillomatous lesions may be seen on palmoplantar surfaces and may cause the patient to walk with a painful, crablike gait, designated crab yaws.41 Pianic onychia are papillomatous nail fold lesions.41 Relapsing cutaneous disease occurs for up to 5 years and tends to involve periorificial and periaxillary sites.

Tertiary Yaws In tertiary yaws, skin manifestations include subcutaneous abscesses, coalescing serpiginous ulcers, keloids, keratoderma, and palmoplantar hyperkeratosis. The bone and joint manifestations include osteomyelitis, hypertrophic or gummatous periostitis, and chronic tibial osteitis. Obstructive hypertrophy of the nasal maxillary processes produces the rare but characteristic goundou.41 Another otorhinolaryngologic complication, termed gangosa, consists of nasal septal or palatal perforation. Macular atrophy and culturepositive aqueous humor suggest that yaws may exhibit neurophthalmologic manifestations. In lower-prevalence areas, a less virulent form of the disease termed attenuated yaws manifests as greasy gray lesions in the skin folds.17,41

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HISTOPATHOLOGIC FEATURES Primary lesions show epidermal acanthosis, papillomatosis, spongiosis, and neutrophilic exocytosis with microabscesses. A diffuse dermal infiltrate of plasma cells, lymphocytes, histiocytes, and granulocytes is seen, which, unlike syphilis, is associated with little or no endothelial proliferation42,43 (Fig. 20-5). A similar histopathology characterizes secondary lesions, which resemble condylomata lata in their epidermal changes but differ by virtue of a diffuse, as opposed to a perivascular, dermal infiltrate (Fig. 20-6). The ulcerative lesions of tertiary yaws histologically resemble those of late syphilis.42 Spirochetes are demonstrated in primary and secondary lesions by dark-field examination and between

 FIGURE 20-5 Yaws, the primary lesion. The biopsy shows psoriasiform epidermal hyperplasia, with an intense lymphohistiocytic and plasma cell infiltrate in the corium.

keratinocytes with silver stains, although unlike T. pallidum, which is also found in the dermis, T. pertenue is almost entirely epidermotropic.43

DIFFERENTIAL DIAGNOSIS The distinction of yaws from syphilis is based on clinical features,44 although localization of the organism in a skin biopsy may be helpful.

 FIGURE 20-6 Yaws, the primary lesion. The biopsy shows an intense angiocentric and diffuse lymphohistiocytic and plasma cell infiltrate.

Pinta

HISTOPATHOLOGIC FEATURES The features of primary and secondary lesions are similar, showing acanthosis; spongiosis; and a sparse dermal infiltrate of lymphocytes, plasma cells, and neutrophils clustered about dilated blood vessels that do not manifest endothelial swelling.46 Lichenoid inflammation, with attendant hyperkeratosis, hypergranulosis, basal layer vacuolopathy, and pigmentary incontinence, may be seen. Tertiarystage lesions show either postinflammatory hyperpigmentation or are depigmented, manifesting complete absence of epidermal melanin; epidermal atrophy and perivascular lymphocytic infiltrates are seen in both. Organisms are seen in all but long-standing lesions.

Endemic Syphilis (Bejel) Endemic syphilis, or bejel, is thought to affect about 2.5 million people.2,47 Caused by T. pallidum endemicum, bejel is largely confined to the arid Arabian peninsula and the southern border of the Sahara Desert,45 where children are the principal reservoir for a disease spread by skin-to-skin contact or via fomites such as communal pipes or drinking vessels. The rare primary-stage skin lesions

HISTOPATHOLOGIC FEATURES The pathology of early lesions of endemic syphilis is not well described, although late lesions are said to show parakeratosis, acanthosis, spongiosis, pigmentary incontinence, and a dermal lymphohistiocytic and plasma cell infiltrate.

Lyme Disease Named after the town of Lyme, Connecticut, where it was first encountered in 1975,48 Lyme disease is caused by the spirochete Borrelia burgdorferi and transmitted by Ornithodoros49 ticks, with Ixodes dammini being the prototypical vector.49,50 Lyme borreliosis is now the most prevalent vector-borne disease in North America, Europe, and Asia, and it has also been reported in Africa.51,52 The United States had roughly 20,000 new cases in 2005.53 Mosquitoes and soft ticks have been shown to be incapable of transmitting the etiologic agent in Europe.54 Of emerging importance is the issue of infection by multiple different species transmitted by the same infected tick. In particular, coinfection of ticks and humans by Ehrlichia chaffeensis, the etiologic agent of human granulocytic ehrlichosis, and by B. burgodorferi, is demonstrable in areas where the two diseases are endemic.55-57 Formerly, such coinfections were thought to reflect spurious or

cross-reacting seropositivities, and fortuitously, both organisms respond to the same antibiotics.58,59 Another tick-borne infection, babesiosis, can also be coexpressed with Lyme disease.57,60 The index patients showed inflammatory arthritis and central nervous system and cardiac symptoms61 preceded by cutaneous erythema. Stage I (early) Lyme disease occurs when hematogenous dissemination from skin lesions of erythema chronicum migrans causes self-limited orchitis, splenomegaly, lymphadenopathy, and mild pneumonitis.62 Neural and cardiac involvement, the latter showing tachycardia and heart blocks due to epiand transmyocarditis, characterize stage II.52,62 Neural involvement includes the classic triad of meningitis, cranial neuritis, and radiculoneuritis.63 Lyme cerebritis may also occur, and alteration of mental status may be the only initial clinical manifestation.64 Stage III Lyme disease involves chronic disease at sites where spirochetes persist, namely, the skin, nervous system, and musculoskeletal system.64,65 The latter encompasses findings typical for any reactive arthropathy syndrome, specifically synovitis and migratory oligoarthritis involving the knee, shoulder, wrist, and temporomandibular and ankle joints.52,62,65

Stage I Lyme Disease—Erythema Chronicum Migrans Erythema chronicum migrans, the distinctive cutaneous manifestation of stage I Lyme disease,66,67 affects the site of inoculation. In the absence of a rash, the diagnosis depends on the demonstration of an antibody response to B. burgdorferi in an appropriate clinical setting.68 Patients who are immunosuppressed, such as those with underlying lymphoproliferative diseases, may never mount a detectable antibody response.69 Patients are often unaware of the frequently painless tick bite.70 Recurrences after appropriate antimicrobial therapy have been reported, although it appears that most of these recurrences represent second tick bite inoculations as opposed to relapses.71 Although it seems counterintuitive, one model suggests that certain animals, such as the lizard Eumeces fasciatus (the fivelined skink), may act as a dilutional host, whereby reservoir incompetence may act to reduce vector infection prevalence and the associated risk of human infection.72 Beginning as an area of scaly erythema or a red papule 3 to 30 days after the tick bite, lesions spread peripherally with central clearing and may reach a diameter of 25 cm.73 Presentations may be atypical

CHAPTER 20 ■ TREPONEMAL AND RICKETTSIAL DISEASES

Involvement in pinta, caused by T. carateum, is restricted to the skin,45 with hypopigmentation being the only significant sequela. Endemic to Central America, pinta is not observed outside the western hemisphere, affects no age group preferentially, is the mildest of the treponematoses, and is declining precipitously in incidence for unknown reasons. Transmission appears to be from lesion to skin, usually between family members.45 The primary lesion, an erythematous papule surrounded by a halo, occurs 1 to 8 weeks after inoculation and may expand by direct extension or through fusion of satellites to form an ill-defined plaque up to 12 cm in diameter on the legs or other exposed sites. The primary lesion in infants classically occurs where the baby was closely held by the affected mother. The secondary lesions, which bear the unfortunate and misleading appellation pintids, manifest months after inoculation as small, erythematous, scaly papules and psoriasiform plaques, and are, like the primary lesions, highly infectious. In the tertiary stage, hypopigmented macules are present over bony prominences, wrists, ankles, and elbows. Symmetric areas of achromia alternate with areas of normal or hyperpigmented, atrophic, or hyperkeratotic skin.

consist of erythematous papules or ulcers of the oropharyngeal mucosa or the skin of the nipple of an uninfected mother nursing an infected infant. The more common initial manifestations are secondary-stage lesions, which are multiple shallow, painless ulcers involving the lips, buccal mucosa, tongue, fauces, or tonsils. Such lesions may be accompanied by hoarseness due to treponemal laryngitis, regional lymphadenopathy, and condylomata lata involving the axillae and anogenital areas. Rarely, the initial presentation may include erythematous, crusted papules, macules, or annular papulosquamous lesions accompanied in some patients by generalized lymphadenopathy or periostitis. The tertiary stage appears as gummatous lesions of the nasopharynx, larynx, skin, and bone that may progress to ulcers that heal as depigmented, sometimes geographic scars with peripheral hyperpigmentation. Bone and joint involvement appears as tibial periostitis mimicking yaws or as destructive lesions of the nasal septum and palate.17,45 Ophthalmologic complications include uveitis, chorioretinitis, choroiditis, and optic atrophy.

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by virtue of showing purpuric, vesicular, or linear lesions. Although lesions typically last for 4 weeks, they may persist for up to 1 year and may be solitary or multiple, the latter reflecting hematogenous dissemination of the spirochete, often with concomitant fever, fatigue, headache, cough, and arthralgia.49 HISTOPATHOLOGIC FEATURES Skin biopsies show superficial and deep angiocentric, neurotropic, and eccrinotropic lymphocytic infiltrates, often accompanied by plasma cells and eosinophils, the former at the periphery and the latter in the center of lesions.67 The dermal alterations may be accompanied by spongiotic epithelial changes (Fig. 20-7), and some cases show edema of blood vessels, transmural migration of lymphocytes and plasma cells, granulomatous vasculitis with luminal thrombosis, lymphohistiocytic neuritis, and interstitial reticular dermal infiltrates with an associated sclerosing reaction.17 The histomorphology varies according to the part of the lesion biopsied: whereas a florid inflammatory cell infiltrate with granulomatous vasculitis and neuritis is seen at the tick bite punctum, a biopsy taken within 1 cm of the edge shows a pauci-inflammatory process with only sparse mononuclear

cells; no eosinophils or plasma cells; and a vasculopathy consisting of endothelial swelling, hyperplasia, and mural edema accompanied by mucinosis74 (Fig. 20-8). Biopsies taken between these two sites show the superficial and deep perivascular lymphocytic, plasma cell, and eosinophilic infiltrate, with variable eczematous alterations described in most histopathology textbooks.17 Although spirochetes have been identified, primarily from the lesional border, in only 40% of patients,67 most patients manifest elevated IgM antibody titers,66 and we and others tend to rely heavily on serology in making the diagnosis.75 The contrary view is that the diagnosis at this stage is largely a clinical one due to the incidence of false-positive and false-negative results.76 It is true that the laboratory diagnosis of Lyme disease remains difficult because the sensitivity and specificity of confirmatory molecular tests are not optimal and culture is insensitive.75,77 The background high seropositivity rates in healthy patients in endemic and nonendemic areas has prompted a two-tiered approach in which seropositive patients undergo a subsequent and more specific Western blot analysis.78,79 Meta-analysis of available molecular methods shows that assays of

skin and synovial fluid have the highest sensitivities and specificities, and those of plasma and CSF have the lowest.77 The application of quantitative PCR methods to the skin lesion of erythema chronicum migrans showed positivity in 80% of patients in one study, with the mean number of spirochetes in 2-mm biopsy specimens ranging from 10 to 11,000; the larger numbers of spirochetes correlated with smaller skin lesions and with shorter duration of skin symptomatology.80 Molecular assays for Lyme disease are best reserved as complementary or confirmatory tools in patients in whom the index of suspicion is high.77 DIFFERENTIAL DIAGNOSIS From the clinical perspective, the differential diagnosis encompasses other forms of annular erythema.81 The differential diagnosis histologically includes other arthropod infestations, drug hypersensitivity, contact reactions, and connective tissue diseases (eg, lupus erythematosus, scleroderma, morphea, Sjögren syndrome, mixed connective tissue disease, relapsing polychondritis). Although tissue eosinophilia and epidermal changes help discriminate Lyme disease from connective tissue disease, differentiation from erythema annulare centrifugum may be impossible. Rare cases manifest tissue necrosis at the primary inoculation site thus mimicking a brown recluse spider bite.82

Stage III Lyme Disease—Dermal Atrophying and Sclerosing Lesions

452

 FIGURE 20-7 Erythema chronicum migrans. Epidermal spongiosis with vesicle formation overlies a dermis showing a sparse nonspecific perivascular lymphocytic infiltrate.

Acrodermatitis chronica atrophicans often appears as diffuse or localized erythema on one extremity, with a “doughy” consistency of the dermis that progresses over months to atrophy; vessels and subcutaneous tissue may become visible to the naked eye.83 Appendage structures may disappear, causing hair loss and hypohidrosis. Located mainly near joints of the upper and lower extremities, sparing the palms, soles, face, and trunk,84 late-stage lesions may show sclerosis in the form of pseudosclerodermatous plaques over the dorsa of the feet, linear fibrotic bands over ulnar and tibial surfaces, or localized fibromas (termed juxtarticular nodes).17,83 Serology is uniformly positive at this stage, and patients often show an elevated erythrocyte sedimentation rate or hypergammaglobulinemia. Other atrophying and sclerosing disorders associated with Lyme disease include anetoderma, atrophoderma of Pasini and Pierini, facial hemiatrophy of PerryRomberg, lichen sclerosus et atrophicus,

combination of cutaneous atrophy with a plasma cell infiltrate should prompt consideration of acrodermatitis chronica atrophicans.

Lymphocytoma Cutis and Malignant Lymphoma

eosinophilic fasciitis, and morphea.17,85,86 In facial hemiatrophy, the skeletal muscle becomes atrophic, with loss of striations, edema, and vacuolation. Ocular and neurologic complications may include iritis, keratitis, optic nerve atrophy, trigeminal neuralgia, and facial palsy.52 HISTOPATHOLOGIC FEATURES The epidermis appears atrophic, with loss of retia and diminution of the granular layer, often surmounted by a keratotic scale. A cell-poor lymphocytic interface dermatitis with vacuolar basal layer degeneration and variable postinflammatory pigmentary alterations ranging from leukoderma to hyperpigmentation is noted in 50% of patients. The papillary dermis shows edema that progresses to eosinophilic homogenization,85,87 accompanied in some cases by a bandlike lymphocytic infiltrate, that may obscure the dermal–epidermal junction in a lichenoid fashion or may show an angiocentric and adnexotropic localization extending to involve the subcutis.83 Eosinophils, neutrophils, and plasma cells may contribute to the inflammatory process.88 Blood vessels, collagen fibers, and elastic tissue may be effaced.88 Endstage lesions show telangiectasia, adnexal atrophy, degenerated or eosinophilic collagen, basophilic fragmented elastic fibers,88 and lipoid phanerosis.87 With respect to the other atrophying disorders, all show a variable sclerodermoid tissue reaction with adnexal atrophy and subcutaneous fibrosis. The histopathology of aneto-

derma, an elastolytic disorder, is discussed elsewhere. DIFFERENTIAL DIAGNOSIS Histologic similarities may be seen between acrodermatitis chronica atrophicans and lupus erythematosus and lichen sclerosus. The

HISTOPATHOLOGIC FEATURES There is a dense nodular or diffuse folliculotropic, eccrinotropic, and neurotropic pandermal infiltrate of small lymphocytes with a variable admixture of immunoblasts, eosinophils, and plasma cells (Fig. 20-9). Germinal centers may be observed, and

 FIGURE 20-9 Lyme disease. Borrelioma: a nodular dermal infiltrate consisting predominatly of small lymphocytes.

CHAPTER 20 ■ TREPONEMAL AND RICKETTSIAL DISEASES

 FIGURE 20-8 Erythema chronicum migrans. A biopsy taken 1 cm inside the advancing lesional rim shows endothelial swelling and dermal mucinosis, with a nonspecific, sparse perivascular lymphocytic infiltrate (Alcian blue).

Lymphocytoma cutis is a benign cutaneous lymphoid hyperplasia ascribed to triggering factors, including drugs, contactants, and infections, implicating an excessive immune response to antigen as its etiologic basis. The demonstration of spirochete-like structures in patients with lymphocytoma cutis who are seropositive for antibodies to Borrelia subspecies is presumptive evidence of a causal relationship.89 The lesions are designated borreliomas and appear clinically as solitary or multiple violaceous nodules and infiltrative plaques with a predilection for the earlobes, nipples, and areolae. Lesions may occur at sites of erythema chronicum migrans or in patients with stage II Lyme disease.17 Malignant lymphoma has also been described.90

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a grenz zone of papillary dermal sparing is characteristic.

454

DIFFERENTIAL DIAGNOSIS Other infections, particularly those due to herpes or mycobacteria, and reactions to insect bites, drugs,91 and contactants, mimic nodular borrelial lymphocytoma cutis, and well-differentiated lymphocytic lymphoma and chronic lymphocytic leukemia mimic the diffuse variant. The presence of eosinophils, plasma cells, and germinal centers enables distinction from malignant lymphoma in some cases, with two notable caveats: the proliferation centers of low-grade lymphoproliferative disease, which mimic germinal centers at low-power microscopy, and the presence of a superficial lymphocytoma cutis pattern overlying an area of malignant lymphoma.

RICKETTSIAL INFECTIONS Rickettsial infections include Rocky Mountain spotted fever (RMSF), rickettsialpox, typhus, scrub typhus, and ehrlichioses. Rickettsiae are obligate intracellular bacteria that are transmitted to humans from infected arthropods.92 Four genera contain significant pathogens: Rickettsia, Orientia, Ehrlichia, and Anaplasma spp. Members of the Rickettsia genus include Rickettsia rickettsii, which causes RMSF; R. conorii, which causes Mediterranean spotted fever or boutonneuse fever; R. africae, which causes African tick bite fever; R. parkeri, which causes Maculatum disease; R. akari, which causes rickettsialpox; R. typhi, which causes murine or endemic typhus; and R. prowazekii, which causes epidemic typhus. Rickettsia species infect and damage endothelial cells, leading to cutaneous and systemic lymphohistiocytic vasculitis, the hallmark and major pathogenetic lesion of vasculotropic rickettsioses. The rickettsial disease of greatest importance in the United States is RMSF,93 which is acquired after the bite of infected Dermacentor subspecies ticks. The next most prevalent vasculotropic rickettsiosis in the United States is flea-borne murine typhus.94 Orientia tsutsugamushi is the etiologic agent of scrub typhus, another vasculotropic rickettsiosis, that occurs predominantly in Asia and is transmitted by larval mites.95-98 Ehrlichia and Anaplasma species that are human pathogens infrequently cause reproducible and characteristic skin lesions; the cutaneous pathology and pathogenesis of these infections are unclear. CLINICAL FEATURES The vasculotropic rickettsioses share many clinical features.

RMSF is a severe febrile illness, usually associated with headaches and rash, that occurs after a tick bite.93,99 The predominant early lesions are blanching macules and papules that may develop into nonblanching petechiae or purpura as the illness progresses (Table 20-3). The eruption typically occurs between the third and fifth days of the illness. These lesions may occur on any cutaneous surface, including the palms and soles, but are observed most frequently on the extremities and trunk. The degree of cutaneous involvement is highly variable and sometimes transient; approximately 10% to 15% of infected patients do not develop a rash.100 When present, the lesions may measure from less than 1 mm in diameter to large and irregular confluent purpuric lesions, many centimeters in size. Rickettsialpox is associated with papulovesicles, but frequently, infected patients also present with macules and papules. Petechial and purpuric lesions are less frequent with rickettsialpox and murine typhus than with RMSF.94,100,101 The site of the vector bite is rarely identified in RMSF, but is frequently identified in Mediterranean spotted fever, rickettsialpox, maculatum disease, and scrub typhus. The site often develops into a dark necrotic eschar between several millimeters and 1 cm in diameter.92,101-103 The incidence of RMSF has increased from 3.3 cases per million population in 1996 to 6.6 cases per million in 2005.104 The annual case fatality

Table 20-3 Rickettsial Infections: Rocky Mountain Spotted Fever

Clinical Features Fever Headache History of tick bite or exposure Macular, maculopapular, or petechial rash may be focal or diffuse Rash occurs approximately 3 to 7 days after onset of fever Histopathologic Features Early: Mixed lymphohistiocytic perivascular infiltrates around dermal vessels Late: Leukocytoclastic vasculitis with karyorrhexis and occasional fibrin thrombi Early and late: Endothelial cell swelling and loss, erythrocyte extravasation, edema Differential Diagnosis Insect-bite reaction Drug reaction Septic vasculitis “Autoimmune” vasculitides

rate was 1.4% between 1997 and 2002, but this is widely accepted as a gross underestimate.105 Risk factors for mortality include older patients treated with chloramphenicol only, patients in whom tetracycline was not used as primary therapy, and delay of therapy greater than 5 days after the onset of symptoms.105 HISTOPATHOLOGIC FEATURES The histopathologic features are similar among the vasculotropic rickettsioses.92 Thus, only the specific changes of RMSF are discussed here (see Table 20-3). Significant findings are confined mostly within the dermis.102,106 The early (3 to 4 days) changes include a mild to moderate mixed lymphohistiocytic infiltrate that forms tight cuffs surrounding and penetrating into the walls of the superficial, middle, and lower dermal capillaries and venules; erythrocyte extravasation; endothelial swelling; and edema. The infiltrate may extend into the perivascular interstitium or may concentrate adjacent to adnexal structures, such as eccrine units. Later (after 6 days), accrued vascular damage frequently yields leukocytoclastic vasculitis that is predominantly lymphohistiocytic, with some neutrophilic infiltrates and karyorrhectic nuclear debris (Fig. 20-10). These later lesions are often associated clinically with palpable, nonblanching petechiae or a hemorrhagic, purpuric rash. Fewer than half of these lesions contain focal fibrin thrombi and well-defined vessel wall necrosis. Endothelial cell swelling and loss are frequent occurrences. The dermal infiltrate sometimes contains plasma cells or eosinophils. Infrequent findings include neutrophilic hidradenitis, perineural lymphocytic infiltration, and neutrophilic lobular panniculitis. Epidermal findings are usually associated with leukocytoclastic vasculitis, probably resulting from underlying vascular compromise, and may include interface dermatitis, with basal vacuolar degeneration and mild dermal–epidermal interface lymphocytic exocytosis. Apoptotic keratinocytes are present infrequently. In rickettsialpox, Maculatum disease, and African tick bite fever, the papulovesicular lesions result from subepidermal separation.101 With infections such as Mediterranean spotted fever, Maculatum disease, African tick bite fever, and rickettsialpox, but not RMSF, the site of the vector bite may form into an eschar that shows severe lymphohistiocytic and neutrophilic infiltrates; endothelial cell proliferation; vascular, dermal, and epidermal necrosis;

 FIGURE 20-10 Rocky mountain spotted fever (RMSF). Leukocytoclastic vasculitis in RMSF (Rickettsia rickettsii infection). One superficial dermal venule is completely obliterated by the necrotizing inflammatory vasculitis and thrombus, and an adjacent venule is relatively spared, owing to the focality of the rickettsial infection.Thrombosis, such as illustrated here, is seen in less than 50% of all diagnostic biopsies from patients with RMSF. The pattern of leukocytoclastic vasculitis is recognized most often in patients with clinical illness exceeding 6 days.

and extensive deposition of nuclear debris that results from the intense inflammation and local proliferation of rickettsiae.101,103 Characteristic spotted fever or typhus group rickettsiae may be visualized using specific antibody reagents and immunohistologic methods, such as immunofluorescence or immunoperoxidase101,102,107 (Fig. 20-11); nonspecific staining methods, such as Gram or Giemsa stains, are nonrevealing and occasionally misleading. Rickettsiae are observed most often in endothelial cells in clusters or “colonies” at sites of severe vasculitis; however, rickettsiae are also observed in adjacent noninflamed vessels. The involvement of a vessel may be eccentric, with inflammation and rickettsiae present only in one wall. Characteristic lesions should be sampled, and multiple leveled sections should be examined, because of the focality of the infection. Prior therapy with tetracycline antibiotics abrogates the ability to detect rickettsiae in biopsy

DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis includes diseases associated with vascular or capillary inflammation (see Table 20-3), including insect bite reaction, drug reaction, septic vasculitis secondary to disseminated intravascular coagulation (DIC), other specific infectious agents, other physical or chemical agents, collagen vascular diseases, mixed cryoglobulinemia, HenochSchönlein purpura, serum sickness, urticarial vasculitis, and vasculitis that occurs secondary to malignancy. Many of the lesions can be differentiated by

 FIGURE 20-11 Rocky mountain spotted fever (RMSF). Immunohistologic demonstration of Rickettsia rickettsii in an infected superficial dermal venule in a patient with RMSF. Note that the rickettsiae are intimately associated with the endothelium, reflecting the intracellular niche of these bacteria. Because of focal infection, several step sections stained by an immunohistologic method, such as immunoperoxidase or immunofluorescence, are recommended (immunoperoxidase stain with rabbit anti-r. Rickettsii, aminoethylcarbazol substrate, hematoxylin counterstain).

CHAPTER 20 ■ TREPONEMAL AND RICKETTSIAL DISEASES

tissue by immunohistologic methods. Immunohistology may be performed rapidly by frozen section or on paraffinembedded, formalin-fixed tissues, with equal sensitivity. The additional histologic details detected with the immunoenzymatic light-microscopic methods are confirmatory because of the co-localization of the intracellular rickettsiae and vascular inflammatory reaction. The sensitivity of immunohistology is approximately 70%, and the specificity is nearly 100% when diagnosis is rendered by those skilled in the interpretation of rickettsial immunohistology. PCR on acutephase blood has not increased sensitivity beyond that determined for immunohistology, and specific rickettsial antibodies are usually not detected by any method during the acute illness.

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other laboratory or histologic methods, including culture or special stains for specific infectious agents. Other laboratory and clinical findings often aid in differentiation. In patients with DIC or sepsis, leukocytoclastic vasculitis with prominent fibrin thrombi are identified frequently, and most have marked abnormalities in coagulation profiles, including prolongations in prothrombin and activated partial thromboplastin times, and positive fibrin split products or D-dimer tests. Patients with RMSF infrequently have true DIC, and coagulation studies are only infrequently and mildly altered.

456

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74. Shulman KJ, Melski JW, Reed KD, et al: The characteristic histologic features of erythema chronicum migrans [abstract]. Lab Invest. 1996;74:46A. 75. Coyle PK, Schutzer SE: Neurologic aspects of Lyme disease. Med Clin North Am. 2002;86:261-284. 76. Edlow JA: Erythema migrans. Med Clin North Am. 2002;86:239-260. 77. Dumler JS: Molecular diagnosis of Lyme disease: review and meta-analysis. Mol Diagn. 2001;6:1-11. 78. Bunikis J, Barbour AG: Laboratory testing for suspected Lyme disease. Med Clin North Am. 2002;86:311-340. 79. Pinto DS: Cardiac manifestations of Lyme disease. Med Clin North Am. 2002; 86:285-296. 80. Liveris D, Wang G, Girao G, et al: Quantitative detection of Borrelia burgdorferi in 2-millimeter skin samples of erythema chronicum migrans lesions: correlation of results with clinical and laboratory findings. J Clin Microbiol. 2002;40:1249-1253. 81. Grau RH, Allen PS, Cornelison RL Jr: Erythema migrans and the differential diagnosis of annular erythema. J Okla State Med Assoc. 2002;95:257-260. 82. Oosterhoudt KC, Zaoutis T, Zorc JJ: Lyme disease masquerading as brown recluse spider bite. Ann Emerg Med. 2002;39:558-561. 83. Burgdorf WHS, Woret WI, Schultes O: Acrodermatitis chronica atrophicans. Int J Dermatol. 1979;18:595-601. 84. Kaufman L, Gruber BL, Philips ME, Benach JL: Late cutaneous Lyme disease: acrodermatitis chronica atrophicans. Am J Med. 1989;86:828-830. 85. Aberer E, Klade H, Stanek G, Gebhart W: Borrelia burgdorferi and different types of morphea. Dermatologica. 1991;182: 145-154. 86. Aberer E, Stanek G, Ertl M, Neumann R: Evidence for spirochetal origin of circumscribed scleroderma (morphea). Acta Derm Venereol (Stockh). 1987;67:225-231. 87. Montgomery H: Dermatopathology. New York: Harper and Row; 1967:766-769. 88. Aberer E, Klade H, Hobisch G: A clinical, histological, and immunohistochemical comparison of acrodermatitis chronica atrophicans and morphea. Am J Dermatopathol. 1991;13:334-341. 89. Hovmark A, Asbrink E, Olsson I: The spirochetal etiology of lymphadenosis benign cutis solitaria. Acta Derm Venereol (Stockh). 1986;66:479-484. 90. Garbe C, Stein H, Dienemann D, Orfanos CD: Borrelia burgdorferi-associated cutaneous B-cell lymphoma: clinical and immunohistologic characterization of four cases. J Am Acad Dermatol. 1991; 24:584-590. 91. Magro CM, Crowson AN: Drug-induced immune dysregulation as a cause of atypical cutaneous lymphoid infiltrates: a hypothesis. Hum Pathol. 1996;27:125-132.

92. Dumler JS, Walker DH: Diagnostic tests for Rocky Mountain spotted fever and other rickettsial diseases. Dermatol Clin. 1994;12:25-36. 93. Walker DH: Rocky Mountain spotted fever: a seasonal alert. Clin Infect Dis. 1995;20:1111-1117. 94. Dumler JS, Taylor JP, Walker DH: Clinical and laboratory features of murine typhus in south Texas, 1980 through 1987. JAMA. 1991;266:1365-1370. 95. Frances SP, Watcharapichat P, Phulsuksombati D, Tanskul P: Investigation of the role of Blankaartia acuscutellaris (Acari: Trombiculidae) as a vector of scrub typhus in central Thailand. Southeast Asian J Trop Med Public Health. 2001;32:863-866. 96. Lerdthusnee K, Khlaimanee N, Monkanna T, et al: Efficiency of Leptotrombidium chiggers (Acari: Trombiculidae) at transmitting Orientia tsutsugamushi to laboratory mice. J Med Entomol. 2002;39:521-525. 97. Walsh DS, Myint KS, Kantipong P, et al: Orientia tsutsugamushi in peripheral white blood cells of patients with acute scrub typhus. Am J Trop Med Hyg. 2001; 65:899-901. 98. Watt G, Kantipong P, Jongsakul K, et al: Passive transfer of scrub typhus plasma to patients with AIDS: a descriptive clinical study. Q J Med. 2001;94:599-607. 99. Sexton DJ, Kaye KS: Rocky mountain spotted fever. Med Clin North Am. 2002;86:351-360. 100. Sexton DJ, Corey GR: Rocky Mountain “spotless” and “almost spotless” fever: a wolf in sheep’s clothing. Clin Infect Dis. 1992;15:439-448. 101. Kass EM, Szaniawski WK, Levy H, et al: Rickettsialpox in a New York City hospital, 1980 to 1989. New Engl J Med. 1994;331:1612-1617. 102. Walker DH: Diagnosis of rickettsial diseases. Pathol Annu. 1988;23:69-96. 103. Walker DH, Occhino C, Tringali GR, et al: Pathogenesis of rickettsial eschars: the tache noire of boutonneuse fever. Hum Pathol. 1988;19:1449-1454. 104. Chapman AS, Murphy SM, Demma LJ, et al: Rocky Mountain spotted fever in the United States, 1997-2002. Vector Borne Zoonotic Dis. 2006;6:170-178. 105. Holman RC, Paddock CD, Curns AT, et al: Analysis of risk factors for fatal Rocky Mountain spotted fever: evidence for superiority of tetracyclines for therapy. J Infect Dis. 2001;184:1437-1444. 106. Kao GF, Evancho CD, Ioffe O, et al: Cutaneous histopathology of Rocky Mountain spotted fever. J Cutan Pathol. 1997;24:604-610. 107. Dumler JS, Gage WR, Pettis GL, et al: Rapid immunoperoxidase demonstration of rickettsia rickettsii in fixed cutaneous specimens from patients with Rocky mountain spotted fever. Am J Clin Pathol. 1990;93:410-414.

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62.

tick-borne diseases in a high-risk population in the northeast United States. Am J Med. 1999;106:404-409. Bakken JS, Dumler JS: Human granulocytic ehrlichiosis. Clin Infect Dis. 2000;31: 554-560. Wormser GP, Horowitz HW, Nowakowski J, et al: Positive Lyme disease serology in patients with clinical and laboratory evidence of human granulocytic ehrlichiosis. Am J Clin Pathol. 1997;107:142-147. Krause PJ, MacKay K, Thompson CA, et al: Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis. 2002;34: 1184-1191. Steere AC, Malawista SE, Snydman DR, et al: Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum. 1977;20:7-17. Sigel LH, Curran AS: Lyme disease: a multifocal worldwide disease. Annu Rev Public Health. 1991;12:85-109. Pachner AR, Steiner I: Lyme neuroborreliosis: infection, immunity, and inflammation. Lancet Neurol. 2007;6:544-552. Chabria SB, Lawrason J: Altered mental status, an unusual manifestation of early disseminated Lyme disease: a case report. J Med Case Reports. 2007;1:62. Endres S, Quante M: Oedema of the metatarsal heads II-IV and forefoot pain an unusual manifestation of Lyme disease: a case report. J Med Case Reports. 2007; 1:44. Asbrink E, Hovmark A: Cutaneous manifestations in Ixodes-borne Borrelia spirochetosis. Int J Dermatol. 1987;26: 215-223. Berger BW: Erythema chronicum migrans of Lyme disease. Arch Dermatol. 1984;120:1017-1021. Gomes-Solecki MJ, Meirelles, L, Glass J., et al: Epitope length, genospecies dependency, and serum panel effect in the IR6 enzyme-linked immunosorbent assay for detection of antibodies to Borrelia burgdorferi. Clin Vaccine Immunol. 2007;14:875-879. Harrer T, Geissdörfer W, Schoerner C, et al: Seronegative Lyme neuroborreliosis in a patient on treatment for chronic lymphatic leukemia. Infection. 2007;35: 110-113. Tibbles CD, Edlow JA: Does this patient have erythema migrans? JAMA. 2007; 297:2617-2627. Krause PJ, Foley DT, Burke GS, et al: Reinfection and relapse in early Lyme disease. Am J Trop Med Hyg. 2006;75: 1090-1094. Giery ST, Ostfeld RS: The role of lizards in the ecology of Lyme disease in two endemic zones of the northeastern United States. J Parasitol. 2007;93:511-517. Cote J: Lyme disease. Int J Dermatol. 1991;30: 500-501.

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CHAPTER 21 Fungal Infections

PART III ■ INFECTIONS

Catherine Lisa Kauffman Victoria Hobbs Hamet Steven R. Tahan Klaus J. Busam Raymond L. Barnhill

458

The kingdom Fungi is a group of heterotrophic eukaryotic organisms composed of cells enclosed by a rigid cell wall containing ergosterol and chitin or other polysaccharides but usually not cellulose. Historically, mycology has often fallen under the discipline of botany, although fungi are more closely related to animals than to plants and are part of the eukaryotic crown group that diverged from each other roughly 1 billion years ago.1 Fungi may be unicellular, such as yeasts, or multicellular, forming long filaments known as hyphae. Hyphae are divided into cells by septa. Various reproductive structures such as conidia and spores develop on hyphae; the morphology of these structures provides the traditional basis for taxonomy. Some genera have the capacity to form yeast, hyphal forms, or both, depending on environmental conditions, a characteristic known as dimorphism. Asexual reproduction is the primary means of propagation for many fungi. Sexual reproduction involves the fusion of two haploid nuclei followed by meiosis. The diploid state is transient and is called the perfect state. Fungi that have the capacity for sexual reproduction have been traditionally classified under the phyla Zygomycota (bread molds, Rhizopus, Mucor species), Basidiomycota (club fungi, including mushrooms and plant pathogens such as rusts and smuts), and Ascomycota (sac fungi, including Aspergillus, Candida, Penicillium species). Ascomycota includes the order Onygenales, which in turn includes the genus Arthroderma.2 Deuteromycota, or fungi imperfecti, no longer recognized as a formal taxon in fungal systematics, was the form phylum used to classify fungi with no known sexual reproduction; most of the pathogenic fungi were classified in this group until subsequent research demonstrated the sexual or so-called “teleomorphic” stage of many species, which were reclassified into other phyla.3-7 In addition, comparison of nucleic acid sequences and

nonsexual phenotypic characteristics allowed further revisions and the incorporation of asexual species, such as Penicillium, into Ascomycota. Many of the medically important species have been classified in the order Onygenales of the phylum Ascomycota; representative members include the dermatophytes and the causative agents of histoplasmosis and blastomycosis. As a matter of convenience, in this chapter, the anamorphic (asexual) classifications will be used. The taxonomy of the kingdom Fungi is in a constant state of flux, particularly as molecular studies have overturned some of the previous classifications. Microsporidia, formerly considered protists, are now considered fungi on the basis of phylogenetic evidence.8,9 Recently, seven phyla have been proposed for the kingdom Fungi: Chytridiomycota, Neocallimastigomycota, Blastocladiomycota, Microsporidia, Glomeromycota, and Ascomycota and Basidiomycota, which together comprise the highly speciose subkingdom Dikarya. In this proposed classification scheme, the clades that have traditionally been classified in the phylum Zygomycota are distributed among the phylum Glomeromycota and four subphyla incertae sedis, including Mucoromycotina, Kickxellomycotina, Zoopagomycotina, and Entomophthoromycotina, pending resolution of ambiguous phylogenetic relationships.10 Owing to their relatively small size and frequent absence of pigment, fungi often are difficult to discern on hematoxylin and eosin (H&E)-stained sections. Histopathologic clues to the presence of a superficial fungal infection include neutrophils within the stratum corneum, foci of parakeratosis, and variation in the thickness and appearance of the stratum corneum. Signs of a deeper fungal infection may include pseudoepitheliomatous hyperplasia, neutrophilic microabcesses or suppurative granulomas within the epidermis and dermis, multinucleated giant cells within a dermal infiltrate, empty spaces within multinucleated giant cells, necrosis, and vascular occlusion with associated secondary ischemic alterations of the epidermis and dermis. The histologic appearance of various fungi in tissue is summarized in Table 21-1.

SUPERFICIAL FILAMENTOUS INFECTIONS

Dermatophytoses Superficial cutaneous fungal infections, referred to as ringworm or tinea, are among the most common infections in humans.

Most of these infections are caused by the anamorphic (asexual) genera Epidermophyton, Microsporum, and Trichophyton; teleomorphic, or sexual, dermatophytes are placed into the genus Arthroderma of the order Onygenales. An important characteristic of dermatophytes is that their ability to parasitize is restricted to dead, keratinized tissue. Dermatophytes are found only within the stratum corneum, the fully keratinized hair shaft, and the nail plate and bed. Distinctive features seen only in culture, particularly of the macroconidia, provide the basis for identification. Epidermophyton floccosum, the pathogenic species of this genus, have snowshoeshaped macroconidia occurring singly or in clusters of two to three cells with smooth, thin to moderately thick walls and one to nine septa. The macroconidia of Microsporum classically are spindle shaped, appear rough, and have thick walls with one to 15 septa. Trichophyton tonsurans has macroconidia with thin, smooth walls and 1 to 12 septa. Macroconidia vary widely in shape and include clavate, cylindrical, and fusiform morphologies.3 Dermatophytes are divided into three categories based on their natural habitat and usual host.11,12 Anthropophilic dermatophytes typically infect only humans. Zoophilic dermatophytes are usually associated with animals but can also infect humans. Geophilic dermatophytes are saprophytes that thrive on keratinous materials found in soil and may also invade keratinous tissues in animals or humans; however, some overlap has been observed between zoophilic and geophilic species.13 Anthropophilic dermatophytes generally produce less inflammation than the zoophilic and geophilic species. Dermatophyte species are distributed geographically; some species are ubiquitous, and others are highly restricted.14,15

Tinea Capitis Dermatophytic infection of the scalp, eyebrows, and eyelashes is called tinea capitis. The most common etiologic agents are Trichophyton and Microsporum species. T. tonsurans has superseded M. audouinii and M. canis as the primary cause of this condition in the United States, as well as in most of North, Central, and South America.16,17 M. canis, a zoophilic organism, is the pathogen for most cases in Europe, especially in Mediterranean and eastern countries. However, a shift in etiology toward anthropophilic dermatophyte species has been observed, especially in urban

Table 21-1 Histologic Appearance of Fungi in Tissue S PORE S IZE

Candidiasis

3-7 μm yeast cells; hyphae 3-5 μm wide. Skin: vagina, mouth, larynx, esophagus—in superficial layers; esophagus and GI ulcers—in submucosa; disseminated—often in foci near blood vessels 3-8 μm yeast cells; short, curved, rarely branching hyphae 2-4 μm diameter; in stratum corneum and follicles 4-8 μm on hair surface, rectangular 2-4 μm, ≤ 8 μm, crowded in hair shaft. Appear polygonal 2° to crowding 3-15 μm; Gelatinous: spores lie in pools of mucin. Granulomatous: few spores, present in giant cells and macrophages 5-15 μm Thick double wall Free in tissue, in giant cells

Pityriasis versicolor M. furfur

Black piedra White piedra, T. beigelii Cryptococcosis

North American blastomycosis

Coccidiomycosis

Paracoccidioidomycosis

Histoplasmosis Sporotrichosis

Chromoblastomycosis

Phaeohyphomycosis

Mycetoma (eumycetoma)

Nocardia

AND

L OCATION

30-60 μm sporangia 4 μm endospores Free in tissue, in giant cells 4-40 μm thick-walled yeast forms intra- and extracellular 2-4 μm pseudocapsule, intra- and extracellular 4-6 μm round to oval bodies; ≤ 8 μm cigar-shaped bodies. Rare branching, nonseptate hyphae

6-l2 μm round to oval muriform bronze-colored forms with central septation (sclerotic bodies) 2-6 μm spores; may be septate hyphae, possibly branching; spores in chains; pseudohyphae; usually but not always pigmented ≤ 5 μm septate hyphal elements in grains that are brown or black; filamentous bacteria present in grains of actinomycetoma Filamentous branching Grampositive, weakly acid-fast bacteria

Actinomycosis

Filamentous branching Gram-positive bacteria, not acid fast, in granules.

Botryomycosis

Gram-positive or -negative cocci or rods in granules 20-30 μm, lack septa, 90° branching 2-4 μm septate hyphae; 45° dichotomous branching; extracellular and intravascular

Mucormycosis Aspergillosis

H ISTOLOGIC F INDINGS

F UNGAL B UDDING

Subcorneal pustules Spongioform pustules Variable acute and chronic dermal infiltrate that may be granulomatous

Blastospores, globose to oval

Hyperkeratosis Possibly slight epidermal hyperplasia

Unipolar globose budding. cells ≤ 8 μm Collarettes Asci and ascospores Arthroconidia along hair shaft only

Epidermal hyperplasia Suppurative granulomas

Narrow, unequal

Pseudoepitheliomatous hyperplasia Suppurative granulomas with necrosis Epidermal hyperplasia Suppurative granulomas

Single, equal, broad-based

Pseudoepitheliomatous hyperplasia Suppurative granulomas Diverse types of granuloma or diffuse intracellular forms Suppurative granulomas with neutrophilic microabscess surrounded by epithelioid and multinucleated histiocytes and an outer rim of lymphocytes Pseudoepitheliomatous hyperplasia Suppurative granulomas Dermal or subcutaneous suppurative granulomas often encapsulated by fibrous wall resembling a cyst Neutrophilic abscesses containing grains; granulation tissue; sinus tracts

Multiple or external budding in “ship’s wheel” arrangement

Endospores in spherules

CHAPTER 21 ■ FUNGAL INFECTIONS

D ISEASE

Narrow, unequal budding Single or occasionally multiple buds

Broad-based equal budding

Sprouting hyphal forms

Neutrophilic abscesses; tuberculoid granulomas on occasion (Nocardia brasiliensis) Neutrophilic abscesses containing “sulfur granules”; sinus tracts; granulation tissue. Neutrophilic abscesses containing granules Necrosis, thrombosis, infarction Thrombosis, infarction granulomatous (Continued )

459

Table 21-1 Histologic Appearance of Fungi in Tissue (Continued ) D ISEASE

S PORE S IZE

Lobomycosis

10 μm; thick double wall

Rhinosporidiosis

In submucosa, ≤ 350 μm

AND

L OCATION

PART III ■ INFECTIONS

in diameter; free in tissue, in giant cells

regions, where the incidence of tinea capitis due to T. tonsurans, mostly in the United Kingdom,18 and T. soudanense and M. audouinii, in France, has increased significantly.19 CLINICAL FEATURES Infection occurs via direct or indirect person-to-person contact. Unlike Microsporum infections, childhood T. tonsurans infections do not always resolve at puberty.15 Also, unlike M. canis, M. audouinii, and M. ferrugineum, which show green fluorescence with Wood lamp, T. tonsurans does not fluoresce. T. schoenleinii, the etiologic agent of tinea favosa, shows a green-gray fluorescence with the Wood lamp. Tinea capitis infections may be smallspore ectothrix, large-spore ectothrix, large-spore endothrix, or tinea favosa (Table 21-2). Small-spore ectothrix is

H ISTOLOGIC F INDINGS

F UNGAL B UDDING

Histiocytic nodules with numerous intracellular organisms and fibroblastic proliferation Pseudoepitheliomatous sporangia; endospores ≥ 7-9 μm Acute and chronic infiltrate in submucosa, hemorrhage

Short thick tubelike structures

caused by Microsporum species. Infection begins with hyphal invasion of the hair follicles. Hyphae grow within the hair shaft toward the hair bulb. As the hair emerges from the follicle, it is covered with a mass of small arthrospores 2 to 5 μm in diameter. Clinical manifestations vary from mild inflammation, as seen in anthropophilic Microsporum species, to severe inflammatory reactions caused by the zoophilic and geophilic Microsporum species. Gray-patch ringworm, typical of M. audouinii infection, is characterized by patches of dull bristles of hair with slight erythema and mild scaling. All hairs in a given area are affected, and lesions spread in a characteristic ring formation. M. canis, M. gypseum, and M. fulvum, the zoophilic and geophilic species, cause more host response, often leading to

Table 21-2 Dermatophytoses D ISEASE Tinea capitis Small-spore ectothrix Large-spore endothrix Large-spore ectothrix Tinea favosa Tinea corporis Tinea faciei Tinea barbae Tinea cruris Tinea pedis Tinea manuum Tinea unguium

460

O RGANISM

Microsporum audouinii,a M. canis,z M. gypseum,g M. fulvum,g M. ferrugineuma Trichophyton tonsurans,a T. violaceum,a T. soudanense,a T. gourvilii,a T. yaoundeia T. mentagrophytes var. interdigitale,a T. mentagrophytes var. mentagrophytes,z T. verrucosum,z T. megniniia T. schoenleiniia (T. violaceum, M. gypseum rare) T. rubrum,a T. mentagrophytes,z M. canis, others T. mentagrophytes, T. rubruma T. mentagrophytes,z T. verrucosum,z T. rubrum,a T. violaceum,a T. megninii,a M. canisz T. rubrum,a E. floccosum,a T. mentagrophytesa T. rubrum,a T. mentagrophytes,a E. floccosuma T. rubrum,a E. floccosum,a T. mentagrophytesaa T. rubrum,a T. mentagrophytes,a.z (E. floccosum,a T. violaceum,a T. schoenleinii,a T. tonsuransa rare)

Key: a = anthropophilic; g = geophilic; z = zoophilic.

Endospores in sporangia hyperplasia, erosions

suppurative folliculitis or kerion formation, characterized by intense inflammation, pus, crusting, and matting of hairs. Large-spore endothrix is caused by T. tonsurans and T. violaceum in the United States. In Africa, T. gourvilii, T. soudanense, and T. yaoundei are common etiologic agents. These anthropophilic species produce black-dot ringworm, caused by intrafollicular hyphae that fragment into 5- to 8-μm-wide arthrospores within the shaft, often resulting in breakage at the level of the follicular ostium. The alopecic patches are smaller than in gray-patch ringworm, and not all hairs in the area are affected. Infections caused by Trichophyton species tend to be more inflammatory than those caused by Microsporum species, and kerion formation is often seen in association with T. violaceum. Large-spore ectothrix infections are caused by T. verrucosum and T. mentagrophytes. Whereas T. verrucosum infections are characterized by arthroconidia 8 to 12 μm in diameter arranged in large, dense chains along hair, T. mentagrophytes infections demonstrate arthroconidia 3 to 4 μm in diameter in chains along the external surface of the hair.17 These organisms often cause suppurative folliculitis with subsequent atrophy of hair follicles, scarring, and patchy permanent alopecia. Tinea favosa (also called favus) is an uncommon clinical presentation that occurs mostly in Eurasia and Africa usually associated with T. schoenleinii. T. violaceum, M. gypseum, and M. canis20 have also been identified as causative agents of favus. Broad hyphae and air spaces develop within the hair shaft without arthrospores. Areas of scales, crusty debris, and masses of mycelium form cup-shaped scutula over the scalp.3 HISTOPATHOLOGIC FEATURES Fungal elements are seen in the stratum corneum, and hyphae invade the hair follicles and grow down the hair shaft toward the

tissue response. The central area may clear as fungus is eliminated, with active proliferation continuing at the periphery, resulting in characteristic annular, scaly patches with raised erythematous or vesicular margins (Fig. 21-1A).3 The natural history varies depending on the attributes of the fungal species and the host. Most cases are caused by T. rubrum, T. mentagrophytes, and M. canis.23 Special expressions of tinea corporis have been recognized. For example, T. rubrum commonly causes extensive eruptions, sometimes with psoriasiform lichenified plaques and nodular granulomatous perifolliculitis (Majocchi granuloma).24

DIFFERENTIAL DIAGNOSIS Seborrheic dermatitis, psoriasis, trichotillomania, alopecia areata, bacterial infection, “tinea” amiantacea, Langerhans cell histiocytosis, lupus erythematosus, pseudopelade, impetigo, folliculitis decalvans, pyoderma, and secondary syphilis may be associated with variable crusting, scaling, perifollicular inflammation, and hair loss and enter into the differential diagnosis of tinea capitis.21,26 Whereas T cells predominate in the infiltrate in acute inflammatory tinea capitis, the infiltrate contains a mixture of both B and T cells in chronic noninflammatory tinea capitis.22

HISTOPATHOLOGIC FEATURES Dermatophytic infections display a spectrum of histologic patterns depending on the causative agent and the host response. For example, dry, scaly patches and plaques, often caused by anthropophilic dermatophytes (see Table 21-2), show hyperkeratosis. Compact orthokeratosis, the presence of neutrophils within the stratum corneum, and the “sandwich sign” may also be clues to a dermatophyte infection.25 The sandwich sign denotes hyphae “sandwiched” in between a superficial normal-appearing basket-weave pattern of orthokeratosis in the stratum corneum and a deeper layer of abnormal stratum corneum showing either parakeratosis or compact hyperkeratosis (Fig. 21-1B). Variable spongiosis and occasional subcorneal or intraepidermal pustule formation may be seen. The dermis contains a mild perivascular inflammatory infiltrate consisting of lymphocytes, histiocytes, eosinophils, and neutrophils. Zoophilic dermatophyte infections tend to be more inflammatory with vesicle formation.

Tinea Corporis CLINICAL FEATURES Ringworm of the glabrous skin is called tinea corporis; it results from proliferation of fungi in the stratum corneum and may be caused by infection by any dermatophyte, with regional differences dictating the prevailing dermatophytic flora.3 Infection of the skin at the site of inoculation spreads centrifugally, followed by a secondary

A

Hyphae within the stratum corneum may be visible even with H&E stain if they are numerous, but they are seen more easily with periodic acid-Schiff (PAS) or methenamine silver staining. In Majocchi granuloma owing to T. rubrum, arthroconidia and mycelia are seen in follicles, and there is a dermal infiltrate of lymphocytes, histiocytes, epithelioid cells, and often foreign body giant cells. Rupture of the follicular wall releases conidia and mycelia, stimulating granuloma formation.24,26 DIFFERENTIAL DIAGNOSIS In cases in which the inflammation is minimal and hyphae are not visualized with routine staining, biopsy of tinea corporis may resemble that of normal skin. Lesions with hyperkeratosis, spongiosis, and mild inflammation may mimic subacute spongiotic dermatitides such as nummular eczema, seborrheic dermatitis, contact dermatitis, and pityriasis rosea. Zoophilic dermatophytic infections may be confused with impetigo, cellulitis, folliculitis decalvans, or other pustular infections.26 Potassium hydroxide preparations usually reveal fungal elements in skin scrapings from tinea corporis. Cultures should be obtained routinely and are positive in 5% to 15% of KOH-negative cases.2

CHAPTER 21 ■ FUNGAL INFECTIONS

keratinizing cells (see Table 21-2). Hyphal growth and arthroconidia formation occur either on the surface of the hair (ectothrix) or within the hair shaft (endothrix). In tinea favosa, hyphae are present within the stratum corneum, in hair shafts, and in scutula, which consist of tangled mycelial elements, sebum, debris, and scales forming a characteristic cup-shaped lesion. Follicular atrophy and a chronic dermal inflammatory infiltrate are present. Histologic examination of a kerion reveals a dense perifollicular and perivascular infiltrate of lymphocytes, neutrophils, plasma cells, and eosinophils in the dermis.3

Tinea Barbae CLINICAL FEATURES Tinea barbae, or ringworm of the beard and mustache, is a disease of men characterized by invasion of terminal hairs of the face and neck. Most cases have been associated with topical steroid use, animal contact, and diabetes. T. verrucosum has been implicated in farm workers; other causative agents include T. rubrum, M. canis, T. mentagrophytes, and

B

 FIGURE 21-1 Dermatophyte infection. (A) Tinea corporis. Characteristic annular, scaly patch with a raised erythematous margin on the chest. (B) Periodic acid-Schiff with diastase stain shows hyphal elements in stratum corneum.

461

T. tonsurans.27 Clinical manifestations are similar to those of tinea capitis, with patches of erythema and scaling and dull, fragile hairs. These organisms produce large-spore ectothrix invasion with spores in chains, often resulting in pustular folliculitis resembling kerion.28

PART III ■ INFECTIONS

HISTOPATHOLOGIC FEATURES Fungal elements often are visible within hair follicles and shafts, with arthroconidia along the shaft and free within the tissues. The cellular reaction is similar to that seen with pustular forms of tinea capitis. DIFFERENTIAL DIAGNOSIS Entities that must be differentiated from tinea barbae include acne, rosacea, papular syphilis, seborrheic dermatitis, and bacterial folliculitis. PAS and methenamine silver stains facilitate visualization of the hyphae.

Tinea Cruris CLINICAL FEATURES Tinea cruris refers to dermatophyte infection of the groin; the most common etiologic agents are T. rubrum and E. floccosum, with a minority of cases attributed to T. interdigitale.2 It is more common in men and involves the perineum, scrotum, perianal area, and frequently the medial aspect of the buttocks. Intertriginous erythema is common, and vesicles may be present. The borders are sharply demarcated, unlike plaques in these areas caused by Candida spp. Lesions are pruritic and often painful.2 HISTOPATHOLOGIC FEATURES Fungi are usually few in number and stain with the PAS reaction or methenamine silver nitrate. Chains of spores, as in Epidermophyton infections, or hyphae, as in Trichophyton infections, are present in the stratum corneum, which is variably parakeratotic and crusted.29 The underlying dermis may contain a scant lymphohistiocytic infiltrate. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes psoriasis, contact dermatitis, and seborrheic dermatitis. Candida intertrigo, which is also in the differential diagnosis, may be diagnosed by the presence of spores and pseudohyphae.

Tinea Pedis

462

CLINICAL FEATURES Tinea pedis (“athlete’s foot”) is the most common form of dermatophytosis.30,31 Occlusion of the feet and, in particular, the digital webspaces is the single most important factor influencing the severity, incidence, and prevalence of the disease.16,32 There

are three clinical varieties. Plantar moccasin-like disease, the most common type, affects the plantar surfaces and is associated with mild erythema, fine scaling, and pruritus. T. rubrum is the usual etiologic agent.30 Nail involvement is common, and patients often have a history of atopy. Interdigital infection, characterized by maceration and erosion between the toes, is related to a combination of dermatophytes (T. rubrum and T. mentagrophytes) and bacteria.31 Vesiculobullous tinea pedis is caused by T. mentagrophytes and is characterized by episodes of intense inflammation along the arch and sides of the foot with scaling between episodes.31

HISTOPATHOLOGIC FEATURES The histopathology of tinea manuum is similar to that of tinea corporis: Fungi are noted in the stratum corneum, which is often hyperkeratotic. Spongiosis may be observed if blisters are present clinically.

HISTOPATHOLOGIC FEATURES Biopsies of tinea pedis are rarely done unless the infections are complicated or unusually severe. In acute tinea pedis, parakeratosis and spongiosis with intraepidermal vesicle formation are seen. A superficial acute and chronic infiltrate with focal exocytosis also may be observed. In chronic tinea pedis, hyperkeratosis and acanthosis are prominent. The dermis may contain a superficial lymphohistiocytic infiltrate.26,29

Tinea Unguium

DIFFERENTIAL DIAGNOSIS Other conditions that may mimic tinea pedis are contact dermatitis, dyshidrosis, pustular psoriasis, secondary syphilis, arsenical keratosis, fixed drug eruption, dermatitis repens, erysipelas, pyoderma, and idiopathic hyperkeratosis.26 Infection with Candida and with bacteria such as Brevibacterium epidermidis, Micrococcus sedantarius, and several gram-negative bacterial species may complicate the presentation.31 A similar hyperkeratotic condition caused by the soil molds Hendersonula toruloidea (now called Nattrassia magiferae) and Scytalidium hyalinum, occurring mainly in West Africa, the Caribbean, India, and the Pacific, has been described.33

Tinea Manuum CLINICAL FEATURES Tinea manuum refers to a dermatophyte infection of the palmar or interdigital surfaces of the hand. Most cases are caused by T. rubrum, although some are owing to T. mentagrophytes or E. floccosum. Tinea pedis often coexists. The usual presentation is unilateral diffuse hyperkeratosis with prominent flexural creases.3 Other presentations include crescentic exfoliating lesions, vesicular lesions, red papular and follicular patches, and erythematous scaly patches on the dorsum of the hand.26

DIFFERENTIAL DIAGNOSIS Psoriasis, candidal infection, chronic pyoderma, contact dermatitis, lichen simplex chronicus, and secondary syphilis resemble tinea manuum. The id, or dermatophytid, reaction is an allergic response occurring on the hand as a result of dermatophytic infection of the feet or other parts of the body. It may mimic tinea manuum or dyshidrotic pompholyx.

CLINICAL FEATURES Onychomycosis is a common fungal infection of the nail apparatus usually caused by anthropophilic dermatophytes and less commonly by yeasts and molds. Tinea unguium is a fungal infection of the nail by dermatophytic species. Onychomycosis affects adults, especially those older than 60 years of age; men; diabetics; immunocompromised individuals; and smokers. There are associations of onychomycosis with psoriasis, peripheral vascular (arterial) disease, and history of trauma to the nail or of previous tinea pedis.34 Onychomycosis is categorized according to clinical presentation into five types.35,36 The most common presentation is distal lateral subungual onychomycosis (DLSO), in which the fungus breaches the onychodermal band at the distal margin of the nail bed, allowing invasion of the ventral aspect of the nail via the hyponychium, the nail bed, or the lateral nail fold. Subungual hyperkeratosis and formation of a yellowishgray mass lift the nail plate off the nail bed; the condition may cause paronychia and onycholysis. White superficial onychomycosis (WSO) affects the third and fourth toenails most commonly and rarely affects the fingernails. This presentation is often caused by Trichophyton interdigitale (formerly T. mentagrophytes var. interdigitale). The fungus invades superficial layers of the nail plate, causing small, superficial, white patches that may merge over the entire dorsal surface of the nail. Dematiaceous or black fungi such as Scytalidium dimidiatum or T. rubrum may invade the nail in the same manner, causing black superficial onychomycosis. Proximal subungual onychomycosis (PSO), which results from fungal invasion of the stratum corneum of the proximal

DIFFERENTIAL DIAGNOSIS Onychomycosis is often caused by Candida and may also be caused by Malassezia furfur43; Trichosporon species42; and molds such as Scopulariopsis brevicaulis, Aspergillus species, Nattrassia mangiferae41 (formerly known as Hendersonula toruloidea), and Fusarium species.38 Bacterial paronychia, psoriasis, eczema, Darier disease, pityriasis rubra pilaris, peripheral circulatory problems, and endocrine disturbances may produce hyperkeratotic nails. Congenital abnormalities such as clubbing, Beau lines, pachyonychia congenita, and nonmycotic leukonychia, as well as drugs, trauma, and chemical irritants, should be excluded.39

Dermatomycoses Dermatomycosis denotes a nondermatophytic fungal infection of the hair, skin, and nails. Dermatomycoses other than

candidiasis, piedra, and tinea versicolor, which are discussed later in this chapter, may be caused by a variety of soil organisms. Nattrassia mangiferae has been implicated in several reports of skin and nail infections, as well as in a verrucous pattern in an immunocompromised patient in Algeria.40 It has more recently been isolated from foot and nail infections in five patients in Brazil.41 Scytalidium hyalinum has been involved in skin and nail infections in patients from the Caribbean and West Africa. The clinical manifestations of these two infections resemble dry, scaly dermatophytic infections.33 Cycloheximide, a usual component of culture media, prevents the growth of these organisms in routine cultures.26 In addition to the soil molds, S. brevicaulis and Aspergillus species, Trichosporon asahii,42 Fusarium species,38 and Malassezia furfur43 have been implicated in onychomycosis. HISTOPATHOLOGIC FEATURES Histologic examination of dermatomycosis reveals hyphal elements that may be indistinguishable from dermatophyte infections.44-46 Culture is necessary for definitive diagnosis.

hematogenous dissemination.50 In oral lesions, the finding of mycelia is useful in differentiating a pathogenic infection. CLINICAL FEATURES The expression of candidal infection may be divided into acute mucocutaneous forms, chronic mucocutaneous forms, and disseminated disease.51 In addition, cutaneous infection may result in intertriginous candidiasis, paronychia, onychomycosis, diaper candidiasis, and candidal granuloma.26 Cutaneous candidal infections generally produce erythema with moist exudates having irregular edges and satellite papules. Subcorneal pustules lead to superficial erosions and peeling. Acute mucocutaneous candidiasis may present as oral thrush, which occurs most often in infants, elderly individuals, and patients with terminal or chronic illnesses.52 (Table 21-3). It is characterized by friable white plaques on the oral mucosa; unlike the plaques of leukoplakia, they can be scraped off easily, revealing an erythematous base.52 Acute atrophic candidiasis presents as a painful erythematous stomatitis. Chronic atrophic candidiasis, which is common among denture wearers, is characterized

CHAPTER 21 ■ FUNGAL INFECTIONS

nail fold, may be associated with paronychia. It is usually caused by T. rubrum, although yeasts and molds have been implicated as well. PSO may be associated with paronychia. A subset of PSO, proximal white subungual onychomycosis (PWSO), typically occurs in immunocompromised patients, in whom it affects the toenails more often than the fingernails, although it has also been reported rarely in immunocompetent individuals. Endonyx onychomycosis results from fungal invasion through the superficial surface and extending deep into the nail plate. This presentation lacks features of hyperkeratosis and onycholysis observed in DLSO and is characterized by milky white patches, coarse pitting, lamellar peeling, and sometimes transverse indentations of the nail plate. There may be an association between endonyx onychomycosis and endothrix scalp infections, especially involving T. soudanense and T. violaceum.34,37 Total dystrophic onychomycosis may be primary, in immunocompromised patients, or secondary, the most advanced clinical presentation characterized by progressive destruction of the entire nail bed and nail plate. In DLSO, hyphal filaments and arthroconidia grow between lamellae of the nail plate, separating them mechanically. There is little to no inflammatory response in the surrounding soft tissue. Fungal concentrations in nail sections are variable, making diagnosis somewhat difficult.26 In white superficial onychomycosis, hyphae and arthroconidia are present only in the superficial layers of the nail.

YEAST INFECTIONS Synonyms: Moniliasis, thrush, candidiasis, vulvovaginitis, muguet.

Table 21-3 Mucocutaneous Candidiasis

Candidiasis

Clinical Features Various acute forms are more common in infants, elderly, pregnant, and diabetic patients Chronic mucocutaneous candidiasis Often associated with cell-mediated immune deficiency May involve genetic transmission Candidal granuloma (rare) Chronic atrophic candidiasis in denture wearers Erythema with irregular margins, moist exudates, and satellite papules Oral friable white plaques that can be scraped off easily Histopathologic Features Spores (3-6 μm), pseudohyphae, and hyphae seen in stratum corneum Subcorneal pustules and vesicles Candidal granuloma Prominent hyperkeratosis and papillomatosis Dense dermal infiltrate with giant cells Differential Diagnosis Dermatophyte infection Impetigo Subcorneal pustular dermatitis Pustular psoriasis

Candidiasis is caused by dimorphic yeastlike fungi of the genus Candida, indisputably the single most important cause of opportunistic mycoses worldwide.47 More than 90% of invasive Candida infections can be attributed to five pathogenic species: C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei, although the list of reported species, now including C. guilliermondi, C. lusitaniae, C. kefyr, C. rugosa, C. famata, C. inconspicua, C. norvegensis, and others, continues to expand. As opportunistic organisms, they depend on a change in host physiology, defenses, or normal flora to colonize, invade, and cause disease. The degree of virulence among species varies greatly, with C. albicans, C. glabrata, and C. tropicalis being the most virulent.47-49 Less virulent species require greater host debilitation to cause disease. C. albicans is part of the normal flora of the gastrointestinal (GI) tract, oral cavity, and vagina.48 C. albicans grows as a budding yeast; whereas hyphal forms are hallmarks of tissue invasion, blastoconidia are thought to be involved in

463

PART III ■ INFECTIONS 464

by asymptomatic erythema of the mucosa that bears the denture.52,53 Inhaled corticosteroids and HIV infection are also associated with chronic oral candidiasis.54 Other conditions involving the oral mucosa, such as perlèche (angular cheilitis), leukoplakia, HIV-associated oral hairy leukoplakia, and median rhomboid glossitis, may predispose the affected individual to mucosal invasion by Candida species. Vulvovaginitis is characterized by pruritus; pain; and a thick, white exudate. Balanitis, more commonly seen in uncircumcised patients, produces white pustules or vesicles on the glans penis. Other acute mucocutaneous forms include infections of the GI tract, including esophagitis, gastritis, and peritonitis. Chronic mucocutaneous candidiasis is a disorder of chronic, recurrent Candida infections of the skin, mucous membranes, and nails in patients with underlying defects in cell-mediated immunity51 (see Table 21-3). Lethal immune deficiencies involving dysgenesis of the thymus (Nezeloff syndrome, DiGeorge syndrome, and the Swiss type of agammaglobulinemia) may present in childhood with mild candidiasis often limited to the oral cavity; death usually occurs before age 2 years from other infections.29 Nonlethal immune deficiencies also present early in life and include endocrinopathy, which is associated with candidiasis of the oral cavity, skin, and nails and appears to be genetically transmitted, and a rare variant called candidal granuloma, which presents with multiple hyperkeratotic, crusted plaques.54-57 Late-onset chronic mucocutaneous candidiasis is associated with thymoma and may accompany myasthenia gravis.21,40 AIDS is often associated with chronic mucocutaneous candidiasis and frequently involves the oral cavity and esophagus.58 Systemic candidiasis is the most common invasive fungal infection in patients with cancer, burns, and AIDS or those undergoing organ transplantation. Candidemia, the most common clinical manifestation, occurs in 50% to 70% of patients with invasive candidiasis, and carries a mortality rate of about 40%,59 down from 80% in the 1970s; this decrease is attributed to early empirical antifungal and improved prophylactic treatment. 60 Approximately 9% of hospital-acquired nosocomial bloodstream infections (BSIs) in the United States have been attributed to Candida species, making the genus the fourth leading cause of nosocomial BSIs. 61 C. glabrata is a rising cause of candidiasis

in neutropenic patients, especially with underlying hematologic malignancies, despite receiving fluconazole prophylaxis.62 Although a less common cause of Candida bloodstream infection in the rest of the world, C. glabrata now ranks second to C. albicans in the United States, with 20% to 24% of Candida BSIs due to this recently emerged opportunistic pathogen.47,63,64 Compared with isolates of C. glabrata from Europe, Latin America, and the Asia-Pacific area, those from North America demonstrated lower susceptibility to azole antifungal agents.47,65 Disseminated candidiasis is associated with cutaneous manifestations in 10% to 13% of patients50,66,67 (Table 21-4). These manifestations are highly variable, ranging from very few to numerous erythematous macules, papules, and nodules that may be associated with purpura, necrotic eschars, subcutaneous abscesses, ecthyma gangrenosum-like ulcers, and nodular folliculitis in heroin users.67-71 Systemic candidiasis with skin manifestations was caused by C. tropicalis in 64% of patients.67 The triad of high fever, papular erythematous rash, and diffuse severe myalgias in neutropenic patients suggests disseminated disease.72 HISTOPATHOLOGIC FEATURES The vesicles and pustules of mucocutaneous candidiasis are characterized histologically by a subcorneal collection of lymphocytes and necrotic debris, with hyphae, pseudohyphae, and yeast cells confined to the stratum corneum (Fig. 21-2). Pseudohyphae

Table 21-4 Disseminated Candidiasis

Clinical Features Cutaneous findings in 10% to 13% of patients Variable skin manifestations C. tropicalis in 64% of cases with skin manifestations Triad of fever, papular erythematous rash, and diffuse severe myalgias in neutropenic patients is highly suggestive Histopathologic Features Pseudohyphae, hyphae, and spores (3-6 μm) in dermis often near blood vessels Spores may show budding Perivascular inflammatory infiltrate Leukocytoclastic vasculitis Differential Diagnosis Aspergillus fumigatus Histoplasma capsulatum May be confused with C. glabrata, which forms spores only

are chains of cells formed by the repeated budding of blastoconidia; although they are separated by septa, mother and daughter cells remain physically attached. Although C. glabrata occurs as yeasts only, other species show numerous hyphae measuring 2 to 4 μm in diameter and a few spores that may show budding and measure 3 to 6 μm in diameter.26,29 The organisms stain well with PAS, methenamine silver, Gridley, and Gram stains.50 In candidal granuloma, hyperkeratosis and papillomatosis are prominent, and parakeratosis and acanthosis may also be noted.57 A dense chronic inflammatory infiltrate with multinucleated giant cells may be found in the dermis and may extend into the subcutis.28,56 The histologic examination of disseminated candidiasis reveals Candida pseudohyphae and yeast cells within the dermis, often near or within blood vessels. Perivascular tissues and blood vessel walls may show edema.66 The epidermis is intact, and small foci of hemorrhage and fibrin exudate may be seen in the middle and lower dermis. The tissue response varies from a perivascular chronic inflammatory infiltrate to a leukocytoclastic vasculitis characterized by groups of neutrophils, nuclear debris, and necrosis in and around blood vessels.66,67 DIFFERENTIAL DIAGNOSIS Oral candidiasis resembles or may coexist with leukoplakia, squamous cell carcinoma, or herpes simplex.52 Esophageal infection may mimic cytomegalovirus, herpes simplex, or peptic ulcer esophagitis. The differential diagnosis for a subcorneal pustule secondary to Candida infection includes dermatophytic infection, impetigo, subcorneal pustular dermatitis, and pustular psoriasis. Candidiasis may be differentiated from dermatophytic infection by the presence of spores and pseudohyphae. The best diagnostic test is the demonstration of pseudohyphal invasion on microscopic examination of mucocutaneous lesions. A positive culture may lend support but is not by itself diagnostic.2 The necrotic pustules and ulcerative plaques of ecthyma gangrenosum, characteristic of Pseudomonas septicemia, resemble the cutaneous findings of disseminated candidiasis.70 Although skin manifestations are relatively uncommon in disseminated candidiasis, biopsy of skin lesions is important because blood cultures are positive in only 25% of cases.73 When blastospores are not seen, Candida pseudohyphae may be confused with Aspergillus hyphae; however, the latter are gram negative. C. glabrata, which does not form

B

A

pseudohyphae, may resemble Histoplasma capsulatum, although the latter usually elicits a granulomatous rather than a pyogenic response.2

Tinea Versicolor Synonyms: Pityriasis versicolor, tinea flava, dermatomycosis furfuracea, chromophytosis.26 Tinea versicolor is one of the most common pigmentary disorders in the world. It is caused by dimorphic, lipophilic yeasts of the genus Malassezia when, for reasons that remain unclear, they transform from the saprophytic state in healthy skin to the pathogenic mycelial state. This genus, of the phylum Basidiomycota, was previously known in the literature as Pityrosporum, with P. ovale and P. orbiculare identified on the basis of microscopic morphology as the pathogenic species. When the genus was initially divided on the basis of lipophilicity, M. furfur emerged as the predominant pathogenic species. A taxonomic revision with classification of the genus into seven species was carried out in 1996, when M. globosa, M. obtusa, M. slooffiae, and M. restricta were added to the genus, which had contained only three species: M. furfur, M. pachydermatis (the only nonlipid dependent species), and M. sympodialis.74,75 Of the identified species, M. globosa, M. sympodialis, and M. furfur probably cause most cases of tinea versicolor; M. globosa is the predominant species associated with the condition in temperate climates.76-79 M. slooffiae, M. restricta, and M. obtusa have also been implicated. CLINICAL FEATURES Tinea versicolor occurs worldwide but has an increased prevalence, up to 40%, in tropical areas owing

to high temperature and humidity80 (Table 21-5). In temperate zones, the incidence is higher during the warmer months of the year.81 The infection does not appear to be contagious and occurs under conditions permitting overgrowth of the fungus such as warm weather and continual perspiration.2,82 Small, red or light brown, scaly macules occur most commonly on the chest, upper back, shoulders, upper arms, and abdomen.81 The macules enlarge and may become either hypo- or hyperpigmented depending on natural skin color and sun exposure. Depigmentation has been attributed to the production by the yeasts of dicarboxylic acids, such as azelaic acid, that competitively inhibit tyrosinase and may have a directly toxic effect on melanocytes.83 Hyperpigmentation appears to be related

Table 21-5 Tinea Versicolor

Clinical Features Caused by Malassezia furfur or M. ovalis Occurs in tropics and warm months of temperate zones Age of onset usually in early twenties in temperate zones Pale to brown, slightly scaling macules over the upper trunk Histopathologic Features Hyperkeratosis and slight acanthosis Superficial dermal lymphohistiocytic infiltrate Hyphae and spores seen in stratum corneum Differential Diagnosis Tinea corporis Candidiasis Spongiotic dermatitis

to an increase in melanosome size.62 Although most cases are asymptomatic, the major complaint is cosmetic because the fungus causes uneven tanning by filtering out ultraviolet radiation. Clinical examination with a Wood lamp may be of use because Malassezia furfur exhibits yellow to yellow-green fluorescence, although, to date, other species of the genus do not.84,85

CHAPTER 21 ■ FUNGAL INFECTIONS

 FIGURE 21-2 Candidiasis. (A) Intertriginous candidiasis characterized by erythematous moist and macerated lesions with erosions, irregular edges, peripheral scaling, and satellite papules and pustules. (B) High magnification illustrating pseudohyphae with branching.

HISTOPATHOLOGIC FEATURES Most commonly, hyperkeratosis, slight acanthosis, spotty pigmentation of the epidermal basal layer, and a superficial perivascular lymphohistiocytic infiltrate are seen.2,86 PAS stain reveals numerous short, multibranching hyphae and spores (so-called “spaghetti and meatballs”) within the stratum corneum. Malassezia species exhibit monopolar budding.84 (Figs. 21-3 and 21-4; see also Table 21-5). DIFFERENTIAL DIAGNOSIS Spongiotic dermatitis, as in eczema, the id reaction, or infection by dermatophytes or Candida species, may be confused with pityriasis versicolor if fungal stains are not obtained.

Malassezia Folliculitis Malassezia folliculitis was previously called Pityrosporum folliculitis. The exact pathogenesis of this disease remains controversial.2,87 The initiating event may be follicular occlusion followed by overgrowth of the organism rather than direct invasion of the follicle. Predisposing factors appear to include occlusion and greasy skin.88 The condition has been associated with tetracycline antibiotics, corticosteroids, and immunosuppression in organ transplant patients.76

465

Table 21-6 Malassezia (Pityrosporum) Folliculitis

PART III ■ INFECTIONS

Clinical Features Caused by Malassezia furfur or M. ovalis Occurs in young to middle-aged adults Pruritic papules on the trunk, shoulders, and occasionally the face Occlusion and greasy skin may predispose to infection Histopathologic Features Numerous spores within dilated, plugged hair follicles Neutrophils, lymphocytes, and histiocytes within follicles and in perifollicular regions Foreign body reaction near ruptured follicles Pools of mucin may be seen within follicles Differential Diagnosis Acneiform drug eruption Dermatophytic or bacterial folliculitis Follicular mucinosis Acne vulgaris

“molluscoid” papules, which have a central depression similar to the papules of molluscum contagiosum, may also be seen.89

 FIGURE 21-3 Tinea versicolor. Periodic acid-Schiff stain with diastase stain highlights short hyphae and spores (so-called “spaghetti and meatballs”) in the stratum corneum.

CLINICAL FEATURES Malassezia folliculitis is a benign condition characterized by follicular papules and pustules occurring predominantly on the back and chest; it is more common in tropical climates and

A

466

HISTOPATHOLOGIC FEATURES Most cases show numerous spores inside the hair follicles that appear widely dilated and are plugged with keratinous material (see Table 21-6). Features of secondary perforating folliculitis may be present. Occasional hyphae have been noted

summer in temperate climates.76 The typical patient is a young to middle-aged adult with pruritic papules on the trunk, shoulders, and occasionally the face (Table 21-6). Pustules, cysts, and

B

 FIGURE 21-4 Malassezia (pityrosporum) folliculitis. (A) The follicle is dilated and infiltrated by neutrophils resulting in follicular pustule formation. There are pityrosporum yeast forms present within the hair follicle. (B) Hyphae and spores in follicular orifice.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes acneiform drug eruptions, dermatophytic or bacterial folliculitis, follicular mucinosis, and acne vulgaris.92

Piedra and Trichosporonosis Synonyms: Tinea nodosa, trichomycosis, molestia de Beigel, trichomycosis nodularis, trichomycosis nodosa, Beigel disease, Chignon disease Piedra, meaning stone in Spanish, is a superficial fungal infection that produces firm nodules along the hair shaft. Two varieties caused by unrelated fungal species have been described. Black piedra is caused by Piedraia hortae, an ascomycete that appears to be related to the family Piedraiaceae.26 The teleomorphic reproductive propagule of the Ascomycota is the ascospore; these are produced in sacs called asci and are formed by the condensation of cytoplasm around the nucleus after meiosis.26 White piedra is caused by yeastlike fungi of the genus Trichosporon, of the class Basidiomycetes, which are found in soil and occasionally in normal skin.2 These organisms were formerly classified as the single species Trichosporon beigelii. Six pathogenic species have been identified, including T. asahii, T. mucoides, T. inkin, T. ovoides, T. asteroides, and T. cutaneum.93-95 The first four species are associated with white piedra, with T. ovoides associated with white piedra of the scalp and T. inkin associated with that of pubic hair. T. asahii and T. mucoides are known to cause deep invasive infections.84,96 Disseminated infection, called trichosporonosis, occurs mostly in immunocompromised patients, particularly those receiving chemotherapy or those with AIDS,97 and is an emerging life-threatening opportunistic disease

associated with hematologic malignancies and neutropenia. 98 CLINICAL FEATURES Black piedra occurs worldwide, with increased frequency in tropical areas, particularly in South America, Southeast Asia, and Africa2,99 (Table 21-7). Although the scalp hair is the most common site of infection, the beard, mustache, and pubic hair may also be affected. Affected individuals have hard, dark brown to black nodules firmly adherent to their hair shafts. The nodules, measuring up to a few millimeters in length and up to 150 μm in thickness, are typically thickest in the center or on one end. The thin areas consist of a layer of aligned hyphae and arthrospores, which are spores resulting from hyphal fragmentation along septa; the thick area is composed of fungal cells cemented together.2 Although unable to penetrate the cortex, the fungal infection begins under the cuticle, disrupting it and growing along the outer surface of the hair.100 Hair follicles and skin are unaffected, and hair breakage is rare. White piedra occurs most commonly in semitropical and temperate areas and in parts of the southeastern United States (Table 21-8). The beard, axillary, and groin hairs are involved most frequently, although the fungus may also affect the scalp hair, eyelashes, and eyebrows. In Brazil, this infection usually affects the scalp.101 Familial spread may occur.99 Genital white piedra has been reported

Table 21-7 Black Piedra

Clinical Features Caused by Piedra hortae Occurs in tropics Usually involves scalp hairs Hard, dark firmly adherent nodules Hair breakage is rare Skin and hair follicles are normal Histopathologic Features Dark nodules, thicker in the center or on one end Tightly packed, dark hyphae fragmenting into arthrospores Rectangular arthrospores (4-8 μm in diameter) Asci containing ascospores within nodules Differential Diagnosis Pediculosis Trichomycosis axillaris (hyphae ≤1 μm or less) Trichorrhexis nodosa Monilethrix trichoptilosis

Table 21-8 White Piedra

Clinical Features Caused by Trichosporon beigelii Occurs in semitropical and temperate areas Usually involves the beard, axillary, or groin hairs Soft, lightly colored nodules on hair; nodules may be scraped off easily Hair breakage occurs near nodules Normal skin and hair follicles Histopathologic Features Loosely adherent, transparent sheath of variable color on shaft Sheath composed of loosely arranged mycelia Mycelia often perpendicular to hair shaft Blastoconidia and arthroconidia (2-4 μm), ≤ 8 μm No asci Differential Diagnosis Same as for black piedra

to be caused by a synergistic infection by coryneform bacteria and T. beigelii.102 White piedra is characterized by soft white, red, green, or light brown nodules along the hair shaft. The nodules may be scraped off easily.99 Fungal infection begins under the cuticle, and the growth is often intrapilar, causing weakness and breakage of hair at fungal nodules.26 The cuticle is usually not disrupted significantly. The hair follicles and skin appear normal. Trichosporonosis is a disseminated infection by Trichosporon species, which presents mainly in patients who are neutropenic due to chemotherapy for hematologic malignancies; infection has been associated with a mortality rate greater than 80%.103 Fungemia may also occur in association with catheters or via the respiratory or GI tract.96 T. asahii and, less commonly, T. mucoides are considered the major etiologic agents of deep invasive infection103 and have been associated with summer-type hypersensitivity pneumonitis initially described in Japan.104 Serum latex agglutination test results for cryptococcal capsular polysaccharide may be positive in patients with trichosporonosis because C. neoformans and Trichosporon share antigens.103 Polymerase chain reaction (PCR) assays have been developed to detect this pathogen because the clinical course resembles those of other systemic mycoses such as candidiasis.105 Although most cases have been reported in immunocompromised patients, a case of invasive trichosporonosis, presenting as meningitis and pneumonia, was recently reported

CHAPTER 21 ■ FUNGAL INFECTIONS

within distended follicles.88 A perifollicular inflammatory cell infiltrate consisting of neutrophils, lymphocytes, and histiocytes is present in the intrafollicular and perifollicular regions, and pools of mucin, which may be confirmed by a colloidal iron stain, may be seen both within and around the follicles.90 A foreign body type of granulomatous reaction near a ruptured follicular wall has been reported.89 The Splendore-Hoeppli phenomenon, which is characterized by a homogeneous, partially laminated core containing Malassezia spores surrounded by a thin layer of darkly stained filaments, may occasionally be seen within the follicle.91 A classic case is illustrated in Fig. 21-4A.

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in a non-immunocompromised host in India.106 Cutaneous lesions, occurring in approximately 30% of patients,107 are characterized by purpuric papules and centrally necrotic or ulcerating nodules typically present on the trunk, arms, and face.97 HISTOPATHOLOGIC FEATURES In KOH preparations, black piedra is characterized by dark, firmly adherent nodules consisting of tightly packed, darkly pigmented hyphae that are segmented into rectangular arthrospores 4 to 8 μm in diameter.2 Asci containing ascospores arranged in groups of eight84 are visible within the nodules. In white piedra, a loosely adherent; transparent; green, red, white, or tan sheath may be seen on the hair shaft. This sheath is composed of disorganized, loosely packed mycelia often arranged at right angles to the hair shaft. Blastoconidia and arthroconidia measuring 2 to 4 μm and occasionally up to 8 μm in diameter are seen, but asci are not. Bacteria may be seen mixed among the fungal elements.26 In disseminated Trichosporon infections, pseudohyphae, numerous rectangular arthroconidia, and small numbers of blastoconidia are seen in the dermis. Vasculitis and vascular thrombosis have also been observed.97 DIFFERENTIAL DIAGNOSIS Other conditions that may lead to perifollicular concretions include pediculosis, trichomycosis axillaris, and trichorrhexis nodosa; additionally, monilethrix trichoptilosis has focal nodelike swellings along the follicle. The hyphae of trichomycosis axillaris are 1 μm or smaller in diameter, compared with 2 to 4 μm in white piedra.

SYSTEMIC MYCOSES

468

Fungal infections acquired through the respiratory route may disseminate by progressive pulmonary infection with systemic spread after failure of the normal cell-mediated immune response or by reactivation of dormant sites of infection with secondary systemic dissemination. Mucocutaneous lesions, which occur in approximately 10% of patients with disseminated disease, sometimes represent the initial presenting sign of disseminated infection. In most cases of cryptococcosis, coccidioidomycosis, and histoplasmosis, the development of skin lesions is essentially diagnostic of systemic disease because primary cutaneous infection is exceedingly rare. For this reason, cryptococcosis will be discussed in this section even though it is a yeast.

Cryptococcosis Synonyms: Torulosis, Busse-Buschke disease, European blastomycosis. The genus Cryptococcus includes more than 30 known species of yeasts, two of which are known to be pathogenic for cryptococcosis in humans: C. neoformans and C. gattii. Previously, these species were classified into three varieties, C. neoformans var. neoformans, C. neoformans var. grubii, and C. neoformans var. gattii, which were classified into five serotypes based on agglutination reactions of the capsular polysaccharide antigens. Based on capsular structural differences, genome sequencing, and DNA fingerprinting, serotype A strains, accounting for more than 95% of cryptococcal cases, are now classified as C. neoformans var. grubii. Serotype D strains have been named C. neoformans var. neoformans. Serotypes B and C strains have been classified as C. gattii.108 C. neoformans is an important opportunistic infection worldwide in persons infected with HIV, and a recent outbreak of cryptococcosis in apparently immunocompetent persons on Vancouver Island, Canada, was attributed to C. gattii.109 Attributed to widespread use of highly active antiretroviral therapy (HAART),110,111 the incidence of cryptococcosis declined in the United States during the 1990s, both in the general population as well as in persons living with AIDS; almost 90% of cases occurred in HIV-infected persons. In 2000 in the United States, the incidence in the general population was 1.3 cases per 100,000, down from 5 cases per 100,000 in 1992, and 7 per 1000 for persons living with AIDS, down from 66 cases per 1000 persons living with AIDS in 1992.110 In a population-based surveillance between 2002 and 2004, the incidence of cryptococcosis in the general population of a south African province was reported at 15 per 100,000,112 a rate much higher than that observed in the general population of the United States even before the introduction of HAART.113 CLINICAL FEATURES Cryptococcosis is caused by Cryptococcus species, a saprophyte found worldwide in soil enriched by bird droppings.114,115 Humans are infected via environmental exposures (Table 21-9). Cryptococcus is unencapsulated in nature; its smallest forms measure less than 2 μm, and thus it lodges in alveolar spaces after inhalation.115 Encapsulation occurs in the lung and is associated with increased virulence because phagocytosis is impaired by concealment by opsonic antibodies.116

Table 21-9 Cryptococcosis

Clinical Features Caused by Cryptococcus neoformans var. neoformans in >80% of cases C. neoformans is found in soil contaminated with bird and bat excreta Usually inhaled, can disseminate to brain, meninges, and cerebrospinal fluid Skin involvement variable—papules, pustules, nodules, plaques, cellulitis Most common systemic fungal infection in AIDS patients Serum latex agglutination valuable in diagnosis of active disease Histopathologic Features Large aggregates of encapsulated, budding, refractile yeast, 5-15 μm in diameter Variable granulomatous infiltrate of lymphocytes, histiocytes, multinucleated giant cells and neutrophils If infiltrate is dense, few organisms are seen; those present are smaller and may lie within macrophages Yeast stains with PAS, methenamine silver and Fontana-Masson Capsule stains with Alcian blue and mucicarmine Differential Diagnosis Blastomycosis Histoplasmosis Lobomycosis

Adults with lymphoma, carcinoma, sarcoidosis, collagen vascular disease, or AIDS or those who are on immunosuppressive therapy may show increased susceptibility to cryptococcus.117-119 Primary cutaneous cryptococcosis is a rare event that occurs after direct inoculation.120 Pulmonary infection often is transient or asymptomatic, and in most instances, cryptococcosis presents as a disseminated or a central nervous system (CNS) infection (eg, as a chronic meningitis or a focal brain lesion resembling a tumor). The phenotypic switching in vivo that results in an altered capsular polysaccharide may inhibit phagocytosis by alveolar macrophages and is associated with an enhanced inflammatory response and greater lethality.121 Cutaneous lesions may appear as erythematous nodular firm, cystic-appearing excrescences; acneiform papules or pustules; crusted or infiltrating plaques; or cellulitis.122 Any of these lesions may ulcerate.123 In individuals with AIDS, numerous nodules resembling giant molluscum lesions are common.124 Serum latex agglutination is valuable in the diagnosis of active disease and in excluding such disease.125

DIFFERENTIAL DIAGNOSIS The differential diagnosis among C. neoformans, B. dermatitidis, H. capsulatum, and lobomycosis may be aided by the Fontana-Masson stain, which stains cryptococci alone black.127

North American Blastomycosis Synonyms: Blastomycosis, Gilchrist disease, Chicago disease

 FIGURE 21-5 Cryptococcosis. A sheet of spores in the gelatinous form of cryptococcosis fills the papillary dermis with little inflammatory reaction.

In contrast to fungal infections that preferentially develop in immunosuppressed individuals, blastomycosis, similar to coccidioidomycosis, paracoccidioidomycosis, and histoplasmosis, is endemic and can infect healthy individuals.128 First

 FIGURE 21-6 Cryptococcosis. Higher magnification discloses Periodic acid-Schiff plus distase–positive spores with a surrounding clear halo characteristic of this organism.

CHAPTER 21 ■ FUNGAL INFECTIONS

HISTOPATHOLOGIC FEATURES In the past, two distinct histologic patterns were described, a granulomatous pattern consisting of a dense mixed infiltrate with few organisms and a gelatinous pattern consisting of little inflammation and large numbers of spores (Figs. 21-5 and 21-6; see also Table 21-9). However, they may both be present and are not of recognizable clinical significance.123,126 The characteristic feature includes aggregates of encapsulated yeasts, often but not always with a granulomatous response and sometimes with necrosis.122,123 The yeast cells range from 2 to 15 μm in diameter and show narrow-based, unequal budding.126 The yeast cytoplasm stains with PAS or methenamine silver and the capsule with Alcian blue or mucicarmine. A combination of PAS and Alcian blue stains highlights the yeast cytoplasm in red and the capsule in blue. C. neoformans stains black with the Fontana-Masson stain, a valuable feature in patients with AIDS who are infected with strains of low virulence and relatively little capsular material.127 Variable acanthosis or ulceration of the overlying skin may be present.127

described in 1894 by Gilchrist, it is caused by Blastomyces dermatitidis, a dimorphic fungus.129 Although called North American blastomycosis because the original cases clustered around states crossed by the Mississippi and Ohio Rivers, it has also been reported in South America, Europe, and Africa.130,131 B. dermatitidis is found in the acidic soil of wooded areas. The typical patient is a man between 25 and 50 years of age with occupational or recreational exposure to the outdoors. Blastomycosis also occurs in dogs. CLINICAL FEATURES Primary cutaneous blastomycosis is a rare disorder that has been described after accidental inoculation in the laboratory or during an autopsy. An ulcerated verrucous plaque arises at the inoculation site followed by lymphangitis and nodules spreading in a sporotrichoid distribution. Spontaneous healing occurs in the ensuing months. The more common clinical forms of blastomycosis are the primary pulmonary, chronic cutaneous, and disseminated forms (Table 21-10). Infection with B. dermatitidis begins with inhalation of conidia. If not cleared by bronchopulmonary macrophages, these conidia transform into yeast forms and multiply in the lung parenchyma, although

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Table 21-10 North American Blastomycosis

470

Clinical Features Caused by Blastomyces dermatitidis Dimorphic fungus, found in acid soil of wooded areas Endemic in South Central and Southeastern United States More common in men with a history of outdoor exposure Age 25-50 years Cutaneous involvement in 70% of patients with disseminated disease Verrucous plaques with peripheral pustules—face, mucosa Occasional ulcers Erythema nodosum associated with pulmonary blastomycosis Usually inhaled, may disseminate to bones and CNS Histopathologic Features Pseudoepitheliomatous hyperplasia Intraepidermal and dermal neutrophilic microabscesses Suppurative granulomatous infiltrate with giant cells Spores are thick walled and 5-15 μm in diameter Present extracellularly, within giant cells, epidermal and dermal abscesses, and granulomas Buds are single and broad based Differential Diagnosis Coccidioidomycosis Tuberculosis Paracoccidioidomycosis Chromoblastomycosis Blastomycosis-like pyoderma Pyoderma gangrenosum Halogenoderma

pulmonary blastomycosis may heal spontaneously.129 Subsequent hematogenous dissemination may occur. The clinical spectrum of pulmonary blastomycosis thus ranges from no symptoms whatsoever in up to 50% of those who have inhaled blastomycosis conidia or spores to an acute or chronic pneumonia. Erythema nodosum may occur during the resolving phase of the acute pneumonia. Patients with acute pneumonia may appear to recover but then return months later with disseminated infection. Chronic pulmonary blastomycosis is often associated with weight loss, fever, night sweats, chest pain, and hemoptysis.124 Chest radiographs are nondiagnostic and may reveal masses in 32% and alveolar infiltrates in 48% of patients as well as cavitation, pleural fibrosis, and hilar adenopathy simulating tuberculosis.128,129

Cutaneous blastomycosis occurs from hematogenous spread in 70% of patients with disseminated blastomycosis.125 These patients develop verrucous plaques with peripheral pustules and occasional ulcerations on the face, mucous membranes, and arms. If cutaneous blastomycosis is present and there is no pulmonary disease, the latter is thought to have resolved spontaneously.129 Osteomyelitis occurs in 25% of patients with disseminated disease, most commonly affecting the spine, pelvis, skull, ribs, and long bones.125,128 Granulomas, suppuration, or necrosis can be contiguous between bone and adjacent soft tissues, leading to subcutaneous abscesses. CNS infections occurs in fewer than 10% of patients and may be associated with meningitis and brain abscess formation.125,129 Infection may also involve the genitourinary tract.125 Serologic tests are of limited value at present because of a high rate of falsepositive and false-negative results. Although a positive immunodiffusion test result is diagnostic, this test has negative results in 10% of patients with disseminated infection and 60% of patients with localized infection.125 A urinary antigen enzyme immunoassay with 92.9% sensitivity and 79.3% specificity has been developed,132 but there is significant cross-reactivity with histoplasmosis antigen.133 Diagnosis is made by histologic examination and fungal culture.

HISTOPATHOLOGIC FEATURES Biopsy of the active border of a plaque or of an ulcer reveals pseudoepitheliomatous hyperplasia. Intraepidermal and dermal neutrophilic abscesses also are seen. The dermis contains a granulomatous infiltrate consisting of lymphocytes, histiocytes, plasma cells, neutrophils, and multinucleated giant cells. B. dermatitidis spores are seen free in the tissue or within giant cells within the foci of suppurative granulomatous inflammation and pseudoepitheliomatous hyperplasia. B. dermatitidis spores measure 5 to 15 μm and have a thick wall consisting of the exterior and interior cell surfaces. An occasional single, broad-based, equal-sized bud is characteristic. Spores can be identified as an empty round space within the cytoplasm of giant cells using H&E stain; however, their visualization is enhanced with PAS or methenamine silver stains125,130 (Fig. 21-7). DIFFERENTIAL DIAGNOSIS Blastomycosis may be distinguished from coccidioidomycosis by the greater number of intraepidermal microabcesses and the much smaller size of the spores (5-15 μm) compared with the sporangia of Coccidioides species. The etiologic agent of paracoccidioidomycosis has multiple buds with a narrow base as opposed to the broad-based buds of B. dermatitidis. Whereas the dematiaceous fungi of chromoblastomycosis appear dark brown on H&E-stained

 FIGURE 21-7 North American blastomycosis. Large spores with surrounding granulomatous inflammation demonstrated by Periodic acid-Schiff staining with diastase. Note halo around cytoplasm of the fungal cell owing to retraction because of shrinkage during processing.

sections, B. dermatitidis appears as an empty space within giant cells.

Coccidioidomycosis

CLINICAL FEATURES Three types of coccidioidomycosis have been described: pulmonary, cutaneous inoculation, and systemic (Table 21-11). Primary pulmonary coccidioidomycosis, which is by far the most common form, occurs in about 40% of individuals exposed to C. immitis and manifests 10 to 14 days after exposure with fever, chest pain, headache, and cough. Chest radiographs may show cavitary pulmonary lesions that usually resolve spontaneously in 3 to 4 months. Simultaneously or in the weeks after pulmonary infection, erythema nodosum and erythema multiforme may occur.137 Only 0.1% to 0.5% of patients with pulmonary coccidioidomycosis go on to develop systemic disease, which may involve the skin, CNS, and musculoskeletal system.137 Systemic disease is more common in Filipinos, African Americans, and Mexicans and affects men more often than women, with the exception of pregnant women. Systemic coccidioidomycosis is associated with skin changes in about 20% of patients. These include granulomatous plaques, pustules, and nodules.140 Erythema nodosum is the most characteristic reactive cutaneous manifestation of dissemi-

Clinical Features Caused by Coccidioides immitis Endemic in arid regions of southwestern United States, Mexico, and South America Dimorphic soil fungus, inhaled with dust Frequency of systemic disease:<0.5% of patients with pulmonary disease develop systemic disease Incidence Filipinos > African Americans > Mexicans > Whites 20% Cutaneous involvement with disseminated disease Granulomatous plaques, pustules, and nodules Erythema nodosum, erythema multiforme Coccidioidin skin test converts weeks following exposure, remains positive for years Histopathologic Features Acanthosis, intraepidermal microabscesses Granulomatous infiltrate Lymphocytes, histiocytes, neutrophils, giant cells Eosinophils Variable abscess formation and necrosis Sporangia are rare but large, ≤ 80 μm in diameter Numerous 1-4 μm endospores in sporangia Present in giant cells or extracellularly Differential Diagnosis North American blastomycosis Tuberculosis verrucosa cutis Halogenoderma Pemphigus vegetans

nated infection, and it tends to occur 1 to 3 weeks after onset of illness.141 Erythema nodosum may have a protective effect against dissemination of coccidioidomycosis in pregnant women.142 An immunosuppressed state or immunosuppressive therapy may activate a latent pulmonary infection and result in systemic disease. Primary cutaneous coccidioidomycosis is quite rare; lesions resemble the verrucous plaques of primary cutaneous tuberculosis and are often associated with lymphangitis and lymphadenitis 2 to 3 weeks after accidental inoculation.139 If a patient has traveled to an endemic area and coccidioidomycosis is suspected, chest radiography and a coccidioidin skin test should be performed. The coccidioidin skin test becomes reactive 2 to 6 weeks after infection and remains positive for years; however, a

negative test result does not rule out disease in immunosuppressed patients.125 Peripheral eosinophilia and eosinophilia of cerebrospinal fluid, the lungs, and other tissues may be seen in disseminated infection, most likely owing to increased interleukin-5 production.138 The presence of complement-fixing antibodies correlates strongly with systemic disease. HISTOPATHOLOGIC FEATURES Examination of the verrucous plaques of primary inoculation coccidioidomycosis reveals acanthosis and a diffuse, dense dermal infiltrate of neutrophils, lymphocytes, histiocytes, plasma cells, eosinophils, and giant cells. Spores are found within the giant cells and free in the tissue139 (see Table 21-11). In the verrucous plaques and papulonodules of systemic coccidioidomycosis, there is acanthosis and formation of intraepidermal microabcesses, although to a lesser degree than in blastomycosis. Endothelial cell proliferation and a perivascular acute and chronic inflammatory infiltrate are seen. In addition to perivascular inflammation, the dermis may contain a granulomatous infiltrate consisting of neutrophils, lymphocytes, histiocytes, plasma cells, eosinophils, and multinucleated giant cells. Within the granulomas, abscess formation and necrosis are seen, both in the verrucous plaques and in the subcutaneous abscesses noted clinically. Leukocytoclasis and focally altered collagen associated with increased dermal mucin may be seen in association with the granulomatous infiltrate.143 The sporangia of Coccidioides species are usually few in tissue sections, but when they are present, they are quite large and thick walled, measuring up to 80 μm (Fig. 21-8). They contain numerous endospores measuring 1 to 4 μm and are present within the giant cells or free in the tissue. Although they may be seen with H&E-stained sections, PAS and methenamine silver highlight the endospores.137 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes both infectious and noninfectious processes that exhibit pseudoepitheliomatous hyperplasia, intraepidermal microabscesses, and suppurative granulomas in the dermis and subcutis. The verrucous plaques may resemble those seen in North American blastomycosis but have fewer microabcesses. Methenamine silver and PAS stains performed on multiple tissue sections should enable recognition of sporangia, which are not seen in North

CHAPTER 21 ■ FUNGAL INFECTIONS

Synonyms: Posada disease, coccidioidal granuloma, desert rheumatism, San Joaquin Valley fever, California disease. Coccidioidomycosis is endemic in the arid and semi-arid regions of the southwestern United States and northern Mexico, and it also occurs in parts of Central and South America. The disease is a significant opportunistic mycosis in patients with HIV134 and organ transplant recipients.135 Coccidioides species are found in the soil, and pulmonary disease is caused by inhalation of contaminated dust. On the basis of genomic analyses, the genus has been divided into two species: C. immitis (strains from California) and C. posadasii (strains from outside California); there is no apparent difference in clinical expression caused by the two species.136 Coccidioidomycosis may occur in cattle, primates, dogs, rodents, and humans in endemic areas.137-140 Coccidioides species are dimorphic fungi that grow in less than 1 week on Sabouraud agar. However, cultures must be carried out under strict precautions because the aleuriospores are highly infectious.

Table 21-11 Coccidioidomycosis

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Table 21-12 Paracoccidioidomycosis

 FIGURE 21-8 Coccidioidomycosis. Note the large characteristic spherules containing endospores. (Courtesy of Dr. D. Mehregan.)

American blastomycosis, tuberculosis verrucosa cutis, halogenoderma, and pemphigus vegetans.

Paracoccidioidomycosis Synonyms: South American blastomycosis, Lutz-Splendore-Almeida disease. Paracoccidioidomycosis is endemic in the humid mountain forests of South and Central America, and it has also been reported in individuals who have previously spent time in these regions.125 It is the most common systemic mycosis in Latin America, with 10 million individuals, or about 10% of the endemic area’s population, presently infected.144,145 Brazil accounts for 80% of reported cases,146 with the highest incidence in the tropical and subtropical forested areas of the southeast147; Columbia and Venezuela have the next highest incidence. Infection occurs after inhalation of the mycelia or conidia of the dimorphic fungus, Paracoccidioides brasiliensis, the causative agent. The precise ecologic niche remains unknown. The organism has been isolated rarely from soil, which has generated debate about soil as the permanent habitat.148 Amazonian armadillos were found to harbor the fungus in their internal organs,149 although they may simply be accidental hosts rather than the natural reservoir.

472

CLINICAL FEATURES Paracoccidioidomycosis typically begins with primary pulmonary infection followed by dissemination to other organs with the development of

ulcerative granulomas of the oral and nasal mucous membranes and sometimes other tissues, including the skin, lymph nodes, and adrenal glands (Table 21-12). The infection may remain subclinical, with only a positive skin test reaction, or may progress to overt disease, usually with a long latency period. More than 90% of paracoccidioidomycosis occurs in adults, with clinical disease rates highest in the 30- to 60year-old age group. Although there are no gender differences in the rates of subclinical infections, as determined by positive paracoccidioidin skin test result, or in childhood disease, there is a striking male predominance of 13:1 in endemic areas and up to 150:1 in Columbia, Ecuador, and Argentina.150 The observed male predominance is thought to be most likely owing to inhibition by estrogens of conidium- and mycelium-toyeast transformation.151,152 Pulmonary paracoccidioidomycosis is characterized by cough, fever, night sweats, and anorexia. In some cases, it resolves without dissemination; however, it may become latent, with possible reactivation years later.125 Bilateral infiltrates, fibrosis, and cavitation may be seen on chest radiographs.152 Mucosal and skin involvement is common in progressive disease, occurring in 60% of patients.144 Progressive painful ulcers develop on the gingivae, tongue, lips, and palate and may lead to perforation of the palate or nasal septum.125 Cutaneous manifestations of paracoccidioidomycosis usually involve the face

Clinical Features Caused by Paracoccidiodes brasiliensis Dimorphic soil fungus of subtropical South and Central America Infection occurs predominently in men Pulmonary infection characterized by fever and weight loss Mucocutaneous involvement in 60% of cases Ulcers of lip, tongue, palate Verrucous plaques, usually on the head and neck Cervical and submandibular adenopathy Difficulty eating, speaking, breathing Histopathologic Features Ulceration, pseudoepitheliomatous hyperplasia Granulomatous infiltrate Lymphocytes, histiocytes, neutrophils, giant cells Occasional necrosis, abscess formation Yeast seen intra- and extracellularly, and in giant cells Thick-walled, refractile, variably sized yeast measure 4-40 μm in diameter Yeast occur singly, in chains, or as a “captain’s wheel” with multiple buds Differential Diagnosis North American blastomycosis Lobomycosis Histoplasmosis Leishmaniasis

but may be disseminated. Acneiform papules or nodules slowly develop into crusted plaques with well-defined, raised borders.144 Complications including difficulty speaking, swallowing, and breathing; scarring fibrosis; and draining sinus tracts may be seen in the late stages of the disease.146 Lymphadenopathy, most often in the cervical and submandibular nodes, may occur in patients with disseminated disease. Hematogenous spread may lead to multiple organ involvement, including adrenal gland destruction, osteomyelitis, and CNS involvement.150 High titers (1:1024) of complementfixing antibodies to paracoccidioidin imply active disease. However, crossreactivity to H. capsulatum, B. dermatitidis, and other fungal pathogens may make interpretation difficult. Some patients experience impaired delayed hypersensitivity.154,155 Immunodiffusion test results are positive in approximately 80% of patients with disease, although cross-reactivity remains a problem with some. Other immunologic assays in addition to a nested PCR assay may serve as useful diagnostic adjuncts.147,156

DIFFERENTIAL DIAGNOSIS If the yeasts occur singly or in chains, it may be difficult to distinguish the etiologic agent of paracoccidioidomycosis from those of North American blastomycosis, lobomycosis, and histoplasmosis. A diligent search for the characteristic “captain’s wheel” is helpful. The agent of North American blastomycosis has a single broad-based bud as opposed to the narrow budding pattern of P. brasiliensis and Lacazia loboi. H. capsulatum buds generally are smaller (2-4 μm) than those of P. brasiliensis.

Classic Histoplasmosis Synonyms: Darling disease, cave disease, Ohio Valley disease Histoplasmosis is caused by two strains of the dimorphic fungus H. capsulatum var. capsulatum and var. duboisii (associated with African histoplasmosis).158 The organism occurs worldwide, particularly in soil contaminated by bird and bat excreta.125 Despite the distinct clinical and histologic appearance of African histoplasmosis, H. capsulatum var. capsulatum and var. duboisii are considered variants of the same species because their yeast forms appear identical after prolonged growth at 37°C.159 CLINICAL FEATURES Classic histoplasmosis is endemic in the Mississippi and Ohio River valleys, Central America, and parts of Southeast Asia and the Mediterranean basin,133 with a positive histoplasmin skin test result in up to 80% of the population in highly endemic areas.160 It occurs in four forms: primary cutaneous inoculation, acute pulmonary infection, chronic pulmonary infection, and disseminated disease (Table 21-13). Before the advent of AIDS, disseminated histoplasmosis was a rare event, occurring in 1 in 100,000 to 1 in 500,000 persons per year.161 In endemic areas, disseminated histoplasmosis may affect 10% of AIDS patients, and for 75% of these, this will be their first manifestation of HIV infection.162 Since the introduction of HAART, disseminated histoplasmosis is less frequent

 FIGURE 21-9 South American blastomycosis. Large spores with a narrow-based budding are seen.

Table 21-13 Classic Histoplasmosis

Clinical Features Occurs worldwide in soil containing bird excreta Common in southeastern and midwestern US, where 80% of population may have a positive historesultplasmin test Pulmonary infection is portal of entry, asymptomatic in vast majority of cases Disseminated disease characterized by Mucosal ulcers Cutaneous nodules, plaques, ulcers, pustules, panniculitis Hepatosplenomegaly Anemia, meningitis Adrenal destruction Histopathologic Features H. capsulatum var. capsulatum, 2-4 μm in diameter, argyrophilic, with pseudocapsule Leukocytoclastic vasculitis, granulomatous infiltrate, panniculitis, ulceration Yeast present in histiocytes, giant cells, and yeast and extracellularly Differential Features Rhinoscleroma Granuloma inguinale Leishmaniasis Cryptococcosis

in persons infected with HIV in the United States, but it continues to be a significant opportunistic infection in Central America.163-165 Primary cutaneous histoplasmosis is extremely rare and results from direct inoculation. It presents as a chancriform ulcer with associated regional lymphadenopathy. Its course may be self-limited, or it may progress to disseminated disease in immunocompromised individuals.166 The vast majority of people who inhale H. capsulatum spores remain asymptomatic. A minority, after an incubation period of 3 weeks, develop flulike symptoms. Erythema nodosum or erythema multiforme may occur during the recovery phase.167 Chest radiographs reveal hilar lymphadenopathy and small, scattered nodules that may heal with calcification.161 Chronic pulmonary histoplasmosis occurs in older men who have a history of chronic obstructive pulmonary disease and is associated with fever, hemoptysis, and weight loss. Segmental interstitial infiltrates may progress to extensive fibrosis, cavitation, and destruction of lung tissue.160 Disseminated histoplasmosis may develop in infants and immunocompromised individuals and may manifest

CHAPTER 21 ■ FUNGAL INFECTIONS

HISTOPATHOLOGIC FEATURES Ulceration is observed commonly, both in mucosal lesions and at the center of the verrucous crusted plaques (see Table 21-12). Pseudoepitheliomatous hyperplasia, as well as a variable dermal granulomatous infiltrate consisting of lymphocytes, histiocytes, neutrophils, and multinucleated giant cells, characterizes long-standing plaques. Necrosis and abscess formation may be seen. T-cell subsets may play a role in immunoregulation because most cells in the granulomas are CD4.157 P. brasiliensis yeasts are seen readily in H&E-, methenamine silver-, or PASstained sections and may be seen intraor extracellularly or within giant cells.126 P. brasiliensis are thick-walled, refractile yeasts of variable size, 4 to 30 μm in diameter (Fig. 21-9). They may be observed singly, in chains, or budding in the distinctive “captain’s wheel” pattern with multiple, small, narrow-based buds surrounding a central large yeast.125,126

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as an indolent chronic illness or as a rapidly fatal one if left untreated.168,169 Hepatosplenomegaly, anemia, and fever may be the presenting signs of acute disseminated histoplasmosis. In later stages, endocarditis, meningitis, and adrenal gland destruction may be seen.161 Mucosal ulcerations occur in 60% of patients with disseminated disease and may involve the oral, nasal, GI, or genital mucosae. 161 In contrast, cutaneous manifestations of disseminated histoplasmosis are present in fewer than 25% of patients.164 These manifestations range from exfoliative erythroderma to nodules, papules, ulcers, acneiform pustules, erythema multiforme, erythema nodosum panniculitis, and diffuse hyperpigmentation from Addison disease.158,164,167,170 HISTOPATHOLOGIC FEATURES H. capsulatum is a small yeast that is 2 to 4 μm in diameter that divides with narrow-based, unequal buds (see Table 21-13). Although it is called capsulatum, it lacks a true capsule, but its cell walls stain strongly with methenamine silver (Fig. 21-10). It usually is seen within the cytoplasm of histiocytes, although it may be seen extracellularly or within giant cells. A halolike clear space is sometimes seen separating the yeast wall from the macrophage cytoplasm.171 Biopsies of lesions from patients having primary cutaneous histoplasmosis and of the ulcers from patients with disseminated histoplasmosis reveal an underlying lymphohistiocytic infiltrate

with H. capsulatum within histiocytes faintly visible with H&E stain but strongly visible with the methenamine silver stain. The pattern of inflammation in patients with disseminated disease is variable and depends on the clinical presentation. Histologic examination of cutaneous papules and plaques reveals leukocytoclastic vasculitis consisting of a granulomatous infiltrate with multinucleated giant cells and variable foci of necrosis.161,172 In Histoplasma panniculitis, the dermal infiltrate extends into the subcutaneous fat, where the organisms may be seen.170 The diagnostic benchmark of all biopsies from histoplasmosis patients is the presence of numerous spores. DIFFERENTIAL DIAGNOSIS The differential diagnosis for parasitized histiocytes includes rhinoscleroma, granuloma inguinale, and leishmaniasis.21 Rhinoscleroma is associated with a plasma cell–rich infiltrate, and the Donovan bodies of granuloma inguinale do not stain with silver or PAS stain. Also, H. capsulatum lacks the kinetoplast of Leishmania. Extracellular H. capsulatum can be distinguished from extracellular Cryptococcus species by the FontanaMasson stain, which stains Cryptococcus species but not H. capsulatum.128 Unlike the yeast forms of Candida glabrata, which are of similar size, the yeast forms of H. capsulatum stain only weakly or not at all with the Gram stain. A commercially available DNA probe for H. capsulatum grown in culture is highly

specific and can confirm the presence of the fungus in culture.173

African Histoplasmosis CLINICAL FEATURES African histoplasmosis, which is endemic in Central and West Africa and on the island of Madagascar, is caused by H. capsulatum var. duboisii and occurs in two forms: localized and disseminated. The localized form is a chronic illness involving the skin, bone, and lymph nodes. Variable numbers of cutaneous papules and plaques may ulcerate, and purulent bone lesions may extend into the adjacent soft tissue, causing a subcutaneous abscess or a draining sinus tract.159 The disseminated form involves the liver, spleen, and other organs in addition to the features of the localized form and often is fatal.174,175 HISTOPATHOLOGIC FEATURES Biopsies of cutaneous plaques reveal a granulomatous infiltrate consisting of lymphocytes, histiocytes, neutrophils, and giant cells. Numerous organisms measuring 8 to 15 μm are present, mostly within the giant cells and histiocytes.159,174,175 (Fig. 21-11).

INFECTIONS BY DEMATIACEOUS FUNGI Dematiaceous fungi are pigment-producing organisms. Several different fungal infections, including sporotrichosis, chromoblastomycosis, phaeohyphomycosis, tinea nigra, and alternaria, can produce pigment.

Sporotrichosis

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 FIGURE 21-10 Histoplasmosis. Spores in clusters and chains are stained with Gomori methenamine silver stain technique and show narrow-based budding. They are usually intracellular. (Courtesy of Dr. F. Von Lichtenberg.)

In 1898, Schenck described a patient in Baltimore in whom an organism was isolated from the arm and index finger.176 The fungus was sent to E.F. Smith at the US Department of Agriculture for further identification and was termed sporotricha. Hoetken and Perkins reported a second patient and named the organism Sporothrix schenckii. Although there were many reports of sporotrichosis in Europe at the beginning of the twentieth century, they have become rare, and most cases are now reported in the United States, Central and South America, Australia, Asia, and South Africa. A major outbreak in the gold mines of Witwatersrand in South Africa in the 1940s allowed for an extensive study of the ecology and distribution of the organism. Sporothrix is a dimorphic fungus that exists as a saprophytic mold in soil, wood, and decaying vegetative matter

Table 21-14 Sporotrichosis

worldwide. There is often a history of traumatic inoculation of the organism into the skin. CLINICAL FEATURES Three major clinical forms are recognized: lymphocutaneous, fixed cutaneous, and disseminated.176 The lymphocutaneous form is the most common disease pattern seen with sporotrichosis, and it results from lymphangitic spread of the infection. A hard nodule develops weeks to months after the infection at the site of inoculation. This nodule may drain seropurulent fluid and become ulcerated. Satellite lesions may follow along the lymphatic drainage system (sporotrichoid spread) with associated lymphadenopathy. The initial lesion may remain for several weeks and ultimately heals with scarring. This form of infection may become chronic if not treated. The clinical differential diagnosis includes mainly leishmaniasis, tuberculoid leprosy, syphilis,147 Nocardia and other fungal infections, and pyoderma gangrenosum. Fixed cutaneous disease refers to localized skin lesions without lymphatic involvement. These lesions rarely lead to systemic disease. They are more difficult to diagnose, and their clinical appearance may vary from ulcerative, verrucous to acneiform, or erythematous. Clinically, many other lesions may need to be considered in the differential diagnosis, most importantly syphilis, cutaneous leishmaniasis, chromomycosis, and verrucous tuberculosis.147

The disseminated form of the disease may occur because of hematogenous or lymphatic spread. It may involve the bone and joints, lungs, CNS, kidneys, and other visceral sites.177 HISTOPATHOLOGIC FEATURES The most important diagnostic use of a biopsy is for microbiologic cultures because the organism is rarely identified histologically. It is a fast-growing fungus; characteristic colonies become apparent within 3 to 5 days. The colony is typically lobated, smooth, or verrucous and becomes brown to black with age. The histologic findings are by and large nonspecific but typically include a suppurative or granulomatous tissue reaction.176,177 Lurie and Still classified the patterns as sporotrichotic, tuberculoid, and foreign body. In a later stage of the lesions, a fairly common granulomatous pattern is a central microabscess surrounded by epithelioid histiocytes surrounded by plasma cells and lymphocytes (Table 21-14 and Fig. 21-12). If organisms are present, a fungal stain may reveal them within asteroid bodies or in the tissue as round to oval spores measuring 4 to 6 μm in diameter (Fig. 21-13). Cigarshaped bodies measuring up to 8 μm are observed much less commonly. There may be single or multiple buds. No capsule is present. Sporotrichoid asteroid bodies are extracellular in contrast to those of sarcoidosis, leprosy, paracoccidioidomycosis, and foreign body reactions.178

CHAPTER 21 ■ FUNGAL INFECTIONS

 FIGURE 21-11 African histoplasmosis. Large yeast forms within cells are demonstrated by Periodic acid-Schiff staining with diastase, mostly within giant cells. (Courtesy of Dr. J.R. Nethercott.)

Clinical Features Caused by sporothrix schenckii Inoculation into skin with trauma Cutaneous and subcutaneous nodules Frequent involvement of lymphatics Three forms: Lymphocutaneous Fixed cutaneous Disseminated Histopathologic Features Early: Nonspecific infiltrate of lymphocytes, neutrophils, plasma cells Established Pseudoepitheliomatous hyperplasia common Suppurative granulomas with concentric zones: Neutrophilic microabscess centrally Cuff of epithelioid and multinucleated histiocytes Outer cuff of lymphocytes and plasma cells Organisms difficult to find in tissue 4-6 μm Round or oval forms or ≤ 8 μm cigar-shaped forms; single or uncommon multiple buds Asteroid bodies may be present Rare branching, nonseptate hyphae Differential Diagnosis Other infectious agents Deep fungi Atypical mycobacteria Blastomycosis-like pyoderma Halogenoderma Pyoderma gangrenosum Systemic vasculitis such as Wegener granulomatosis

DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis includes conditions with pseudoepitheliomatous hyperplasia and other granulomatous tissue reactions, particularly other fungal and mycobacterial infections, tularemia, and cat-scratch disease.

Chromoblastomycosis Synonyms: Chromomycosis, verrucous dermatitis, Pedroso disease, Fonseca disease, Gome disease, black blastomycosis, and Carrión mycosis. Pedroso described the first case in Brazil in 1911 (published in 1920). Rudolph published the first clinical characterization of the disease in 1914. Chromoblastomycosis is primarily a disease of tropical and subtropical regions, but it may also occur in temperate climates.179 Its inoculation is typically related to penetrating wounds, splinters, and thorns and is associated with outdoor activity or agricultural work.

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and scratching may lead to satellite lesions. The disease rarely spreads to noncutaneous sites. A potential cutaneous complication is the development of squamous cell carcinoma in a longstanding lesion. KOH preparations may be diagnostic by revealing pigmented sclerotic bodies. The clinical differential diagnosis includes other fungal or mycobacterial infections, particularly tuberculosis, leprosy, and blastomycosis, as well as leishmaniasis, botryomycosis, and tertiary syphilis.

 FIGURE 21-12 Sporotrichosis. Suppurative granuloma containing an asteroid body. (Courtesy of Dr. S. Seopela.)

Various saprophytic hypomycetous fungi of the Dematiaceae (darkly pigmented fungi) family, including Fonsecaea pedrosoi (most common), Phialophora verrucosa, Cladophialophora carrionii (synonym Cladosporium carrionii), and less commonly, Fonsecaea compacta and Rhinocladiella aquaspersa, may cause chromoblastomycosis.147 Cultures of each of these organisms yields slow-growing green to black colonies that are distinguished from each other by the microscopic appearance of the fungi. These

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organisms have been isolated from decaying wood or soil. CLINICAL FEATURES The initial lesion is an erythematous papule that subsequently develops into one or multiple coalescing warty papules or plaques. Carrión described five clinical presentations: nodules, tumors, plaques, warty lesions, and scarring lesions.180 They typically occur on an extremity. The patients are usually otherwise well. Pruritus is frequently associated with the condition,

 FIGURE 21-13 Sporotrichosis. Round to oval spore forms with budding demonstrated with Gomori methenamine silver stain. (Courtesy of Dr. F. Von Lichtenberg.)

HISTOPATHOLOGIC FEATURES Biopsy of a papule or plaque usually shows hyperkeratosis and epidermal hyperplasia, often with a pseudoepitheliomatous pattern, overlying a suppurative and granulomatous dermatitis181 (Table 21-15 and Fig. 21-14). The organisms may vary in number but can be recognized easily on routine H&E-stained sections. The spores may be present free in tissue or located within giant cells. They are round to oval and bronze colored, measuring 6 to 12 μm in diameter, usually with a central septation. They have been called Medlar bodies; sclerotic bodies; or descriptively, “copper pennies.” DIFFERENTIAL DIAGNOSIS When septation is present within a dividing sclerotic body, the findings are diagnostic and

Table 21-15 Chromoblastomycosis

Clinical Features Caused by Fonsecaea pedrosoi, Fonsecaea compactum, Cladosporium carrionii, Phialophora verrucosa, Rhinocladella acquaspersa most common Primary innoculation into skin, however extremities are the most frequent site, often distal Verucous plaques, nodules, tumors Scarring, central clearing Histopathologic Features Pseudoepitheliomatous hyperplasia Suppurative granulomas Organisms do not require a special stain Pigmented (“chestnut brown”) Sclerotic (septate) bodies Medlar bodies (“copper pennies”) Differential Diagnosis Other infectious processes Phaeohyphomycosis Other deep fungi Mycobacteria and atypical mycobacteria Halogenoderma Pyoderma gangrenosum

 FIGURE 21-14 Chromoblastomycosis. Suppurative granuloma with pigmented sclerotic (medlar) bodies.

distinguish chromoblastomycosis from phaeohyphomycosis, in which budding occurs and the characteristic septations are not found. Phaeohyphomycosis may also exhibit septate hyphae, pseudohyphae, branching hyphae, and spores in chains. Pigmentation is not always present in the latter organisms. In rare cases, squamous cell carcinoma may develop in the setting of chronic chromoblastomycosis.182

Phaeohyphomycosis Ajello coined the term phaeohyphomycosis in 1974 to encompass infections caused by dematiaceous fungi that have hyphal elements and grow by budding. The most common fungi in this group are Exophiala jeanselmei and Wangiella dermatitidis.183 The list of etiologic organisms continues to grow; some species are known to be neurotropic, including Cladophialophora bantiana, Bipolaris spicifera, Exophilia species, Wangiella dermatitidis, Ramichloridium obovoideum, and Chaetomium atrobrunneum, and may lead to brain abscess.96 CLINICAL FEATURES The spectrum of clinical presentations is broad and includes subcutaneous pseudocysts and ulcerated and verrucous lesions. In immunocompromised patients, dissemination may occur. Whereas E. jeanselmei is typically present in pheomycotic cysts, W. dermatitidis is more often associated with ulcerating and verrucous lesions.184

HISTOPATHOLOGIC FEATURES This histologic reaction pattern is that of a suppurative or mixed inflammatory cell infiltrate with a granulomatous tissue reaction (Table 21-16). There may be fibrous encapsulation of cystlike lesions (phaeomycotic cyst) (Fig. 21-15). Foreign material, such as vegetable

Table 21-16 Subcutaneous Phaeohyphomycosis

Clinical Features Caused by Exophiala and Phialophora species most commonly Inoculation into skin Extremities, particularly fingers, wrists, knees, ankles Usually solitary nodule Histopathologic Features Usually circumscribed, encapsulated “phaeomycotic cyst” Suppurative granuloma within “cyst” Epidermis and dermis may be unaffected Organisms: Usually pigmented but not always Morphologic spectrum Budding yeast forms Pseudohyphae Candida-like hyphae with branching, septa, and in chains Differential Diagnosis Chromoblastomycosis Mycetoma and related conditions Candida species

DIFFERENTIAL DIAGNOSIS Phaeohyphomycosis must be distinguished from chromoblastomycosis. In contrast to chromoblastomycosis, the fungi in phaeohyphomycosis are budding spores producing chains and have more abundant hyphal elements. True sclerotic bodies with thick walls and septa are absent. The differential diagnosis also includes hyalohyphomycosis, which lacks pigment, and other dematiaceous eumycotic mycetomas in which fungal elements are clumped together like grains.

CHAPTER 21 ■ FUNGAL INFECTIONS

matter or a splinter, may occasionally be observed. Pseudoepitheliomatous hyperplasia and intradermal neutrophilic microabcesses may be seen at the surface of nodules or verrucous plaques. 185 Fungi are typically abundant and often are located in or near suppurative foci. They are brown colored and measure 2 to 6 μm but may be larger (Fig. 21-16). The fungi in phaeohyphomycosis are budding spores often producing chains and have abundant hyphal elements that may be septate or branching or may exhibit pseudohyphae. Pigmentation may not always be obvious, and a Fontana-Masson stain may be needed to demonstrate melanin.

Tinea Nigra Alexandre Cerqueira provided the first description of this superficial dermatomycosis in Brazil in 1891. The fungus was named Cladosporium werneckii, which has been renamed Hortaea werneckii.84 The fungus produces pigment and is most common in tropical regions. It is not a dermatophyte.26 CLINICAL FEATURES The lesions are typically asymptomatic and present as brown macules with minimal scale. They tend to expand slowly and almost always affect the palms, but they may also occur on the soles.186 The major clinical differential diagnosis is melanoma of acral skin.187 HISTOPATHOLOGIC FEATURES Abundant branching brown hyphal elements are usually present in the upper stratum corneum (Fig. 21-17). There tends to be associated parakeratosis and a mild superficial dermal perivascular inflammatory cell infiltrate. Deep dermal lesions are not known to occur with the agent of tinea nigra, which distinguishes this disease from other dematiaceous mycoses.

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 FIGURE 21-15 Phaeohyphomycosis. Well-circumscribed, cyst-like lesion in the deep dermis.

ALTERNARIOSIS Alternaria species are saprophytic fungi whose natural habitat is soil and plants. They are one of the most ubiquitous fungi in indoor and outdoor environments. Among immunocompetent hosts, workers exposed to logs and wood dust are at highest risk for infection. Predisposing factors include occupational or recreational exposure to soil,

diabetes mellitus, and skin trauma. Alternaria species are also opportunistic, causing cutaneous infection in patients with immunosuppression or debilitating disease, such as solid organ transplant recipients.188,189 CLINICAL FEATURES Exogenous and endogenous forms of alternariosis may occur in humans, for whom Alternaria are usually nonpathogenic. In the exogenous form,

organisms are inoculated directly by trauma, such as a wood splinter. Skin manifestations include ulcers and warty and granulomatous plaques. Onychomycoses and keratomycoses as well as combinations of the two have been reported.190 Most patients with the endogenous form of alternariosis are immunocompromised. In the endogenous form, infection occurs via the lungs by inhalation. Skin lesions develop subsequent to hematogenous spread. The organisms often involve the deep dermis and subcutis.191 However, Alternaria may also colonize preexisting superficial lesions. They tend to be indolent in their presentation but are often difficult to cure. Unlike other common opportunistic infections, Alternaria infections show little propensity to disseminate. Extracutaneous lesions have been reported to involve the eyes, sinonasal region, bones, and peritoneum. The respiratory tract is the main site of allergic reactions to Alternaria. HISTOPATHOLOGIC FEATURES The reaction pattern is that of a suppurative and granulomatous dermatitis or panniculitis. In onychomycosis or keratomycoses, fungal elements may be present in thickened layers of keratin without much associated inflammation. The organisms are brown and present as broad, branching septate hyphae, 5 to 7 μm thick, and round to oval spores, often doubly contoured and measuring 3 to 10 μm (Fig. 21-18). They tend to be clustered. The spores may be free in tissue or within macrophages. DIFFERENTIAL DIAGNOSIS Alternaria infections must be distinguished from the other phaeohyphomycoses. It is also important to consider Alternaria in onychomycoses so that nondermatophytic pathogens of nail infections are not overlooked.192

MYCETOMA AND CLINICALLY SIMILAR CONDITIONS

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 FIGURE 21-16 Phaeohyphomycosis. Neutrophilic and granulomatous infiltrates with pigmented budding yeast forms.

Mycetoma is a chronic infectious disease localized to the skin or subcutaneous tissue. This disease is characterized by tumefaction, draining sinuses, and the presence and extrusion of aggregates (grains) of microorganisms. Whereas eumycetoma is caused by a fungus, actinomycetoma may be caused by either endogenous anaerobic bacteria (Actinomyces species), which is called actinomycosis, or by aerobic bacteria, including Actinomadura species, Nocardia brasiliensis, and Streptomyces species.147 Mycetoma is

 FIGURE 21-17 Tinea nigra.A confluent mass of pigmented hyphal elements from the skin surface is seen.

typically initiated by percutaneous trauma. Mycetomas have been classified into three different groups based on the micromorphology of their grains: botryomycosis (cocci or short rods), actinomycetoma (thin, branching, intertwined filaments), and eumycetoma (thick, branching, intertwined filaments).

Mycetoma (Eumycetoma) Eumycetoma is caused by a fungus and is endemic in equatorial Africa, the

Middle East, India, and Mexico. The grains of fungi may be nonpigmented or pigmented (dematiaceous fungus). The most prevalent dematiaceous fungal agent of eumycetoma is Madurella mycetomatis, the predominant etiologic agent in India and Africa. A common nonpigmented etiologic agent of eumycetoma in North America is Pseudallescheria boydii. Although not an endemic disease in the Amazon rainforest, where actinomycetoma is the more common type, true fungal mycetoma in Brazil is most commonly caused by Acremonium species and Madurella grisea.147

 FIGURE 21-18 Alternaria species. Budding spores are demonstrated with Gomori methenamine silver stain.

HISTOPATHOLOGIC FEATURES The typical finding includes an aggregate of microorganisms (grain) in a microabscess surrounded by granulation tissue and fibrosis (Table 21-17 and Fig. 21-19). Neutrophils are often numerous, and a granulomatous tissue reaction is common. Eumycotic grains

Table 21-17 Mycetoma and Related Conditions

Clinical Features Caused by True fungus (eumycetoma, maduromycosis) Aerobic actinomycete (actinomycetoma or pseudomycetoma) Inoculation into skin after trauma Localized infection of skin, subcutis, fascia, bone Tumefactive nodules Ulceration Draining sinuses with extrusion of sclerotia (grains, granules) in exudates Bone involvement is often extensive Histopathologic Features Neutrophilic abscesses contain sclerotia (grains, granules) Surrounding granulation tissue Granulomatous inflammation Sinus tracts Organisms in sclerotia: Circumscribed mass of hyphae with or without associated host tissue or soil Distinction of organisms based on color, texture, shape, internal architecture True fungi Often filaments in granules from actinomycosis, usually without pigment Differential Diagnosis Other infections characterized by ulceration, tumefaction, draining sinuses Chromobastomycosis Botryomycosis Dermatophyte infection Actinomycosis

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CLINICAL FEATURES Most affected patients live in tropical or subtropical regions.193 The etiologic agents of mycetoma are usually associated with woody plants and soil. After the initial trauma, a small nodule develops that subsequently expands and frequently drains into a sinus tract. Sinuses rarely occur before 3 months’ duration. Sinuses may close, and organisms may be discharged with subsequent healing. Many times new nodules form after the initial one has healed. With time, the lesions may extend deeply and involve bone, forming cavities. Fungus may ultimately even spread via the lymphatics to visceral sites. Seventy percent of all mycetomas involve the foot.

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Table 21-19 Color of Grains in Actinomycetoma (Pseudomycetoma) O RGANISM

G RAIN C OLOR

Nocardia brasiliensis Nocardia asteroides

White White (when present) White to yellow Pink or cream Yellow or brown Red

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Nocardia otitidiscaviarum Actinomadura madurae Streptomyces somaliensis Actinomadura pelletieri

 FIGURE 21-19 Mycetoma species. Pigmented granule within the abscess.

or granules (also known as sclerotia) are poorly organized collections of about 5-μmthick septate hyphal elements, which in the case of dematiaceous fungi are brown or black.194 The micromorphology of the grains helps to distinguish eumycetomata from actinomycetomata and botryomycosis (see below) (Tables 21-18 and 21-19). DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other infectious causes of tumefactive lesions exhibiting ulceration and draining sinuses, such as chromoblastomycosis, botryomycosis, actinomycosis, and pseudomycetomas owing to dermatophytes. In general, the presence of granules and their characteristic features

allows separation of eumycetoma from the latter entities. For example, neither chromoblastomycosis nor dermatophyte infection are associated with the formation of true grains. Botryomycosis and actinomycosis are characterized by grains that contain bacteria rather the hyphae found in eumycetoma.

Nocardiosis Nocardia and Streptomyces species are free-living soil organisms. They are gram-positive, aerobic, branching, filamentous bacteria, whose filaments often fragment to coccobacillary forms; they are frequently acid fast. The majority of

Table 21-18 Organisms Causing Mycetoma

Acremonium falciforme Acremonium kiliensis Acremonium recifei Aspergillus flavus Aspergillus nidulans Corynespora cassicola Curvularia geniculata Curvularia lunata Cylindrocarpon cyanescens Cylindrocarpon destructans Exophiala jeanselmei Fusarium spp. Fusarium moniliforme Fusarium oxysprum Fusarium solani Fusarium solani var. coeruleum

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Fusarium solani var. minus Hormonema spp. Leptosphaeria senegalensis Leptosphaeria tompkinsii Madurella grisea Madurella mycetomatis Neotestudina rosatiii Phialophora verrucosa Plenodomus avramii Ploycytella hominis Pseudallescheria boydii Pseudochaetosphaeronema larense Pyrenochaeta mackinnonii Pyrenochaeta romeroi Scopulariopsis brumptii

human infections in the United States are associated with members of the Nocardia asteroids complex, a term that includes four species not differentiated in earlier reports: N. asteroides sensu stricto type VI, N. farcinica, N. nova, and N. abscessus.195 Other medically significant species include N. brasiliensis, N. otitisdiscaviarum, and N. pseudobrasiliensis.196 Nocardiosis is seen worldwide, infects predominantly immunocompromised individuals, and has a wide variety of clinical manifestations. It is relatively uncommon but is increasingly reported in the literature, possibly due to increases in the immunocompromised population as well as improved laboratory identification. In immunocompromised hosts and those with multiple brain abscesses, the mortality rate of disseminated nocardiosis has been reported to be greater than 85%.197 CLINICAL FEATURES Nocardiosis is opportunistic and usually presents as pulmonary disease acquired through inhalation, with dissemination from the lungs manifested as bacteremia, empyema, brain abscess, pericarditis, synovitis, or soft tissue infection (which may present as actinomycetoma or cellulitis). Less frequently, primary cutaneous nocardiosis results from percutaneous trauma with soft tissue inoculation that induces local abscess formation, even in healthy hosts. Skin involvement may occur via dissemination from another site, typically in an immunocompromised host.198,199 N. brasiliensis may be associated with a lymphocutaneous presentation that resembles sporotrichosis.195 Thus cultures are important in defining the disease. HISTOPATHOLOGIC FEATURES Basophilic gram-positive filamentous structures (1 μm in diameter) that are sometimes stainable with modified acid-fast methods195 are usually present in aggregates (Fig. 21-20). In visceral nocardiosis, in contrast to the “sulfur granules” of Actinomyces species that cause actinomycosis, the filaments

 FIGURE 21-20 Nocardiosis. Filamentous bacteria stained with Fite-Faraco reaction. (Courtesy of Drs. S. Lucas and F. Von Lichtenberg.)

in Nocardia tend to break up into short bacillary segments similar to Mycobacterium tuberculosis (Table 21-20). However, in mycetomas, grains similar to the sulfur granules of Actinomyces may be formed. The inflammatory tissue reaction is usually that of a suppurative and granulomatous dermatitis. In localized cutaneous nocardiosis, an abscess is usually present. In the diagnostic workup, pus, exudate, or abscess drainage material may be submitted for cultures. Tissue biopsies should also include a sample for microbiology. It is important to indicate on the laboratory requisition sheet that Nocardia is suspected to guarantee adequate recovery of the organisms. Colonies can usually be detected in 10 days to 2 weeks. DIFFERENTIAL DIAGNOSIS Nocardia must be distinguished from other infective agents producing suppurative granulomas. Special stains and cultures are essential for diagnosis. Nocardia are often weakly acid fast (ie, Ziehl Nielsen negative, but Fite Faraco positive). On Gram stain, they show a beaded and filamentous pattern similar to that of Actinomyces.

Actinomycosis Actinomycosis is a chronic suppurative infection noted for the production of “sulfur granules.” The disease is caused by several members of the order of Actinomycetales, most commonly by Actinomyces israelii.200 They are anaerobic saprophytic gram-positive bacteria present in the normal flora of the mouth and GI and urogenital tracts. Infection is often

associated with mucosal trauma, such as from dental procedures or surgery. CLINICAL FEATURES Three major clinical presentations have been described: cer-

Table 21-20 Nocardiosis

Clinical Features Caused by Nocardia asteroides, N. brasiliensis, N. otitidiscaviarum most commonly Men more commonly affected than women Age 30-50 years most common Immunosuppressed host more susceptible Inoculation into skin after trauma common Localized pyoderma, nodule Lymphocutaneous form resembling sporotrichosis Actinomycetoma Other presentations Systemic Pulmonary Central nervous system Extrapulmonary Histopathologic Features Neutrophilic abscess in dermis, subcutis Occasional tuberculoid granulomas Organism: Filamentous, gram-positive, acid-fast, obligate aerobe Grains may be observed Differential Diagnosis Localized infection from bacteria, fungi, mycobacteria Lymphocutaneous syndromes as from sporotrichosis, atypical mycobacteria Mycetoma and actinomycetoma (pseudomycetoma)

HISTOPATHOLOGIC FEATURES The lesion typically begins as a cellulitis with subsequent abscess formation and fibrotic induration (Table 21-21). Discharge of the “sulfur granules” from sinus tracts is

Table 21-21 Actinomycosis

Clinical Features Caused by Actinomyces israelii most commonly Men more commonly affected than women All ages, but middle-aged men in particular Inoculation into tissue after trauma Painful cellulitis followed by Soft, fluctuant lesions Draining sinuses Woody induration Clinical presentations Oral, cervicofacial Thoracic Abdominal Histopathologic Features Sinus tracts Neutrophilic abscesses containing “sulfur granules” Sulfur granules Round, oval, or crescent-shaped forms that are basophilic centrally with an eosinophilic border (Splendore-Hoeppli material) Composed of gram-positive, filamentous, branching bacteria < 1 μm in diameter Positive for Gomori methenamine silver and Giemsa stains, in addition to Gram stain Not acid fast Differential Diagnosis Botryomycosis (Staphylococcus, Pseudomonas, Eschericheria, Proteus, eg, species) Nocardiosis Other suppurative infections

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vicofacial, thoracic, and abdominal.200 The disease may also disseminate in immunocompromised patients. Cervicofacial actinomycosis accounts for more than 50% of cases. It typically occurs in the premandibular region as a discrete, slowly growing swelling. Subsequent abscess formation and drainage via sinus tracts are common. Potential complications include osteomyelitis. If infected oral material is aspirated, pulmonary infection may develop (thoracic form, 15% of actinomycoses). Abdominal infection usually occurs after traumatic rupture of the intestine. Appendicitis with perforation is the most common precipitating event. In recent years, an increase in the abdominal– pelvic form has been observed, possibly related to an increased and prolonged use of intrauterine devices.201

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common. Histologically, these are aggregates of Actinomyces organisms that appear as round to oval bodies up to 10 mm in diameter (Fig. 21-21A). The organisms may appear yellow on routine H&E stains attributable to sulfur accumulation (Figs. 21-21B and 21D). An eosinophilic fringe (Splendore-Hoeppli phenomenon) is frequently seen. At high magnification, the granules are seen to be composed of filamentous branching bacteria measuring less than 1 μm in diameter. In tissue, these structures typically are surrounded by macrophages. They can be highlighted by a Gram and silver stain (Fig. 21-21C).

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DIFFERENTIAL DIAGNOSIS Actinomycosis needs to be distinguished from eumycetoma (branching filamentous hyphal structures >1 μm) and botryomycosis (gram-positive coccal forms or short, gram-negative rods).

Botryomycosis Botryomycosis is an uncommon chronic bacterial infection usually caused by staphylococci and less commonly by other organisms such as Pseudomonas, Proteus, or Escherichia coli. Although the pathogenesis is poorly understood, reduced host resistance may perpetuate growth of lower-virulence organisms in a symbiotic fashion. There are two forms: visceral and integumental. The latter is the more common form and is often associated with trauma or foreign body or chronic wound contamination. CLINICAL FEATURES Lesions may affect not only the skin but also the internal organs and bone. The skin lesions typically consist of small, tender nodules with seropurulent discharge from draining sinuses.202,203 Tonsillar botryomycosis may cause tonsillar hypertrophy.204

A

B

C

D

HISTOPATHOLOGIC FEATURES Common epidermal changes include hyperkeratosis, hyperplasia, and spongiosis. In the dermis, there is a mixed inflammatory cell infiltrate composed of neutrophils, lymphocytes, and histiocytes, often with granulation tissue205 (Table 21-22). Within the inflammatory infiltrate, there are usually granules of tightly clustered gram-positive cocci (Fig. 21-22). Sometimes the granules are surrounded by amorphous eosinophilic material, creating the so-called “Splendore-Hoeppli phenomenon.” This effect of seemingly radiating lateral projections gives the granules a striking similarity to actinomycotic granules.203 The eosinophilic material has been found to contain immunoglobulins and is likely produced by the host’s response to bacterial antigens. In some instances, Pseudomonas or Proteus species may cause the same phenomenon, giving

 FIGURE 21-21 Actinomycosis. (A) The organisms may appear yellow on routine hematoxylin and eosin sections attributable to sulfur accumulation. (B) There is a focus of granular eosinophilia whereby higher power magnification discloses filamentous structures, some of which appear yellow. (C) The organisms are highlighted by a Gomori methenamine silver stain. (D) Note the “sulfur granule” within the abscess that is composed of branching filamentous bacteria.

Table 21-22 Botryomycosis

rise to granules mimicking Actinomyces species.191 In those instances, the granules are composed of tight clusters of gramnegative rods. DIFFERENTIAL DIAGNOSIS Botryomycosis must be discriminated from other infections associated with the formation of grains. Nocardia species exhibit aerobic,

ZYGOMYCOSES The taxonomy of the traditional phylum Zygomycota is in a state of flux because numerous phylogenetic studies have indicated that the phylum is not monophyletic. A recent reclassification scheme proposes to redistribute the clades among the phylum Glomeromycota206 and four unplaced subphyla: Mucormycotina, Kickxellomycotina, Zoopagomycotina, and Entomophthoromycotina, pending resolution of phylogenetic relationships among the clades.10 Traditionally, fungi characterized by the formation of wide ribbon-like aseptate hyaline hyphae (coenocytic hyphae) and sexual reproduction by the production of zygospores have been classified in the phylum

 FIGURE 21-22 Botryomycosis. A group of basophilic granules lining an ulcer contains gram-positive staphylococci surrounded by acute inflammation.

Zygomycota. The class Zygomycetes contains two orders that contain agents pathogenic of zygomycosis in humans: the Mucorales and Entomophthorales. Among the Mucorales, members of the genera Rhizopus, Mucor, Absidia, Rhizomucor, Apophysomyces, and Cunninghamella bertholletiae have been identified as pathogenic to humans; Rhizopus species are the most commonly implicated causative agents of human zygomycosis.207 The order Entomophthorales is distinguished from the order Mucorales by the production of asexual sporangioles and by their compact and glabrous mycelial morphology; Entomophthorales contains the genera Conidiobolus and Basidiobolus, which contain species pathogenic of human zygomycosis. Whereas the Mucorales usually affect immunocompromised individuals, the Entomophthorales may infect both normal and compromised individuals.117 Disease caused by the class Zygomycetes is called zygomycosis.207 In the past, zygomycosis was commonly called mucormycosis, reflecting the predominance of the order Mucorales in the disease, but this designation led to confusion because many of the causative organisms were found to belong to genera other than Mucor, including Absidia; Rhizomucor; and Rhizopus, which is the predominant pathogen of rhinocerebral mucormycosis.208 In addition, the term “mucormycosis” discounted the role of the order Entomophthorales in the disease category. The term phycomycosis, formerly used interchangeably with mucormycosis and entomophthoramycosis, has fallen out of favor. For historical reasons and for clarity, in this chapter, the term mucormycosis applies to diseases caused by members of the order Mucorales, and entomophthoramycosis denotes disease caused by members of the order Entomophthorales. The zygomycetes invade arteries, forming thrombi that compromise perfusion, leading to tissue infarction and necrosis. Although less common than other invasive fungal infections, such as candidiasis and aspergillosis, zygomycosis has emerged as an important infection, especially among immunocompromised individuals,208 including hematopoietic stem cell transplant recipients and patients with hematologic malignancies. Among the general population, zygomycosis may cause acute, rapidly progressive infections, especially in patients with diabetes mellitus, patients receiving deferoxamine treatment, intravenous drug users, and others without apparent immunologic impairment.113,210

CHAPTER 21 ■ FUNGAL INFECTIONS

Clinical Features Caused by staphylococci, Pseudomonas, and Proteus, species E. coli Tender nodules with draining sinuses Internal organs and bones may be affected Histopathologic Features Neutrophilic abscesses containing granules Granules may exhibit Splendore-Hoeppli phenomenon Granulation tissue Sinus tracts Granules contain Gram-positive or -negative cocci or rods without branching filaments Differential Diagnosis Actinomycosis Mycetoma (eumycetoma and actinomycetoma)

filamentous, branching, gram-positive bacteria whose bacterial filaments fragment to coccobacillary forms and are sometimes positive by modified acidfast staining. Actinomycosis is typified by grains containing gram-positive, filamentous, branching bacteria that are obligate anaerobes and non–acid fast. Eumycetoma demonstrates grains that are often (but not always) brown or black and contain true fungi (ie, filamentous hyphal elements).

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Mucormycosis

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Synonyms: Zygomycosis, phycomycosis. CLINICAL FEATURES The Mucorales are ubiquitous saprophytic organisms found in soil and on decomposing organic material such as fruit and bread.211 They can be cultured as normal flora from the feces and oral and nasal cavities of healthy individuals, but infection with tissue invasion occurs mainly in immunosuppressed patients.212,213 Large numbers of sporangiospores are released into the air and then inhaled, causing pulmonary and nasal sinus infection (Table 21-23). Less commonly, ingestion or cutaneous inoculation may cause disease.214 Risk factors include diabetes mellitus, diabetic ketoacidosis, neutropenia, leukemia, burns, prior skin trauma, iron chelation therapy (deferoxamine or desferrioxamine), iron overload states, broadspectrum antibiotic therapy, intravenous drug use, and the use of elasticized adhesive tape.207,211,215 Sporangiospores that have escaped host defense mechanisms may germinate into the hyphal form capable of invading blood vessels, which may lead to hematogenous dissemination or infarction and necrosis. Defects in macrophages or neutrophils increase an individual’s susceptibility to systemic infection. Macrophages prevent the transformation of Rhizopus species, the most common etiologic agent of mucormycosis, from its yeast to its hyphal form.216 Neutrophils are able to damage the hyphal form.217

Table 21-23 Mucormycosis

Clinical Features Most common pathogens: Rhizopus, Absidia, Mucor Mucorales are found in soil and in decomposing organic matter Risk factors: diabetes, leukemia, neutropenia, skin ulceration, burns, use of adhesive tape Ecthyma-like necrotic crust surrounded by cellulitis Histopathologic Features Necrosis, thrombosis, infarction Large, broad ≤30 μm in diameter hyphae Hyphae branch at 90° angles and lack septa Hyphae often present in vessel walls Differential Diagnosis Conidiobolus Basidiobolus Aspergillosis (see aspergillosis—Table 21-4)

484

The clinical forms of mucormycosis are rhinocerebral, pulmonary, GI, cutaneous, and disseminated. Rhinocerebral mucormycosis occurs most commonly in uncontrolled diabetics who rapidly develop fever, unilateral headache, periorbital or perinasal swelling, and drainage of discolored pus.213-217 If not treated with aggressive debridement and antifungal therapy, Mucorales species can invade brain tissue and bone and cause death within days.125 Pulmonary and GI mucormycosis are the most common types that can progress to the disseminated form, which is 100% fatal if untreated and is associated with widespread abscess formation and necrosis of multiple organs, including the brain, heart, and spleen.215 Two variants of cutaneous mucormycosis have been described: subacute and rapidly progressive. The subacute form occurs in an otherwise healthy host exposed to contaminated adhesive tape and begins as vesicles and pustules that progress to eschars. The rapidly progressive form occurs in compromised patients and is characterized by an ecthyma-like necrotic black crust surrounded by cellulitis. If untreated, it may progress to disseminated disease.211,218 Unfortunately, serologic diagnostic tests are not clinically useful.207 Molecular techniques based on PCR restriction fragment length polymorphism have recently identified some of the major Mucorales species in histopathologic samples219 and are a continuing focus of laboratory research. HISTOPATHOLOGIC FEATURES Extensive necrosis and vascular damage characterize the eschar. Only the hyphal form of Mucorales species are seen in tissue. The hyphae are broad (≤30 μm in diameter) with bulbous lateral protrusions. They often appear hollow; lack microscopically visible septa; branch at variable up to 90° angles; and are visible with H&E, PAS, and methenamine silver stains 211 (Fig. 21-23). The organisms typically exhibit intravascular localization. At times, the infection may localize in the subcutis and be associated with a striking pattern of paucicellular necrotizing panniculitis (see Fig. 21-23A and B). DIFFERENTIAL DIAGNOSIS The hyphae of Aspergillus and Fusarium species branch at an acute angle, show dichotomous branching, and often exhibit septa. Tissue culture is extremely helpful when hyphae are scarce or distorted in tissue.

Entomophthoramycoses Conidiobolus and Basidiobolus species, similar to the etiologic agents of mucormycosis, are found in soil and plant detritus.220,221 Both species occur mainly in the tropical regions of Africa, South America, and Southeast Asia and produce extensive soft tissue swelling without skin involvement.222,223

Conidiobolus CLINICAL FEATURES The major human pathogen of the genus, C. coronatus, typically infects men from 20 to 60 years of age involved in agricultural work in areas of tropical rainforests in West Africa, although cases have been reported worldwide.207,221 Infection begins in the nasal mucosa, commonly presenting as chronic sinusitis, and spreads to the nose, forehead, periorbital region, and cheeks, occasionally causing lymphedema and epistaxis in some cases.125 C. incongruus has also been implicated in human disease.207 Distant dissemination is unusual but has occurred in association with both C. coronatus and C. incongruus in immunocompetent and immunocompromised patients.207 Horses and mules also can develop nasal granulomas owing to Conidiobolus species.221 The diagnosis depends on physical examination with biopsy and culture of tissue, although serologic tests are also available, and an immunodiffusion test for C. coronatus can be useful for diagnosis and monitoring patients’ therapeutic response.207 HISTOPATHOLOGIC FEATURES Conidiobolus species cause a granulomatous tissue reaction consisting of lymphocytes, histiocytes, neutrophils, plasma cells, foreign body giant cells, and numerous eosinophils. Foci of necrosis may be seen within the granulomas that extend from the dermis to the subcutaneous tissue. Fungal hyphae may be observed within the giant cells and are thin-walled, broad (4 to 10 μm in diameter), and occasionally septate. They are rimmed by a thick eosinophilic sheath visible in H&E- or PAS-stained sections.221

Basidiobolus CLINICAL FEATURES Entomophthoramycosis caused by Basidiobolus species are typically a childhood disease, with the majority of patients younger than 10 years of age.220,222 Basidiobolus species are endemic in Uganda and other areas of

B

C

D

CHAPTER 21 ■ FUNGAL INFECTIONS

A

E  FIGURE 21-23 Mucormycosis. (A) There is striking paucicellular fat necrosis. Even at this power, numerous pleomorphic broad-based fungal elements are seen that appear as negative shadows, although with an eosinophilic membranous borders. (B) Higher power magnification reveals the extent of tissue infiltration by the organism, although with the prominent tissue necrosis attributable to angioinvasion. (C) The biopsy shows extensive permeation of the biopsy sample by fungal elements that are morphologically indistinguishable from aspergillosis. (D)The organisms demonstrate regular septation and with 45° branching exhibiting intravascular localization. (E) Large, empty-appearing hyphae without septa show 90° branching.

Africa, India, and parts of Asia, but it is found worldwide.207 It begins as a slowly growing, painless, rubbery nodule, usually on the lower extremities or buttocks. Gradually, there is progressive

subcutaneous swelling, and additional nodules may appear.223,224 The mode of transmission is unknown, although insect bites, minor trauma, and direct contact with contaminated feces have

been suggested as modes to transmit the etiologic agent. Basidiobolus species are a saprophyte and part of the normal flora of the GI tract of reptiles and amphibians. It has

485

PART III ■ INFECTIONS

been hypothesized that the practice of using “toilet leaves” (plants used in lieu of toilet paper) contaminated by Basidiobolus species in soil and excreta is implicated in the perineal occurrence of disease. Although culture remains the standard for diagnosis, serology and an immunodiffusion test have been useful for diagnosis and monitoring response to treatment of this disease.207 HISTOPATHOLOGIC FEATURES The dermis and subcutaneous tissues contain a mixed granulomatous and eosinophilic infiltrate that may replace fat (similar to entomophthoramycosis caused by Conidiobolus species). Septate, branching hyphae measuring 7 to 15 μm are seen within the granulomas, particularly toward the edge of the clinical lesion. The hyphae are surrounded by eosinophilic material (Splendore-Hoeppli phenomenon) a few microns thick.220,224 DIFFERENTIAL DIAGNOSIS In the tropics, filarial skin swellings must be considered in the differential diagnosis. Basidiobolus and Conidiobolus species are similar histologically. Diagnosis is made on the basis of clinical presentation, typical histopathologic findings, and tissue culture.

Aspergillosis Aspergillus species are ubiquitous saprophytes found in soil, air, and decaying organic matter. Hospital renovations or construction sites producing contaminated dust have been implicated in outbreaks of aspergillosis.26,225

486

CLINICAL FEATURES Aspergillosis is a leading cause of opportunistic infection among immunocompromised patients, especially those with leukemia and solid organ or bone marrow transplant recipients. The incidence is increasing,113 and it is the second most common nosocomial fungal infection, exceeded only by candidiasis, in neutropenic hosts.226 Other risk factors for aspergillosis include AIDS227 and high-dose corticosteroid therapy. The true incidence is probably higher because many cases remain undiagnosed. A. fumigatus is the most common human pathogen of the genus, followed by A. flavus, A. niger, and A. terreus. Aspergillus in Latin signifies “holy water sprinkler,” so named because of the distinctive fruiting body shape of each Aspergillus species.86 Infections due to A. terreus appear to be increasing in frequency,96 increasing from 2.1% of Aspergillus infections in 1996 to 10% in 2001 in one study.228 In a multicenter

surveillance conducted in 2001 to 2002, among hematopoietic stem cell transplant recipients, A. flavus and A. terreus accounted for 19% and 16%, respectively, of Aspergillus infections.229 Both increased compared with data from the 1990s, when 90% of cases were due to A. fumigatus.113 The emergence of A. terreus is of concern because of its apparently reduced susceptibility to amphotericin B compared with A. fumigatus.96 The respiratory tract is the usual portal of entry. Localized lung disease may occur as allergic aspergillosis in atopic individuals and as fungus balls (aspergillosis) or necrotizing pneumonia in patients with a history of lung disease such as sarcoidosis, tuberculosis, or pneumoconioses. In acute invasive aspergillosis, widespread growth of Aspergillus species in lung tissue leads to infarction. Predisposing conditions for this rapidly progressive and often fatal infection are neutropenia, hematologic malignancy, long-term immunosuppressive therapy for organ transplantation, and chronic granulomatous disease in children (Table 21-24). Hematogenous dissemination may affect multiple sites, including the CNS, eyes, heart, bone, kidneys, liver, spleen, and skin.227,230 Cutaneous aspergillosis may arise as a primary infection or secondary to disseminated disease. Primary cutaneous aspergillosis generally occurs in immunocompromised hosts at sites where the skin is disrupted by catheters, burns, or trauma or occluded by contaminated adhesive tape.227,230,231 It begins as an erythematous macule, papule, or nodule that may develop a hemorrhagic bulla with subsequent ulceration, resulting in a centrally necrotic eschar. KOH preparations from the intermediate-stage blister roof may reveal hyphae.232 Cutaneous aspergillosis may also disseminate in immunocompromised patients.227 In disseminated aspergillosis, cutaneous disease occurs in 5% to 11% of patients and presents as five main types: solitary necrotizing dermal plaque, subcutaneous granuloma or abscess, persistent maculopapular eruption with suppuration or necrobiosis, transient erythema or erythroderma, and progressive confluent granulomas.233,234 HISTOPATHOLOGIC FEATURES In both primary and disseminated cutaneous aspergillosis, histologic examination of the dermis and subcutaneous fat reveals numerous septate hyphae (2 to 4 μm in diameter) that branch at a 45° angle and exhibit dichotomous branching235 (Fig. 21-24). The hyphae are optimally visualized with methenamine

Table 21-24 Aspergillosis

Clinical Features Ubiquitous in decaying organic matter, soil, and dust Caused by Aspergillus flavus, A. niger, and A. fumigatus Predisposing conditions: neutropenia, hematologic malignancy, organ transplantation–associated immunosuppression, chronic granulomatous disease Primary cutaneous aspergillosis associated with burns, catheter sites, hospital construction dust, and adhesive tape Primary cutaneous aspergillosis: ecthyma-like papule with central necrosis Lungs are usually portal of entry heading to disseminated disease, metastases in 5-11% of patients—necrotizing plaques, subcutaneous granulomas or abscesses, maculopapular eruption, erythema Hematogenous dissemination may involve CNS, liver, spleen, heart, kidneys, and eyes Histopathologic Features Septate hyphae (2-4 μm diameter) that branch at a 45° angle, dichotomous Variable granulomatous infiltrate: neutrophils, lymphocytes, histiocytes, and giant cells In disseminated disease, hyphae may be intravascular and invade vessel walls Differential Diagnosis Aspergillus Septa Present Diameter 2-4 μm 45° Dichotomous

Mucor Absent ≤ 30 μm 90° Bulbous lateral protrusions

silver or PAS stains (see Table 21-24). Ulceration; pseudoepitheliomatous hyperplasia; necrosis; and a granulomatous infiltrate of neutrophils, lymphocytes, histiocytes, and giant cells may be seen. 230,231,235 In disseminated disease, hyphae may be seen within dermal vessels as well as invading vascular walls.233 Pseudoepitheliomatous hyperplasia has been reported with cutaneous aspergillosis, with irregularly acanthotic epidermis with deep invaginations in the dermis, and an intense inflammatory reaction in the superficial and deep dermis.236 DIFFERENTIAL DIAGNOSIS Zygomycosis also may display vascular involvement. However, Aspergillus species may be distinguished from Mucorales species by the hyphal width, the angle and pattern of dichotomous branching, and the

lesion, which may be surrounded by a rim of erythema. The prognosis of disseminated fusariosis in neutropenic patients is poor. HISTOPATHOLOGIC FEATURES The morphologic findings are similar to those of aspergillosis, both in culture and tissue sections. There is a striking tendency for the organism to exhibit angioinvasion with resultant ischemic necrosis of the skin and subcutis (Fig. 21-23C and 21-23D). Fusarium species have characteristic sickle-shaped, multiseptate macroconidia.103

 FIGURE 21-24 Aspergillosis. The hyphae are smaller than those observed in mucormycosis and exhibit 45° dichotomous branching.

visibility of septa. In some instances, cultures may be necessary to make the latter distinction. Culture of bronchial fluid has high specificity but a sensitivity of only 30% to 50%, and even open lung biopsy can yield false-negative test results.237 In 2003, a serum enzymelinked immunosorbent assay (ELISA) test for the detection of galactomannan, an Aspergillus antigen, became available in the United States, and although it is of low sensitivity, it appears to be specific and has been used for early diagnosis of invasive aspergillosis in patients after hematopoietic stem cell transplantation.238

Hyalohyphomycoses The term hyalohyphomycoses is used to denote opportunistic infections caused by colorless (hyaline) molds that, although taxonomically diverse, are seen in tissue as septate, branching, filamentous, colorless hyphae and cause diseases other than aspergillosis, the most common hyalohyphomycosis, that have not been previously discussed. The number of organisms causing hyalohyphomycosis continues to increase and includes Fusarium, Acremonium, Paecilomyces, Scedosporium, and Trichoderma species. Culture is necessary to identify these agents because many of them tend to exhibit resistance to antifungal agents.96,103

Fusarium CLINICAL FEATURES Fusarium species, a common soil fungus, cause a broad

spectrum of human infections, including superficial, locally invasive, and disseminated infections, depending on host factors. Three species are implicated in human infections: F. solani, F. oxysporum, and F. moniliforme. Fusarium species are frequent causes of corneal and nail infections and deep localized infections such as mycetomas and have emerged as a cause of disseminated mycoses among cancer patients undergoing chemotherapy and hematopoietic stem cell transplantation.103 Cutaneous infection may develop as a complication of ulcers, surgical trauma, and burns, especially in neutropenic patients. Disseminated Fusarium infection, similar to aspergillosis, may arise after pulmonary inhalation or as a result of spread of cutaneous disease. Risk factors for fusariosis include prolonged neutropenia and T-cell immunodeficiency.239 Similar to Aspergillus species, Fusarium species are angioinvasive and lead to tissue infarction in neutropenic patients. However, unlike Aspergillus species, Fusarium species continuously release spores, consisting of phialides and phialoconidia, into the blood; this intravascular adventitious sporulation is associated with a higher rate of positive blood cultures and dissemination of infection.103 The clinical presentation is usually fever in the setting of neutropenia; positive blood cultures, with or without lung or sinus involvement; and characteristic cutaneous lesions239 that range from subcutaneous painful lesions to an ecthyma gangrenosum-like necrotic

Acremonium species are found in soil and may cause nail and corneal infections. In patients with severe medical conditions or predisposing factors, such as chronic granulomatous disease, cardiac valve prostheses, or renal failure, both Paecilomyces and Acremonium species may be associated with fatal infections of the lung, brain, heart, peritoneum, and bones.240 Paecilomyces species, also found in soil, have been implicated in outbreaks of corneal infection and endophthalmitis.240,241

CHAPTER 21 ■ FUNGAL INFECTIONS

Acremonium and Paecilomyces

HISTOPATHOLOGIC FEATURES Histologic sections of cutaneous plaques or subcutaneous abscesses reveal septate, 2- to 4-μm-diameter hyphae branching at an acute angle. Culture is required to further characterize the species causing hyalohyphomycosis.240,241

SCEDOSPORIUM Formerly associated with asymptomatic colonization, Scedosporium species are emerging as a cause of infection in accidentally injured people as well as in immunocompromised individuals.103 S. apiospermum (teleomorph Pseudoallescheria boydii) and S. prolificans are dematiaceous opportunistic fungi that share similar morphology and clinical behavior with other opportunistic hyaline molds; they exhibit resistance to antifungal agents.96 S. apiospermum is implicated in mycetoma and deep-seated infections, such as CNS abscesses, and disseminated infection in bone marrow transplant recipients and other neutropenic patients.96 The respiratory tract is the main portal of entry for immunocompromised hosts. 1 0 3 S. prolificans may cause bone and soft tissue infections in immunocompetent persons

487

after percutaneous trauma, as well as in disseminated disease in immunocompromised hosts.96

TRICHODERMA

PART III ■ INFECTIONS

Previously considered nonpathogenic, Trichoderma species are filamentous fungi that have emerged as opportunistic pathogens in immunocompromised patients and patients undergoing peritoneal dialysis. T. Longibrachiatum has caused fatal disseminated disease in several bone marrow transplant recipients and a renal transplant recipient.96,242

Penicillium marneffei CLINICAL FEATURES P. marneffei, the only known thermally dimorphic Penicillium, is an endemic pathogen in Southeast Asia, where it has emerged as a significant cause of disseminated infection in HIV-infected patients residing or traveling to the area. The third most common opportunistic infection after tuberculosis and cryptococcosis in AIDS patients in northern Thailand, P. marneffei infection is considered an AIDS-defining illness within Southeast Asia, China, and India.103,243 Although most common in adults with HIV infection, penicilliosis has also been observed in immunocompetent children and adults. Infection begins with flulike symptoms and a papular eruption that progress to necrotic cutaneous ulcers and abscesses, generalized lymphadenopathy, hepatosplenomegaly, and death if not treated.77,161 Among serologic methods, a combination of ELISAbased antibody and antigen tests for diagnosis of P. marneffei in HIV-positive patients had a sensitivity of 88%, a positive predictive value of 100%, and a negative predictive value of 96%.243 HISTOPATHOLOGIC FEATURES The organism in tissue sections resembles H. capsulatum, except yeast cells multiply by binary fission rather than by budding.161 The multiplying cells are elongated and have prominent cross-walls.244,245 Reactions in tissue range from granulomatous and suppurative to necrotizing.103

MISCELLANEOUS MYCOSES

Keloidal Blastomycosis (Lobo Disease) 488

Synonyms: Lobomycosis, Amazonian blastomycosis, lacaziosis, leper of the Caiabi, pseudoleprosy, keloidiform

blastomycosis, miraip and piraip (“that which burns” in the Tupi language).246-248 CLINICAL FEATURES First described by Jorge Lobo in 1930, lobomycosis is characterized by slowly growing cutaneous and subcutaneous keloidal nodules and plaques that occur on the cooler regions of the body, such as the ears, face, arms, and legs (Table 21-25). Infection may be asymptomatic or associated with a burning sensation and is usually preceded by trauma such as an animal or insect bite. The onset is generally insidious, with nodules increasing in size and number over years. It occurs in the New World tropics, especially among indigenous tribes inhabiting the Amazon and Orinoco River basins.246,248 The natural reservoir of L. loboi is unknown, and it is thought to be an obligate pathogen.147,249,250 Lobomycosis has been reported involving two species of dolphins, namely, marine dolphins (Tursiops truncatus) and marine-freshwater dolphins (Sotalia fluviatis), in endemic areas and beyond, including the waters off the coasts of Florida, Texas and southern Brazil, the Spanish-French coast, and the Suriname river estuary.249 The clinical presentation of lobomycosis is similar in dolphins and humans, involving the dermis and subcutaneous tissues, and rarely the lymph nodes, while sparing other organs.249 A human case, presumably acquired in Venezuela 2.5 years earlier, was reported in 2000 in a United States man.251 It is the most common subcutaneous mycosis in Manaus,147 a city of more than 1 million

Table 21-25 Lobomycosis

Clinical Features Caused by Loboa loboi (Paracoccidioides loboi) Has not been grown in culture Occurs in South America near Amazon and Orinoco Rivers Slow-growing keloidal plaques and nodules Also infects dolphins Histopathologic Features Atrophic or acanthotic epidermis Granulomatous infiltrate in lower dermis and subcutaneous tissues Numerous uniform (10 μm), round P. loboi with transparent cytoplasm and thick double wall P. loboi form beads joined by thin bridges Differential Diagnosis Leishmaniasis Paracoccidioidomycosis Cryptococcosis

inhabitants on the Rio Negro near the confluence that forms the Amazon River in Brazil. The causative agent of lobomycosis has never been cultivated in vitro, a fact that left its taxonomic relation to other organisms contentious and enigmatic for many years after Jorge Lobo’s description of the disease and organism, which he believed to be related to Paracoccidioides brasiliensis on the basis of micromorphologic similarity. The organism has been called various names, including Glenosporella loboi, Glenosporopsis amazonica, Loboa loboi, Lobomyces loboi, and Paracoccidioides loboi. In 1999, Taborda et al proposed the monotypic genus Lacazia to accommodate the type species Lacazia loboi, the causative agent of lobomycosis.249 Subsequent phylogenetic analyses using the two 18S small-subunit ribosomal DNA (SSU rDNA) molecules indicated that L. loboi is a distinct species and is the sister taxon of the dimorphic fungal pathogen Paracoccidioides brasiliensis and that both species belong in the order Onygenales with other dimorphic fungal pathogens.250 These findings and the observation that the antigenic gp43 protein of P. brasiliensis cross-reacts with sera of patients with lobomycosis led to molecular studies showing that the two species share some similar DNA sequences.252 Spontaneous remission with persistence of fungi in scar tissue may occur.246 Affected individuals have defective cellmediated immunity, which is also a predisposing factor for paracoccidioidomycosis.253 Infiltrating squamous cell carcinoma has been reported to develop in the long-standing plaques in 1% or fewer of patients.254 HISTOPATHOLOGIC FEATURES There is variable acanthosis and hyperkeratosis, with epidermal atrophy in some instances. The lower dermis and subcutaneous tissues contain a granulomatous infiltrate composed mainly of giant cells and macrophages. Large numbers of L. loboi are seen, mostly within the cytoplasm of giant cells and histiocytes, but also extracellularly, surrounded by histiocytes.253,254 Fibrosis, hyalinization, and loss of adnexal structures owing to inflammation are observed occasionally. L. loboi are fairly consistent in size, averaging about 9 μm in diameter, and appear as globose to subglobose, thickwalled, yeast-like cells ranging from 5 to 12 μm in diameter. Cells reproduce by single and multiple budding, with blastoconidia attached to the mother cell by narrow tubular connections, demonstrating a beaded appearance.250 (see Table 21-25).

In H&E-stained sections, the cytoplasm appears empty or contains a central pale nucleus and is surrounded by the thick double-contoured wall measuring 1 μm. Methenamine silver stain is better than PAS stain for demonstrating L. loboi, which typically form chains joined by thin bridges. The cell wall contains constitutive melanin that is detectable by the FontanaMasson stain.249

Rhinosporidiosis Rhinosporidiosis is a chronic granulomatous infection of the mucocutaneous tissues that affects humans and animals. The etiologic agent is Rhinosporidium seeberi, an organism that has never been cultured successfully in a cell-free medium, isolated from nature or transmitted to experimental animals.26,255 In 1986, Levy and colleagues256 reported in vitro cultivation in a human neoplastic epithelial cell culture line; however, cultivation of the organism was not confirmed by others. R. seeberi occurs in tissues as very large spherules, called sporangia, that typically measure 250 to 350 μm in diameter and contain endospores.257 The taxonomic relationship of R. seeberi with other organisms remained elusive for more than a century. Guillermo Seeber, who first described rhinosporidiosis in Argentina in 1900, regarded the sporangium of the organism to be a sporozoan related to the coccidia. On the basis of morphologic and histochemical characteristics, R. seeberi was classified as a fungus, although its taxonomy remained controversial. In 1999, phylogenetic analysis of R. seeberi’s 18S SSU rDNA and that of 23 other microorganisms led to the conclusion that the organism was not actually a fungus but rather belonged

CLINICAL FEATURES Rhinosporidiosis is characterized by large polypoid growths that usually involve the nasal, ocular, or nasopharyngeal mucosa. The incidence is higher in men and in those aged 20 to 40 years. Whereas nasopharyngeal infections are more prevalent in men, ocular infections are more common in women.147 Less commonly, this process may involve the skin, oropharynx, larynx, urethra, vagina, rectum, bone, and brain.255 The disease affects both humans and animals and occurs most commonly in India, Sri Lanka, and other parts of South Asia, but it has also been reported elsewhere, including the Americas, Africa, and Europe.147,261,262 The modes of infection and transmission are unknown, although stagnant water and dust have been suspected as possible sources263,264 (Table 21-26). The most commonly affected site is the nose, accounting for approximately 70% of cases. The presentation often involves unilateral obstruction or epistaxis, although bilateral involvement is common in the later stages. A bloodtinged mucoid discharge, often containing spores and sporangia, may be noted, and local pruritus is sometimes reported.265 Infection usually begins as a sessile tumor that may develop into a globoid pedunculated polyp weighing 20 g or more.26 The color, ranging from pink to red, is caused by vascularization and free blood. Macroscopically visible whitish spherules or round bodies representing bulging sporangia impart a mottled appearance to the polyp and give it a characteristic strawberry appearance. Septal perforation is common.264 HISTOPATHOLOGIC FEATURES The surface of the polypoid mass is stratified squamous or columnar epithelium with slight hyperkeratosis and hyperplasia, although areas of thinning and erosion, particularly near mature sporangia, may be present (see Table 21-26). Numerous spores and sporangia in various developmental stages are noted in the submucosa, along with

Table 21-26 Rhinosporidiosis

Clinical Features Highest prevalence in India and Sri Lanka Nasal area involved in 70% of cases Large polypoid, globoid, pedunculated, mottled nodules Conjunctiva involved in 15% of cases, more in drier climates Sessile or stalked growth involving palpebral conjunctiva Cutaneous infection rare Autoinoculation more common than primary cutaneous origin Papules evolve into verrucous nodules that may ulcerate Hematogenous dissemination very rare Numerous small (0.5-2.0 cm) nodules that may ulcerate Other mucocutaneous sites in 8% of cases Histopathologic Features Mild hyperkeratosis, hyperplasia, and areas of thinning near sporangia Sporangia (30-350 μm) in submucosa Endospores (7-9 μm) within sporangia, free in tissue, and inside giant cells Submucosal infiltrate of neutrophils, lymphocytes, histiocytes, plasma cells, and multinucleated giant cells Prominent vascularity, hemorrhage, and hemosiderin disposition Differential Diagnosis Midline lethal ficial granuloma Cryptococcus neoformans Coccidioides immitis Spherules 30-60 μm, colorless, and flattened

CHAPTER 21 ■ FUNGAL INFECTIONS

DIFFERENTIAL DIAGNOSIS A granulomatous infiltrate with histiocytes may also be observed in leishmaniasis and lepromatous leprosy; however, the presence of numerous fungi can facilitate the distinction between lobomycosis, leishmaniasis, and leprosy. More numerous organisms are seen in lobomycosis than in paracoccidioidomycosis or cryptococcosis. In addition, whereas L. loboi shows characteristic branching chains of similarly sized blastoconidia joined by narrow tubular connections, giving a beaded appearance, P. brasiliensis reproduces by multiple budding of mother cells that grow large and thick walled compared with the daughter cells, sometimes in a characteristic configuration resembling a captain’s wheel.

in a recently described group of fish parasites referred to as the DRIP clade258,259 (Dermocystidium, rosette agent, Ichthyophonus, and Psorospermium), located near the animal-fungal divergence nearly 1 billion years ago.1 This group of microbes, some of which are known fish pathogens, has been reclassified as the protistal class Mesomycetozoae. Recent molecular evidence suggests that the genus Rhinosporidium may comprise multiple host-specific strains, which may partially explain the failure of experimental rhinosporidiosis.260

histiocytes, neutrophils, lymphocytes, and plasma cells; multinucleated giant cells, usually of the foreign body type are seen occasionally185 (Fig. 21-25). Whereas spores usually range from 7 to 9 μm in diameter, sporangia vary greatly in size from 60 to 450 μm or more in diameter147; refractile spores may be noted free in tissue, often close to the surface, and within giant cells.258,265 Release of spores from a spherule appears to incite a polymorphonuclear leukocyte response, and prominent vascularity, hemorrhage, and hemosiderin deposition are often seen.26 In addition to the neovascularization, necrosis and neutrophilic microabcesses may be seen. The walls of the spherules and spores stain with Gomori methenamine silver, Gridley, and PAS stains. DIFFERENTIAL DIAGNOSIS Nasal and ocular disease may resemble midline lethal facial granuloma because of the dense inflammatory infiltrate; however, cytologic atypia

489

22.

23. 24. 25. 26.

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27.

28.

 FIGURE 21-25 Rhinosporidiosis. Large sporangia are present in the nasal submucosa. (Courtesy of Dr. F. Von Lichtenberg.)

30.

is not seen in patients with rhinosporidiosis. Cryptococcosis may cause polypoid tumors that may be differentiated from rhinosporidiosis by microscopic tissue examination.26 R. seeberi and C. immitis both produce spherules in the yeast tissue phase; however, on direct examination, R. seeberi spherules are globose, brown, and much larger than C. immitis spherules, which are colorless, not perfectly spherical, and measure 30 to 60 μm in diameter.257

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65. Pfaller MA, Messer SA, Boyken L, et al: Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to seven systemically active antifungal agents: a global assessment from the ARTEMIS Antifungal Surveillance Program conducted in 2001 and 2002. J Clin Microbiol. 2004;42:3142-3146. 66. Bodey GP, Luna M: Skin lesions associated with disseminated candidiasis. JAMA. 1974;229:1466-1468. 67. Grossman ME, Silvers DN, Walther RR: Cutaneous manifestations of disseminated candidiasis. J Am Acad Dermatol. 1980;2:111-116. 68. File TM Jr, Marina OA, Flowers FP: Necrotic skin lesions associated with disseminated candidiasis. Arch Dermatol. 1979;115:214-215. 69. Benson PM, Roth RR, Hicks CB, et al: Nodular subcutaneous abscesses caused by Candida tropicalis. J Am Acad Dermatol. 1987;16:623-624. 70. Fine JD, Miller JA, Harrist TJ: Cutaneous lesions in disseminated candidiasis mimicking ecthyma gangrenosum. Am J Med. 1981;70:1133-1135. 71. Collignon PJ, Sorrell TC: Disseminated candidiasis: evidence of a distinctive syndrome in heroin abusers. Br Med J. 1983;287:861-862. 72. Jarowski CJ, Fialk MA, Murray HW: Fever, rash, and muscle tenderness: a distinctive clinical presentation of disseminated candidiasis. Arch Intern Med. 1978;138(4):544-546. 73. Bodey GP: Fungal infections complicating acute leukemia. J Chron Dis. 1966; 19(6):667-687. 74. Guého E, Midgley G, Guillot J: The genus Malassezia with description of four new species. Antonie Van Leeuwenhoek. 1996;69:337-355. 75. Gupta AK, Batra R, Bluhm R, et al: Skin diseases associated with Malassezia species. Am Acad Dermatol. 2004;51(5): 785-798. 76. Crespo-Erchiga V, Florencio VD: Malassezia species in skin diseases. Curr Opin Infect Dis. 2002;15:133-142. 77. Gupta AK, Kohli Y, Faergemann J, Summerbell RC: Epidemiology of Malassezia yeasts associated with pityriasis versicolor in Ontario, Canada. Med Mycol. 2001;39:199-206. 78. Dutta S, Bajaj AK, Basu S, Dikshit A: Pityriasis versicolor: socioeconomic and clinico-mycologic study in India. Int J Dermatol. 2002;41:823-824. 79. Crespo-Erchiga V, Florencio VD: Malassezia yeasts and pityriasis versicolor. Curr Opin Infect Dis. 2006;19:139-147. 80. Marples MJ: The incidence of certain skin diseases in western Samoa: a preliminary survey. Trans R Soc Trop Med Hyg. 1950;44:319-332. 81. Roberts SOB: Pityriasis: a clinical and mycological investigation. Br J Dermatol. 1969;81:315-326. 82. Borelli D, Jacobs PH, Nall L: Tinea versicolor: epidemiologic, clinical and therapeutic aspects. J Am Acad Dermatol. 1991;25:300-303. 83. Nazzaro-Porro M, Passi S: Identification of tyrosinase inhibitors in cultures of Pityrosporum. J Invest Dermatol. 1978;71: 389-402. 84. Weiss R, Raabe P, Mayser P: Yeasts of the genus Malassezia: taxonomic classification

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CHAPTER 21 ■ FUNGAL INFECTIONS

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sive cutaneous involvement in a patient with AIDS. J Am Acad Dermatol. 1999;40(2):350-355. Rodriquez G, Sarmiento L: The asteroid bodies of sporotrichosis. Am J Dermatol. 1998;20(3):246-249. Binford CH, Connor DH. Pathology of Tropical and Extraordinary Diseases. Washington, DC: Armed Forces Institute of Pathology; 1976:585-586. Carrión A: Chromoblastomycosis. Ann NY Acad Sci. 1950;50:1255-1282. Elgart GW: Chromoblastomycosis. Dermatol Clin. 1996;14:77-83. Bonifaz A, Carrasco-Gerard E, Saul A: Chromoblastomycosis: clinical and mycologic experience of 51 cases. Mycoses. 2001;44:1-7. Ajello L, George LK, Steigbigel RT, Wange CJK: A case of phaeohyphomycosis caused by a new species of Phialophora. Mycologia. 1974;66:490-498. Zeifer A, Connor DH: Phaemycotic cyst: a clinicopathologic study of 25 patients. Am J Trop Med. 1980;29:901-911. Patterson JW, Warren NG, Kelly LW: Cutaneous phaeohyphomycosis due to Cladophialophora bantiana. J Am Acad Dermatol. 1999;40:2. Gupta AK, Chaudhry M, Elewski B: Tinea corporis, tinea cruris, tinea nigra, and piedra. Dermatol Clin. 2003;21:395-400. Smith SB, Beals SL, Elston DM, et al: Dermoscopy in the Diagnosis of Tinea Nigra Plantaris. Washington, DC: National Library of Medicine; 2001. Vieira R, Veloso J, Afonso A, Rodrigues A: Cutaneous alternariosis in a liver transplant recipient. Rev Iberoam Micol. 2006;23:107-109. Gallelli B, Viviani M, Nebuloni M, Marzano AV, et al: Skin infection due to Alternaria species in kidney allograft recipients: report of a new case and review of the literature. J Nephrol. 2006;19(5):668-672. Mitchel AJ, Solomon AR, Beneke ES, et al: Subcutaneous alternariosis. J Am Acad Dermatol. 1983;8:673-679. Pedersen NB, Mardh PA, Hallber T, et al: Cutaneous alternariosis. Br J Dermatol. 1976;94:201-209. Arrese JE, Pierard-Franchimont C, Peirard GE: Onychomycosis and keratomycosis caused by Alternaria sp. Am J Dermatopathol. 1966;18:611-613. Khandara KC, Mahapatra LN, Seghal VN, et al: Black mycetoma of foot. Arch Dermatol. 1964;89:867-870. McGinis MR: Mycetoma. Dermatol Clin. 1996;14:97-104. Saubolle MA, Sussland D: Nocardiosis: review of clinical and laboratory experience. J Clin Microbiol. 2003;41(10): 4497-4501. Chedid MBF, Chedid MF, Porto NS, et al: Nocardial infections: report of 22 cases. Rev Inst Med Trop S Paulo. 2007;49(4):239-246. Agterof MJ, van der Bruggen T, Tersmette M, et al: Nocardiosis: a case series and a mini review of clinical and microbiological features. Neth J Med. 2007;65(6):199-202. Boudoulas O, Camis C: Nocardia asteroides infection with dissemination to skin and joints. Arch Dermatol. 1985; 121:898-900. Warren NG: Actinomycosis, nocardiosis, and actinomycetoma. Dermatol Clin. 1996;14:85-95.

200. Bennhoff: Actinomycosis: diagnostic and therapeutic considerations and a review of 32 cases. Laryngoscope. 1984; 94:1198-1217. 201. Yegüez JF, Martinez SA, Sands LR, Hellinger MD: Pelvic actinomycosis presenting as malignant large bowel obstruction: a case report and a review of the literature. Am Surg. 2000; 66(1):85-90. 202. Binford CH, Dooley JR: Botryomycosis, in Binford CH, Connor DH (eds). Pathology of Tropical and Extraordinary Diseases. Washington, DC: Armed Forces Institute of Pathology; 1970:561. 203. Bishop GF, Greer KE, Horwitz DA: Pseudomonas botryomycosis. Arch Dermatol. 1976;112:1568-1570. 204. Harman RRM, English MP, Halford M, et al: Botryomycosis. Br J Dermatol. 1990;102:215-222. 205. Waisman M. Staphylococcal actinophycosis (botryomycosis). Arch Dermatol. 1962;86:525-529. 206. Schübler A, Schwarzott D, Walker C: A new fungal phylum, the Glomeromycota: phylogeny and evolution. Mycol Res. 2001;105:1413-1421. 207. Ribes JA, Vanover-Sams CL, Baker DJ: Zygomycetes in human disease. Clin Microbiol Rev. 2000;13(2):236-301. 208. Auluck A: Maxillary necrosis by mucormycosis. A case report and literature review. Med Oral Patol Oral Cir Bucal. 2007;12:E360-E364. 209. Sanchez M, Ponge-Wilson I, Moy JA, Rosenthal S: Zygomycosis and HIV infection J Am Acad Dermatol. 1994;30: 904-908. 210. Geller J, Peters M, Su WP: Cutaneous mycormycosis resembling superficial granulomatous pyoderma in an immunocompetent host. J Am Acad Dermatol. 1993;29:462-465. 211. Wirth F, Perry R, Eskenazi A, et al: Cutaneous mycormycosis with subsequent visceral dissemination in a child with neutropenia: a case report and review of the pediatric literature. J Am Acad Dermatol. 1997;36:336-341. 212. Sugar AM: Agents of mycormycosis and related species, in Mandell GL, Bennett JE, Dolin R (eds). Principles and Practice of Infectious Diseases, 4th ed. New York: Churchill Livingstone; 1995:2311-2321. 213. Levy SA, Schmitt KW, Kaufman L: Systemic zygomycosis diagnosed by fine needle aspiration and confirmed with enzyme immunoassay. Chest. 1986;90(1): 146-148. 214. Craig N, Lueder F, Pensler JM, et al: Disseminated Rhizopus infection in a premature infant. Pediatr Dermatol 1994;11:346-350. 215. Adam R, Hunter G, DiTomasso J, Comerci G: Mucormycosis: emerging prominence of cutaneous infections. Clin Infect Dis. 1994;19:67-76. 216. Waldorf AR: Immunology of fungal diseases. Immunol Ser. 1989;47:243-271. 217. Diamond RD, Krzesicki R, Epstein B, Jao W: Damage to hypal forms of fungi by human leukocytes in vitro: a possible host defense mechanism in aspergillosis and mycormycosis. Am J Pathol. 1978;91:313-328. 218. Lehrer RI, Howard DH, Sypherd PS, et al: Mucormycosis. Ann Intern Med. 1980; 93(1):93-108. 219. Machouart M, Larché J, Burton K, et al: Genetic identification of the main

CHAPTER 21 ■ FUNGAL INFECTIONS

158. Dijkstra JW: Histoplasmosis. Dermatol Clin. 1989;7: 251-258. 159. Nethercott JR, Schachter RK, Givan KF, Ryder DE: Histoplasmosis due to Histoplasma capsulatum var. duboisii in a Canadian immigrant. Arch Dermatol. 1978;114:595-598. 160. Chaker MB, Cockerell CJ: Concomitant psoriasis, seborrheic dermatitis, and disseminated cutaneous histoplasmosis in a patient infected with human immunodeficiency virus. J Am Acad Dermatol. 1993;29:311-313. 161. Goodwin RA, Loyd JE, Des Pres RM: Histoplasmosis in normal hosts. Medicine. 1981;60:231-266. 162. Eidbo J, Sanchez RL, Tschen JA, Ellner KM: Cutaneous manifestations of histoplasmosis in the acquired immune deficiency syndrome. Am J Surg Pathol. 1993;17(2):110-116. 163. Gutierrez ME, Canton A, Sosa N, et al: Disseminated histoplasmosis in patients with AIDS in Panama: a review of 104 cases. Clin Infect Dis. 2005;40:1199-1202. 164. Cohen PR, Bank DE, Silvers DN, Grossman ME: Cutaneous lesions of disseminated histoplasmosis in human immunodeficiency virus-infected patients. J Am Acad Dermatol. 1990;23: 422-428. 165. Johnson PC, Khardori N, Najjar AF, et al: Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome. Am J Med. 1988; 85:152-158. 166. Tesh RB, Schneidau JD: Primary cutaneous histoplasmosis. New Engl J Med. 1966;275(11):597-599. 167. Medeiros AA, Marty SD, Tosh FE, Chin TDY: Erythema nodosum and erythema multiforme as clinical manifestations of histoplasmosis in a community outbreak. New Engl J Med. 1996;274(8):415-420. 168. Kauffman CA, Israel KS, Smith JW, et al: Histoplasmosis in immunosuppressed patients. Am J Med. 1978;64:923-932. 169. Weinberg GA, Kleiman MB, Grosfeld JL, et al: Unusual manifestations of histoplasmosis in childhood. Pediatrics. 1983;72:99-105. 170. Abildgaard WH, Hargrove RH, Kalivas J: Histoplasma panniculitis. Arch Dermatol. 1985;121:914-916. 171. Petit N, Bonnet E, Chapel F, et al: Cutaneous biopsies for diagnosis of histoplasmosis in an HIV patient. Infection. 1994;22(6):426-427. 172. Kalter DC, Tschen JA, Klima M: Maculopapular rash in a patient with acquired immunodeficiency syndrome. Arch Dermatol. 1985;121:1455-1456. 1458-1459. 173. Kauffman CA: Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20(1):115-132. 174. Khalil M, Iwatt AR, Gugnani HC: African histoplasmosis masquerading as carcinoma of the colon: report of a case and review of literature. Dis Colon Rectum. 1989;32:518-520. 175. Simon F, Chouc PY, Herve V, et al: Localisations osteoarticulaires de l’histoplasmose africaine (Histoplasma duboisii): a propos d’un cas et revue de la literature. Rev Rhumatol. 1994;61:829-838. 176. Davis BA: Sporotrichosis. Dermatol Clin. 1996;14:69-76. 177. Ware AJ, Cockerel CJ, Skkiest DJ, et al: Disseminated sporotrichosis with exten-

493

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221. 222. 223.

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224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

494

opportunistic Mucorales by PCR-restriction fragment length polymorphism. J Clin Microbiol. 2006;44(3):805-810. Vismer HF, De Beer HA, Dreyer L: Subcutaneous phycomycosis caused by Basidiobolus haptosporus. S Afr Med J. 1980; 58:644-647. Gugnani HC: Entomophthoramycosis due to Conidiobolus. Eur J Epidemiol. 1992;8:391-396. Scholtens REM, Harrison SM: Subcutaneous phycomycosis. Trop Geogr Med. 1994;46:371-373. Bittencourt AL, Araujo MG, Fontoura MS: Occurrence of subcutaneous zygomycosis (entomophthoramycosis basidiobolae) caused by Basidiobolus haptosporus with pulmonary involvement. Mycopathologia. 1980;71:155-158. Antonelli M, Vignetti P, Dahir M, et al: Entomophthoramycosis due to Basidiobolus in Somalia. Trans R Soc Trop Med Hyg. 1987;81:1186-1187. Greenbaum RS, Roth JS, Grossman ME: Subcutaneous nodule in a cardiac transplant: cutaneous aspergillosis. Arch Dermatol. 1993;129:1191-1194. Tuon FF: A systematic literature review on the diagnosis of invasive aspergillosis using polymerase chain reaction (PCR) from bronchoalveolar lavage clinical samples. Rev Iberoam Micol. 2007;24:89-94. Hunt SJ, Nag C, Gross KG, et al: Primary cutaneous aspergillosis near central venous catheters in patients with the acquired immunodeficiency syndrome. Arch Dermatol. 1992;128:1229-1232. Baddley JW, Pappas PG, Smith AC, Moser SA: Epidemiology of Aspergillus terreus at a university hospital. J Clin Microbiol. 2003;41(12):5525-5529. Morgan J, Wannemuehler KA, Marr KA, et al: Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol. 2005; 43(suppl 1):S49-S58. Stiller MJ, Teperman L, Rosenthal SA, et al: Primary cutaneous infection by Aspergillus ustus in a 62-year-old liver transplant recipient. J Am Acad Dermatol. 1994;31:344-347. Mowad CH, Nguyen TV, Jaworsky C, Honig PJ: Primary cutaneous aspergillosis in an immunocompetent child. J Am Acad Dermatol. 1995;32:136-137. Grossman ME, Fithian EC, Behrens C, et al: Primary cutaneous aspergillosis in six leukemic children. J Am Acad Dermatol. 1985;12:313-318. Skaria AM, Chavaz P, Hauser C: Metastatische aspergillus-pannikulitis bei blastischer transformation eines myelodysplastischen syndromes und agranulozytose. Hautarzt. 1995;46:579-581.

234. Findlay GH, Roux HF, Simson IW: Skin manifestations in disseminated aspergillosis. Br J Dermatol. 1971; 85(suppl 7):94. 235. Romero LS, Hunt SJ: Hickman catheterassociated primary cutaneous aspergillosis in a patient with the acquired immunodeficiency syndrome. Int J Dermatol. 1995;34:551-553. 236. Geol R, Wallace ML: Pseudoepitheliomatous hyperplasia secondary to cutaneous Aspergillus. Am J Dermatopathol. 2001;3:224-226. 237. Enoch DA, Ludlam HA, Brown NM: Invasive fungal infections: a review of epidemiology and management options. J Med Microbiol. 2006;55:809-818. 238. Foy PC, van Burik JA, Weisdorf DJ: Galactomannan antigen enzyme-linked immunosorbent assay for diagnosis of invasive aspergillosis after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13(4):440-443. 239. Nucci M, Anaissie E: Fusarium infections in immunocompromised patients. Clin Microbiol Rev. 2007;20(4):695-704. 240. Shing MM, Ip M, Li CK, et al: Paecilomyces varioti fungemia in a bone marrow transplant patient. Bone Marrow Transplant. 1996;17:281-283. 241. D’Castro LC: Sporotrichosis-like lesions caused by a Paecilomyces genus fungus. Int J Dermatol. 1994;33:275-276. 242. Chouaki T, Lavarde V, Lachaud L, et al: Invasive infections due to Trichoderma species: report of 2 cases, findings of in vitro susceptibility testing, and review of the literature. Clin Infect Dis. 2002;35: 1360-1367. 243. Vanittanakom N, Cooper CR, Fisher MC, Sirisanthana T: Penicillium marneffei infection and recent advances in the epidemiology and molecular biology aspects. Clin Microbiol Rev. 2006;19(1): 95-110. 244. Nelson KE, Sirisanthana T: Disseminated Penicillium marneffei infection in a patient with AIDS. New Engl J Med. 2001; 344(23):1763. 245. Supparatpinyo K, Khamwan C, Baosoung V, et al: Disseminated Penicillium marneffei infection in Southeast Asia. Lancet. 1994;344(8915):110-113. 246. Rodríguez-Toro G: Lobomycosis. Int J Dermatol. 1993;32:324-332. 247. Rodríguez-Toro G, Tellez N: Lobomycosis in Colombian Amerindian patients. Mycopathologia. 1992;120:5-9. 248. Paniz-Mondolfi AE, Jaimes OR, Jones LD: Lobomycosis in Venezuela. Int J Dermatol. 2007;46:180-185. 249. Taborda PR, Taborda VA, McGinnis MR: Lacazia loboi gen. nov., comb. nov., the etiologic agent of lobomycosis. J Clin Microbiol. 1999;37(6):2031-2033.

250. Herr RA, Tarcha EJ, Taborda PR, et al: Phylogenetic analysis of Lacazia loboi places this previously uncharacterized pathogen within the dimorphic Onygenales. J Clin Microbiol. 2001;39(1): 309-314. 251. Burns RA, Roy JS, Woods C, et al: Report of the first human case of lobomycosis in the United States. J Clin Microbiol. 2000;38(3):1283-1285. 252. Vilela R, Mendoza L, Rosa PS, et al: Molecular model for studying the uncultivated fungal pathogen Lacazia loboi. J Clin Microbiol. 2005;43(8):3657-3661. 253. Pecher SA, Fuchs J: Cellular immunity in lobomycosis (keloidal blastomycosis). Allergol Immunopathol. 1998;16(6):413-415. 254. Fuchs J, Milbradt R, Pecher SA: Lobomycosis (keloidal blastomycosis): case reports and overview. Cutis. 1990; 46:227-234. 255. Azadeh B, Baghoumian N, el-Bakin OJ: Rhinosporidiosis: immunohistochemical and electron microscopic studies. J Laryngol Otol. 1994;108:1048-1054. 256. Levy MG, Meuten DJ, Breitschwerdt EB: In vitro cultivation of Rhinosporidium seeberi: interaction with epithelial cells. Science. 1986;234:474-476. 257. Gori S, Scasso A: Cytologic and differential diagnosis of rhinosporidiosis. Acta Cytol. 1994;38(3):361-366. 258. Herr RA, Ajello L, Taylor JW, et al: Phylogenetic analysis of Rhinosporidium seeberi’s 18S small-subunit ribosomal DNA groups this pathogen among members of the protoctistan Mesomycetozoa clade. J Clin Microbiol. 1999;37(9): 2750-2754. 259. Fredricks, DN, Jolley JA, Lepp PW, et al: Rhinosporidium seeberi: a human pathogen from a novel group of aquatic protistan parasites. Emerg Infect Dis. 2000;6(3): 273-282. 260. Silva V, Pereira CN, Ajello L, Mendoza L: Molecular evidence for multiple host-specific strains in the genus Rhinosporidium. J Clin Microbiol. 2005;43(4):1865-1868. 261. Caldwell GT, Roberts JD: Rhinosporidiosis in United States: report of a case originating in Texas. JAMA. 1938;110:1641. 262. Norman WB: Rhinosporidiosis in Texas. Arch Otolaryngol. 1960;72:361-363. 263. Thianprasit M, Thagerngpol K: Rhinosporidiosis. Top Med Mycol. 1989;3: 64-85. 264. Karunaratne WAE: Rhinosporidiosis in Man. London: Athlone Press; 1964. 265. Thomas T, Gopinath N, Betts RH: Rhinosporidiosis of the bronchus. Br J Surg. 1956;44:316-319.

CHAPTER 22 Viral Infections Clay J. Cockerell James J. Lyons

GENERAL PRINCIPLES OF VIRAL INFECTIONS All viral infections are initiated by entry of the infectious particle, the virion, into the host cell by pinocytosis or phagocytosis. Viruses differ in the types of cells they infect, having tropisms for different tissues, such as human papillomaviruses (HPVs), which have a tropism for epithelial cells. Viruses reach target cells through inhalation, ingestion, or direct inoculation. After entry into the cell, enzymes remove the outer layer of the virus, the capsid, and viral nucleic acid is released into the cell. This may be followed either by active viral replication, leading to an acute viral infection, or alternatively, viral nucleic acid may be incorporated into the host nucleic acid, leading to a latent infection. Different steps are required for viral replication depending on the agent in question. In some viruses, such as

skin, the eruption resolves. This is the case with the echoviruses, coxsackie A, most togaviruses, and rubella. Some RNA viruses are able to enter epidermal cells and replicate, leading to cytolysis and vesicles such as in the vesicular exanthem of some coxsackie A viruses. Replication in epidermal cells is characteristic of many DNA viruses after direct inoculation into the epidermis. Intraepidermal viral replication may lead to the formation of vesicles and pustules that develop as a consequence of focal necrosis and a secondary inflammatory response in which there may be spongiosis, ballooning degeneration, or acantholysis accompanied by an infiltrate of inflammatory cells consisting of lymphocytes, neutrophils, eosinophils, and plasma cells. Vesicular lesions are caused most commonly by poxviruses, herpes simplex, varicella zoster, and some coxsackieviruses. Antibody production is stimulated by cutaneous viral infection and may serve to prevent spread of infection through the bloodstream. However, the cellmediated immune response primarily mediated by cytotoxic CD8 lymphocytes is the major local inflammatory reaction that is induced and is the prime means of containing the infection as well as leading to its resolution. Immunocompromised hosts, however, have an inability to halt the spread of the infection, often eventuating in serious consequences. Factors that affect the distribution of eruptions in viral infections are poorly understood. Viruses tend to localize in areas that have been traumatized previously, in dependent areas, and at sites of preexisting inflammation, which may explain the distribution in some cases. However, the reasons for the cephalocaudal progression in rubella and the centripetal distribution of varicella are unknown.

CHAPTER 22 ■ VIRAL INFECTIONS

Viruses are the most prevalent of all infectious agents and are also the smallest, ranging in size from 20 to 300 nm in diameter. The term filterable agent was used to refer to viruses before they could be visualized reliably because they pass through 0.22-μm filters that retain other organisms. All viruses are obligate intracellular parasites that depend on the host cell’s metabolism for replication. They are classified primarily by the nucleic acid content of their core (either DNA or RNA) because they contain only a single type of nucleic acid. They are also classified on the basis of the shape of their protein coat, or capsid, which is either spherical or cylindrical.1 Classification based on symptoms has proven useful to clinicians because certain viruses preferentially affect different organs such as the skin, the nervous system, or the respiratory tract. Skin changes are often prominent manifestations of human viral infections, and the histopathologic changes associated with them vary from nonspecific features such as those seen in viral exanthems to pathognomonic inclusion bodies in herpesvirus and cytomegalovirus (CMV) infections.1

enteroviruses, viral RNA acts as a messenger and is almost directly infectious because it is translated immediately by host ribosomes into viral proteins. Other RNA viruses, such as influenza viruses, have non-infectious RNA that first must be transcribed into messenger RNA by a polymerase enzyme. Retroviruses, such as the human immunodeficiency viruses, are RNA viruses that contain reverse transcriptase, an enzyme that synthesizes DNA from viral RNA. DNA viruses are generally more complex and transcribe messenger RNA from their own DNA using either host cell enzymes or intrinsic viral polymerases. In active infections, nucleic acid replication occurs, followed by the synthesis of proteins. In general, the time required for new virus production in acute infections is measured in hours, with thousands of new virions being formed in each cell. Newly formed virions are released from the infected cell and spread to adjacent ones. During this process, the cell itself may be destroyed through lysis or may only be damaged and still survive.2 Other viruses cause cell proliferation or neoplastic transformation, such as warts or carcinomas caused by HPV. Latent viral infections may be productive of virions or may remain silent. In some cases, latent infections become reactivated, leading to the production of new virions, infection of adjacent cells, and active disease. Viral exanthemata are produced primarily as a consequence of the host response to viruses present in the skin. Virus particles are disseminated through the bloodstream. Some have a direct tropism for endothelial cells, such as parvovirus B19, CMV, and togaviruses. The latter group of viruses cause cytotoxic nonimmunologically mediated damage by accerating apoptosis or through the mechanism of molecular mimicry rendering the endothelial cell antigenic or damaging the vessel via immune complexes (ie, an Arthus type III reaction). Regardless of the exact mechanism of microvascular injury, the result ischemia and tissue infarction. Most viruses are recognized by the host as being foreign and incite antibody responses and cell-mediated immunity. Circulating immune complexes consisting of antibody and viral antigens may localize in dermal blood vessels, inciting an inflammatory reaction that leads to the development of a cutaneous eruption, usually with a clinical appearance of erythematous macules and papules. In the case of most RNA viral infections, there is no replication of virus, and after the virus is cleared from the

VIRAL EXANTHEMS The term viral exanthem refers to a cutaneous eruption, usually widespread, that develops as a consequence of a viral illness (Table 22-1). They usually present as generalized eruptions of erythematous macules, papules, and vesicles, often in association with fever. Individuals of any age may be affected, although they develop in children most commonly. The eruption may develop either as a consequence of direct viral infection of the skin or secondary to the host’s immune response to the virus. Because viral exanthems may have subtle clinical and histopathologic features

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Table 22-1 Viral Exanthems DISEASES

ETIOLOGY

CLINICAL FEATURES

HISTOPATHOLOGIC FEATURES

DIFFERENTIAL DIAGNOSIS

Measles

Measles virus/RNA virus

Superficial psoriasiform spongiotic dermatitis with dyskeratotic keratinocytes Warthin-Finkeldy giant cells

Drug eruption, rubella, fifth disease, Kawasaki disease, scarlet fever

Rubella (German measles)

Rubella virus/RNA virus

Parvovirus B19/DNA virus

Sparse superficial perivascular dermatitis with slight spongiosis, Turk cells (atypical lymphocytes) in peripheral blood and in skin infiltrate Sparse superficial perivascular dermatitis and focal spongiosis

Scarlet fever, infectious mono-nucleosis, fifth disease, typhus, RMSF, secondary syphilis, and toxoplasmosis

Fifth disease (erythema infectiosum)

Roseola (exanthem subitum)

HHV-6 DNA virus

Incubation period of 9-10 days Erythematous macules and papules first on the face then spread to neck, trunk, and extremities Koplik spots “Butterfly” facial rash, Forsheimer spots, centrifugal spread, cervical and occipital lymphadenopathy (Winterbottom sign) Incubation period of 2 weeks “Slapped cheeks” sparing circumoral areas, reticulated erythematous eruption on extensor extremities Incubation period of 4-7 days Rose-pink macules and papules on trunk sparing face

Sparse superficial perivascular dermatitis

Varicella (chickenpox) and herpes zoster

Varicella-zoster virus/DNA virus

Rubella, measles, fifth disease, scarlet fever, and morbilliform drug eruptions Miliaria crystallina, id reaction

Hand, foot, and mouth disease

Coxsackie virus A16, A5, A10, A7, A9, B1, B3, B5

Acute exanthem of HIV infection

HIV-1/RNA virus

Infectious mononucleosis

EBV/DNA virus

Acute exanthem of CMV

CMV/DNA virus

that may not be recognized easily, definitive diagnosis may be difficult and often requires correlation of physical findings, laboratory data, epidemiologic data, and historical features.

Measles 496

Measles is caused by an RNA virus that is 120 to 140 nm in size and is classified as a paramyxovirus. It is in the same

Incubation period of 11-20 days Vesicles 1-3 mm surrounded by red halo “dew drop on a rose petal” Herpes zoster, painful vesicles within a sensory dermatome Incubation period of 3-6 days Papulovesicles, and ulceration of palate buccal mucosa “Football”-shaped vesicles on dorsa of fingers and toes Incubation period of 3-6 weeks Morbilliform eruption involves trunk, chest, and upper arms Pharyngitis, fever and cervical adenopathy, splenomegaly, lymphocytosis, pinkish macules and papules on trunk and upper arms Similar to EBV “mononucleosis syndrome”

Steel-gray nuclei, margination of chromatin, multinucleated giant cells, acantholysis associated with leukocytoclastic vasculitis and inflammation of nerves Spongiosis, ballooning, and epidermal necrosis with superficial perivascular dermatitis

Juvenile rheumatoid arthritis, erythema multiforme, rubella, bilateral facial erysipelas

Varicella, herpes simplex, erythema multiforme

Superficial perivascular , dermatitis spongiosis, and necrotic keratinocytes Superficial perivascular, dermatitis spongiosis and parakeratosis, atypical lymphocytes in infiltrate

Drug eruption, CMV, infectious mononucleosis Drug eruption, CMV, toxoplasmosis

Similar to other viral exanthemata with characteristic “owl’s eye” inclusions in cytoplasm and nuclei of endothelial cells

Infectious mononucleosis, toxoplasmosis

family as the virus that causes mumps. Measles is an acute contagious viral disease characterized by coryza, cough, conjunctivitis, and Koplik spots that precede the appearance of a generalized eruption of pink to red macules and papules. The disease has a worldwide distribution, affecting primarily children between the ages of 3 and 6 years of age. It is a disease of winter and spring, with a peak incidence in March or April, and

it is spread via aerosolized respiratory droplets.3 The period of infectivity lasts from several days before cutaneous manifestation to as many as 5 days after lesions appear. Persons immunized with killed measles vaccine between the years 1961 and 1968 and subsequently exposed to wild measles virus are at risk for atypical measles.4 Vaccination efforts have led to decreasing mortality from measles with

an estimated 757,000 deaths worldwide from measles in 2000 versus 242,000 deaths in 2006.5

HISTOPATHOLOGIC FEATURES Skin biopsy specimens of fully developed lesions typically show slight psoriasiform

DIFFERENTIAL DIAGNOSIS Early in the course of infection when Koplik spots are present, the clinical diagnosis is not difficult; however, in the absence of Koplik spots, measles can be confused with other morbilliform eruptions, including Kawasaki disease, rubella, scarlet fever, roseola, erythema infectiosum, infectious mononucleosis, and drug eruptions. The characteristic intracellular inclusions and the multinucleated giant cells are helpful in establishing the diagnosis. Atypical measles must be distinguished from conditions such as erythema multiforme, Rocky Mountain spotted fever (RMSF), infectious mononucleosis, and drug eruptions, as well as typical measles.

Rubella (German Measles) Rubella is caused by a small 50- to 85-nm RNA virus that is a member of the togavirus family. It is a disease of schoolaged children and adolescents, although young children often escape the illness. Outbreaks commonly develop in isolated populations such as on military bases and in schools. As with measles, there is a worldwide distribution, with a peak incidence in the spring months. Although it is spread by droplets from infected individuals, prolonged contact is required for transmission. The period of infectivity

lasts from the end of the incubation period to disappearance of the cutaneous eruption, which is usually between 16 and 18 days. If infection occurs during the first trimester of pregnancy, severe fetal malformations may occur. CLINICAL FEATURES Initially, patients have a mild prodrome of 2 to 3 weeks’ duration characterized by fever and catarrh. An exanthem manifest as pinpoint petechiae may be seen on the soft palate in 20% of patients during this phase, which is known as Forsheimer sign. Lymphadenopathy then develops and is followed by a cutaneous eruption that begins on the face, involving the malar area (butterfly distribution), and spreads to involve the postauricular areas and eventually the trunk and extremities (see Table 22-1). Although it is characteristic, the eruption may be absent in 25% of patients. There is centrifugal spread with coalescence on the trunk with concomitant fading on the face. The eruption is characterized by bright red, slightly raised macules and fine papules. A mild branny desquamation may be seen in the resolution phase. Cervical and occipital lymphadenopathy is highly characteristic and has been termed Winterbottom sign. Splenomegaly, arthralgia, thrombocytopenia, purpura, and testicular pain are noted occasionally.7 Rubella acquired during pregnancy is associated with a significant incidence of fetal abnormalities. The skin is involved in the fetal rubella syndrome because it is a site of extramedullary hematopoiesis, manifesting clinically as bluish purple papules in the skin. This finding has been termed the blueberry muffin baby syndrome.8,9 The differential diagnosis of this sydndrome includes infiltrative neoplastic lesions of the skin, cutaneous vascular anomalies, and other conditions associated with dermal extramedullary hematopoiesis such as congenital CMV infection.10 Patients who receive the live, attenuated rubella vaccine occasionally may develop mild symptoms of rubella with an eruption, lymphadenopathy, and arthralgias. HISTOPATHOLOGIC FEATURES Little has been published about the histopathology of the cutaneous eruption of rubella, but in the few cases examined, a sparse infiltrate of lymphocytes around superficial blood vessels in the dermis associated with slight spongiosis has been observed (Fig. 22-1; see also Table 22-1). Atypical lymphocytes known as Turk cells may be

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CLINICAL FEATURES In typical, uncomplicated disease, the illness has three characteristic phases (Table 22-1). Initially, an asymptomatic incubation period of almost 9 to 10 days takes place. This is followed by a prodromal stage with malaise, fever, coryza, and cough that lasts about 3 to 4 days. The ensuing cutaneous eruption is present for up to 6 days. The typical Koplik spots, originally described by Dr. Henry Koplik in New York, are pinpoint red dots with minute bluish-white specks located primarily on the soft palate and buccal mucosa, especially opposite the second molar (enanthem). They usually precede the onset of skin changes by 1 to 2 days and may coalesce to involve the entire pharynx. Similar spots may appear on the conjunctiva and the mucosa of the gastrointestinal (GI) tract. The cutaneous eruption is characterized by discrete erythematous macules and papules that first appear on the face, especially behind the ears and on the forehead, and spread to involve the neck and trunk before finally involving the extremities. It usually takes approximately 3 days for the eruption to reach its maximum intensity before beginning to wane. Individual lesions are pinkish to red and may be petechial or hemorrhagic. With resolution, the lesions acquire a brownish color and desquamate with a fine, branny scale. In some cases, there may be extensive capillaritis leading to marked hemorrhage with involvement of the respiratory and GI tract, so-called black measles. In rare cases, especially in tropical zones, there may be bullae. Atypical measles differs from the usual form of the disease in that patients may be more severely ill, experiencing high spiking fevers to 40°C (104°F) with severe headache, prostration, nausea, and vomiting followed by sore throat, conjunctivitis, photophobia, and cough with pleuritic chest pain. On the third to fourth day of the illness, an eruption begins on the distal extremities that manifests first as edema of the hands and feet. An eruption of urticarial and erythematous macules and papules develops that may become purpuric or vesicular, often in an inverse photodistribution. Koplik spots are not seen. The entire process usually lasts from 3 to 10 days.

hyperplasia of the epidermis, variable amounts of spongiosis with parakeratosis, and occasional dyskeratotic keratinocytes (see Table 22-1). There is also a sparse infiltrate of lymphocytes surrounding the blood vessels in the superficial dermis associated with extravasation of erythrocytes. In some cases, especially in severe hemorrhagic and bullous forms, there may be true lymphocytic vasculitis of the small blood vessels. In the epidermis, there are variable numbers of syncytial giant keratinocytes with about three to 20 nuclei6 These are the Warthin-Finkeldy giant cells and represent the cutaneous equivalent to cells that are seen in visceral sites such as the lung. Both cytoplasmic and intranuclear inclusions are seen. In addition, there are multinucleated lymphoid cells with intranuclear and sometimes cytoplasmic inclusions in the dermis. Koplik spots have the same morphologic changes, but more giant cells are usually seen. Atypical measles demonstrates similar histologic changes, although there may be more vascular involvement because deposition of immune complexes is thought to play a role in the development of the eruption.

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the face wanes, a characteristic reticulated erythematous eruption of macules and papules appears within days on the extensor extremities and buttocks that may spread to the hands and feet. The exanthem disappears in 7 days, but erythema may persist for as long as 10 days. Recurrences of the eruption up to 21 days after its onset are common, especially after inciting stimuli such as sunlight, heat, cold, and emotional excitement from bathing or exercise. A variant of the condition known as the papular purpuric gloves and socks syndrome caused by the parvovirus B19 virus is manifest as symmetric acral painful edema and erythema that progresses to purpuric papules and petechiae. Associated systemic symptoms include fever, anorexia, and arthralgias.18  FIGURE 22-1 Viral exanthem. The lesion shows slight acanthosis of the epidermis and a nonspecific superficial perivascular lymphocytic infiltrate.

present in the circulation and therefore coincidentally in the inflammatory infiltrate in the skin. Extramedullary hematopoiesis of fetal rubella syndrome is manifest histologically by a diffuse dermal infiltrate of hematopoietic precursors, especially of myeloid elements. Because some of these cells may appear primitive and cytologically atypical, it is important to not mistake this process for leukemia cutis. DIFFERENTIAL DIAGNOSIS The exanthem of rubella may resemble that of rubeola, scarlet fever, erythema infectiosum, measles, eruptions caused by coxsackievirus and echovirus, infectious mononucleosis, scarlet fever, typhus, RMSF, secondary syphilis, and toxoplasmosis. The butterfly facial eruption associated with occipital lymphadenopathy is highly suggestive. It is important that an accurate diagnosis be rendered so that pregnant women can be removed from possible exposure.

Erythema Infectiosum (Fifth Disease)

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Erythema infectiosum, also known as fifth disease, is caused by parvovirus B19, a single-stranded DNA encapsulated virus. The disease is endemic, and local outbreaks among school-aged children are common. The virus is spread by aerosolized droplets to individuals who are in close contact.11,12 The disease has an incubation period of 2 weeks. Intrauterine

infection may cause hydrops fetalis and death. Parvovirus B19 infection of erythroid progenitor cells may result in a transient aplastic crisis or chronic red cell aplasia.13 In addition to fifth disease, studies have suggested a possible association between parvovirus B19 and select vasculitic syndromes, including HenochSchönlein purpura and Wegener granulomatosis, as well as connective tissue disease, especially pediatric dermatomyositis and Behcet disease14 The virus is tropic to endothelium and likely to keratinocytes and by accelerating apoptosis via upregulation of the tumor necrosis factor-a pathway renders the infected cells antigenic, resulting in the production of autoantibodies.14,15 Papular acrodermatitis of childhood, also known as Gianotti-Crosti syndrome, has long been associated with hepatitis B virus, as well as a variety of other viral and bacterial agents. An association with parvovirus B19 has been reported.16,17 CLINICAL FEATURES Patients usually develop malaise, nausea, and low-grade fever for 1 to 2 days before developing the distinctive cutaneous eruption, which appears suddenly. A diffuse or figurate erythema begins macular and becomes somewhat indurated, developing a well-defined border situated on the cheeks and sparing the circumoral areas, resulting in a “slapped cheeks” appearance (see Table 22-1). As the eruption of

HISTOPATHOLOGIC FEATURES As with rubella, the histopathology of erythema infectiosum has been described only rarely. There is a superficial perivascular infiltrate of lymphocytes and occasional histiocytes with subtle dermal edema (see Table 22-1). Slight spongiosis may also be seen. The fully evolved gloves and socks syndrome demonstrates vacuolar interface change with necrotic keratinocytes and dermal hemorrhage.19 DIFFERENTIAL DIAGNOSIS Drug eruptions as well as exanthems of echovirus, enterovirus, measles, juvenile rheumatoid arthritis, scarlet fever, bilateral facial erysipelas, erythema multiforme, and rubella may give similar findings, but the typical reticulate pattern of the eruption on the arms, coupled with the “slapped cheeks” appearance, is usually distinct and allows the diagnosis to be rendered.

Roseola (Exanthem Subitum) Roseola is a contagious, self-limited disease of infancy with short duration that usually lasts for 3 to 5 days. The etiologic agent is human herpesvirus (HHV)-6, which is a member of the family Herpesvirinae.17,20 The virus is a double-stranded DNA enveloped virus having a morphology similar to that of other herpesviruses.21 CLINICAL FEATURES Roseola most commonly infects infants, with a peak incidence of 2 years; up to 30% of children may be affected. Roseola is rare in infants younger than age 6 months, however. The virus is spread through aerosolized droplets, and after an incubation period of 4 to 7 days, there is a sudden onset of high fever (as high as

39.6°C, or 103°F) (see Table 22-1). Palpebral edema is often the first sign of the infection. Accompanying symptoms include hematuria, coryza, vomiting, restlessness, and an erythematous pharynx. Mild cervical and occipital adenopathy develops commonly. The fever subsides suddenly after 3 to 5 days, after which an eruption of rose-pink macules and papules up to 3.5 mm in diameter appear on the trunk and neck, often sparing the face. The eruption fades within 1 to 2 days without sequelae. In some cases, there may be no eruption.

DIFFERENTIAL DIAGNOSIS Other viral exanthemata, including rubella, measles, fifth disease, infectious mononucleosis, scarlet fever, and morbilliform drug eruptions, should be considered in the differential diagnosis.

Dengue Fever Dengue viruses are members of the Flaviviridae family in the Togavirus group and are single-stranded RNA viruses that are transmitted by insect vectors, most commonly the Aedes mosquito.22 The disease is endemic in the Americas, especially in the Caribbean basin, Mexico, and northern South America. There are pockets of disease in the United States, as well as imported cases.23 CLINICAL FEATURES The incubation period is 2 to 8 days after a mosquito bite. The onset of the infection is heralded by the abrupt onset of chills, fever, headache, conjunctival injection, severe bone pain (“break bone fever”), arthralgias, myalgias, low back pain, and an exanthem. The exanthem is morbilliform and central in distribution. Petechiae may be seen with initial infections, although hemorrhagic manifestations (dengue hemorrhagic fever) are seen more commonly with secondary infections and represent manifestations of a hyperimmune state that develops on second exposure to the virus. Bleeding manifestations include petechiae; purpura; and bleeding of the gums, nose, GI tract, and in association with menses. Uncomplicated dengue resolves within 5 to 7 days, although it may recur. Hemorrhagic dengue may be fatal.

DIFFERENTIAL DIAGNOSIS Depending on which type of infection is present, the differential diagnosis will vary. For the morbilliform eruption, scarlet fever, measles, rubella, toxoplasmosis, syphilis, drug eruption, and the acute HIV seroconversion reaction must be distinguished. For hemorrhagic dengue, meningococcemia, RMSF, and other forms of vasculitis must be distinguished.

Hand, Foot, and Mouth Disease Hand, foot, and mouth disease is a mucocutaneous disorder that characteristically involves only a few localized sites and is most frequently caused by coxsackie A viruses and less commonly by coxsackie B viruses and enterovirus 71. The disease is most common in children and is highly contagious. Most outbreaks occur between June and October.25,26 CLINICAL FEATURES The illness begins with fever up to 101°F (38.6°C) with associated malaise, soreness of the throat and mouth, and refusal to eat. Cough, headache, diarrhea, and arthralgias may be present. Initially, small reddish macules appear on the oropharynx with evolution to small papulovesicles that are 1 to 3 mm in size (see Table 22-1). The latter lesions ulcerate with development of a yellow-gray base and red areola. Ulcerations are most prevalent on the palate, buccal mucosa, tongue, and gingiva. The hands and feet are involved commonly, especially the sides and dorsa of the fingers and toes. As with mucosal lesions, initially there are reddish macules that evolve into oval or football-shaped vesicles with a surrounding red halo. Rarely, lesions may be disseminated, especially in patients with altered cutaneous barrier function, such as in atopics. The process usually resolves without incident after several days. HISTOPATHOLOGIC FEATURES A variably intense inflammatory infiltrate is present

in the superficial dermis consisting primarily of lymphocytes, but there may be variable numbers of neutrophils and eosinophils. The most prominent changes are in the epidermis in fully developed lesions, where there is intracellular edema (ballooning), spongiosis, and localized epidermal necrosis. Usually there is minimal epidermal hyperplasia. In time, there is confluent epidermal necrosis, crusting, and slough of degenerated epithelium with reepithelialization.27 Mucosal ulcers may appear quite similar to aphthous ulcers. There is a localized ulceration, beneath which there is an infiltrate of lymphocytes, plasma cells, and neutrophils. DIFFERENTIAL DIAGNOSIS Other viral vesicular disorders that may be confused with hand, foot, and mouth disease include varicella, herpes simplex virus (HSV) infection, and exanthems induced by other coxsackieviruses as well as echoviruses. Erythema multiforme also may appear similar, especially when there is involvement of the palms and soles. Distinction of hand, foot, and mouth disease from the latter conditions is based on clinical features, balloon degeneration of keratinocytes, and absence of characteristic viral cytopathic changes as in herpes simplex.

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HISTOPATHOLOGIC FEATURES The histologic changes of roseola are similar to those of the other viral exanthemata described earlier, namely, a sparse perivascular infiltrate of lymphocytes in the dermis with minimal other changes. No specific findings are seen that allow the diagnosis to be made in the absence of clinical correlation.

HISTOPATHOLOGIC FEATURES The morbilliform eruption appears similar to other exanthemata described earlier with the characteristic perivascular infiltrate of lymphocytes and slight spongiosis. Hemorrhagic dengue demonstrates numerous extravasated erythrocytes and may show changes of an immune complex– mediated leukocytoclastic vasculitis with marked thrombosis. In a recent study in which skin biopsy material was obtained from 32 patients with hemorrhagic dengue fever, there was no apparent correlation between histopathologic features and prognosis.24

Acute Exanthem of HIV Infection AIDS is caused by HIV-1, which is a 100-nm lentivirus consisting of singlestranded RNA. The virus contains the enzyme reverse transcriptase and is thus subclassified as a retrovirus because, after entry into target cells, complementary DNA is formed from the RNA template by this enzyme in the production of infective virions, which contrasts with the usual mechanism of transcription. The primary target cell is the helper (CD4+) T-lymphocyte.28 Infection leads to progressive deterioration of the cellmediated arm of the immune system through continued destruction of target cells. Over time, opportunistic infections and neoplasms develop that eventually prove fatal to the host. Many of these conditions involve the skin, and although they may not be not life threatening, they are the source of significant morbidity. The acute reaction associated with HIV seroconversion refers to an acute viral prodrome associated with a cutaneous eruption that corresponds to the acute infection with HIV-1. The infection is transmitted via exchange of blood or body fluids, specifically semen and vaginal secretions, so sexual contact is of

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prime importance in the spread. HIV disease is most prevalent in homosexual men in the United States and in heterosexual populations in central Africa. The incidence is increasing rapidly in the Far East, South America, and India. There are two main subtypes; one is more aggressive and is spread more readily through male homosexual contact. In contrast, the other strain is more slowly progressive, has a greater tropism for epithelial cells, and is spread more readily by heterosexual contact. After infection, there is an incubation period of 3 to 6 weeks, during which time there is marked viremia with widespread dissemination of the virus accompanied by an acute syndrome that develops in 70% to 80% of individuals. Within 1 to 3 months, there is a marked immune response to the virus that results in a dramatic decline in the viremia. A latency period follows that includes a gradual but relentless decline in the CD4 cell number.29 CLINICAL FEATURES The acute HIV exanthem is usually characterized as a benign, often subclinical disorder (see Table 22-1). Patients are highly infectious during this period. The incubation period ranges from 3 to 6 weeks and varies with the route of infection, being shorter for hematogenous transmission and with larger viral inocula. Patients develop malaise and soon thereafter develop fever that can be as high as 102°F (39.2°C) or, occasionally, higher. Night sweats; pharyngitis; fatigue; lymphadenopathy; and a morbilliform eruption that involves the trunk, chest, back, and upper arms develop within 1 to several days.30 The eruption consists of pinkish macules and fine papules that may be urticarial and develop on the trunk and spread to involve the proximal extremities, neck, and occasionally, the face. Occasionally, lesions may be more inflamed, and necrotizing lesions have been observed. Most cases resolve without incident after 4 to 5 days, although a severe form of acute HIV infection may develop with persistent HIV p24 antigenemia, recurrent viremia, rapid decline in CD4+ cell numbers, and accelerated disease progression. Systemic manifestations include pneumonitis, esophagitis, meningitis, abdominal pain, and melena. Skin changes that may be seen include urticaria, perleche, palatal and esophageal ulcers, enanthemata, and candidiasis.31 Herpes infections may also supervene. The prognosis for patients who have prolonged symptomatic primary HIV infection is significantly poorer than for those with asymptomatic or mild

primary infection; 78% of the former group of patients progress to Centers for Disease Control and Prevention (CDC) group IV at 3 years compared with 10% from the latter group.32 The pathogenesis of the acute HIV exanthem has not been fully elucidated but is thought to correspond to widespread infection of cells with HIV. This most likely leads to release of cytokines and inflammatory mediators that result in expression of disease.33 Langerhans cells/dendritic cells (LCs/DCs) are the only resident epidermal cells that express the CD4 antigen,34 and as such, cutaneous LCs/DCs are early targets for HIV-1. Infection of these cells occurs in both cutaneous and mucosal sites and often precedes seroconversion. These cells most likely serve as a viral reservoir and source of viral antigen presentation to T cells, activating a T-cell response.35 HISTOPATHOLOGIC FEATURES Histologic evaluation of skin biopsies taken from the morbilliform eruption demonstrates an infiltrate consisting primarily of lymphocytes with occasional plasma cells around blood vessels of the superficial vascular plexus (see Table 22-1). There are also slight spongiosis and occasional individually necrotic keratinocytes in the epidermis. These findings are similar to those observed in other viral exanthemata, as well as in morbilliform drug eruptions. However, dermal infiltrates with greater cellular density and epidermal necrosis have been reported. Immunocytochemistry has revealed that most of the infiltrating cells in skin lesions are CD4+ T cells with an admixture of CD8+ cells.36 Although no specific laboratory findings other than evidence of HIV infection, such as the expression of HIV p24 antigen or antibodies directed against HIV, are usually found, an elevated erythrocyte sedimentation rate, leukopenia, and cerebrospinal fluid lymphocytic pleocytosis may be observed. In the case of fulminant acute HIV infection, laboratory findings of profound immunosuppression, as alluded to earlier, may be demonstrated. CLINICAL FEATURES OF CUTANEOUS MANIFESTATIONS OF HIV INFECTION The cutaneous manifestations that develop as a consequence of the immune deficiency induced by HIV may be categorized as infections, neoplasms, pruritic conditions, and papulosquamous and related inflammatory diseases of the skin, as well as alterations of the hair, nails, and mucosa (Table 22-2). Many of these

Table 22-2 Cutaneous Manifestations of Human Immunodeficiency Virus Infections Other viral infections erpes simplex virus ytomegalo virus pstein-Barr virus Molluscum contagiosum Bacterial infections Bacterial folliculitis Impetigo Bacillary angiomatosis Botryomycosis Mycobacterial infections Syphilis Parasitic infections Ectoparasitic infestations Fungal infections Blastomycosis Candidiasis Coccidioidomycosis Cryptococcosis Histoplasmosis Paracoccidioidomycosis Sporotrichosis Neoplasms Kaposi sarcoma Lymphoma Inflammatory conditions Psoriasis Seborrheic dermatitis Eosinophilic folliculitis Papular eruption of AIDS Many others

appear similar to those observed in immunocompetent hosts, but because of the immunocompromised state of the patient, they may have unusual appearances or may be much more severe. Herpesvirus infections, including herpes simplex and zoster, CMV, and Epstein-Barr virus (EBV), are quite common in these patients.37 Herpes simplex and zoster may lead to persistent necrotizing ulcers with extensive scarring.38 Chronic verrucous lesions may develop that may simulate other lesions of the skin with epithelial hyperplasia, including neoplasms and granulomatous infections. CMV infection may induce ulcers or purpuric papules that simulate leukocytoclastic vasculitis. EBV infection in patients with AIDS leads to oral hairy leukoplakia, which is manifest as white verrucous plaques on the sides of the tongue.39 HPV infections are also common and produce findings similar to those discussed below. Molluscum contagiosum very commonly affects

bacteremia in patients with AIDS are due to these organisms.43 Virtually any of the mycobacteria, especially Mycobacterium haemophilum and M. avium-intracellulare, may be observed in patients infected with HIV; skin lesions may develop in up to 10% of HIV-infected patients with systemic mycobacterial infections.44 Infection with M. bovis after bacille CalmetteGuérin (BCG) vaccination in a patient with HIV infection has also been reported. Mycobacterial skin lesions may assume a number of different appearances, including small papules and pustules that resemble folliculitis, atopic dermatitis-like eruptions, localized cutaneous abscesses, suppurative lymphadenitis, nonspecific ulcerations, palmar and plantar hyperkeratoses, and sporotrichoid nodules. Syphilis is common in patients with HIV infection, and of all reported cases of syphilis, 25% develop in HIV-infected hosts.45 It may assume a number of forms in these patients, ranging from classic papulosquamous lesions with involvement of the palms, soles, and mucous membranes to unusual manifestations such as rapid progression from the primary chancre to gummatous tertiary lues in a matter of months, lues maligna (syphilis with vasculitis), sclerodermiform lesions, rupial verrucous plaques, extensive oral ulcerations, keratoderma, deep cutaneous nodules, rubeoliform eruptions, and widespread gummata. Almost 100 cases of bacillary angiomatosis, a condition caused by rickettsialike organisms Bartonella (formerly Rochalimaea) henselae and quintana have been reported in patients with HIV infection.46,47 There are a number of different clinical manifestations of this disorder, many of which are visceral. Cutaneous vascular lesions are the most common and often present in their earliest form as small pinpoint reddish to purple papules. The latter lesions may resemble pyogenic granulomata and are seen in two-thirds of patients with cutaneous disease. They range in number from one to several thousand and in size from 1 mm to several centimeters. Lesions may ulcerate, be covered by a crust, or both. The second most common skin lesion is the subcutaneous nodule, which occurs in approximately 50% of patients with skin lesions. The latter may be located deeply in the subcutis, extending into soft tissue and bone. Two cases of deeply seated skeletal muscle pyomyositis have been reported. When bone is involved, lesions are generally osteolytic in nature. Nondescript crusted ulcerations, plaques, and cellulitis

may also be seen in 5% to 10% of patients. Viscera may be involved either as disseminated vascular lesions or as bacillary peliosis hepatis of the liver. Although virtually every organ system may be affected, the liver and spleen are the most common sites. In addition to bacterial and fungal infections, a number of parasitic infections and ectoparasitic infestations may be encountered in patients with HIV infection. Some of these include scabies, both classic and crusted types; demodicidosis; Pneumocystis carinii infection; acanthamebiasis; leishmaniasis; and toxoplasmosis. As with other infections, these may occur either as localized conditions or as multiorgan visceral disease. The clinical manifestations of the latter conditions may be unusual, so skin biopsies and cultures often are necessary to establish an accurate diagnosis. Scabies may present in a number of different ways clinically in patients with HIV infection. Hyperkeratotic plaques on the palms, soles, trunk, or extremities may develop with an appearance similar to crusted scabies in other settings. In other patients, only scattered pruritic papules accompanied by a slight scale of the trunk and extremities may be seen. A widespread papulosquamous eruption that may resemble atopic dermatitis, as well as scalp and facial scaling that may mimic seborrheic dermatitis, has also been reported. Characteristic burrows may be difficult to identify, so virtually any patient with a scaly, persistent pruritic eruption should have their skin lesions scraped and examined histologically in search of mites of scabies. P. carinii in the skin may have several different clinical manifestations.48 The most commonly reported form is that of friable reddish papules or nodules seen in the ear canal or nares. Small, translucent, molluscum contagiosum-like papules; bluish cellulitic plaquelike lesions; and deeply seated abscesses also have been observed. Acanthamebiasis consists of painful nodular lesions with ulcerations usually on the trunk or extremities. Blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis,49 histoplasmosis,50 paracoccidioidomycosis, and sporotricosis are some of the systemic fungal infections that occur in HIV-infected individuals. Other rarer fungal infections have also been noted, including zygomycosis, aspergillosis, and disseminated dermatophytosis. As with the other conditions described earlier, the mucosal and cutaneous lesions may have varied and unusual clinical morphologies.

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HIV-infected patients, especially those with CD4+ counts below 250 cells/dL. There are characteristically waxy, translucent, umbilicated papules that may be widespread and commonly involve the face, trunk, and genitalia. In some cases, the latter lesions may become quite large and simulate neoplasms, especially keratoacanthoma.40 Bacterial infections are also encountered commonly in these patients.41 Bacterial folliculitis, impetigo, bacillary angiomatosis, botryomycosis, Pseudomonas infections, streptococcal axillary lymphadenitis, mycobacterial infections, syphilis, and other venereal diseases may be seen. These disorders may be localized or widespread, involving many organs. Most banal bacterial infections such as folliculitis and impetigo are caused by Staphylococcus and Streptococcus, organisms, which are commonly encountered in immunocompetent hosts. Staphylococcus aureus is the most common cutaneous and systemic bacterial pathogen in HIV-infected adults. Folliculitis is generally manifest as widely distributed acneiform papules and pustules. In some cases, the bacterial density may increase significantly as a consequence of immunodepression, leading to botryomycosis or ecthyma.42 These disorders appear as nondescript verrucous papules or as necrotizing ulcerations, respectively. Soft tissue and deeply seated bacterial infections such as cellulitis, pyomyositis, deep soft tissue abscesses, and necrotizing fasciitis may also develop. These generally are manifest as diffuse, red, warm, tender areas in the skin. Although conventional impetigo is observed most commonly on the face and shoulders, in patients with HIV, infection it often involves axillary, inguinal, and other intertriginous locations. The infection usually begins with painful, red macules that generally progress to superficial vesicles with subsequent rupture and oozing of serous and purulent fluid. Botryomycosis is caused most commonly by S. aureus and often occurs after staphylococcal folliculitis with formation of bacterial colonies in the dermis. Clinically nondescript papules or plaques localized to the trunk, neck, or extremities develop and may be surrounded by pustules. An atypical plaquelike staphylococcal folliculitis has been described in patients with HIV infection. This appears as violaceous plaques up to 10 cm in diameter, with superficial pustules and crusts occurring in the groin, axilla, or scalp. Infection with Pseudomonas spp. is also seen, and up to 8% of all cases of

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In addition to infectious disorders, a number of non-infectious cutaneous signs and symptoms develop in these patients. Some of these include psoriasiform dermatoses such as seborrheic dermatitis, psoriasis,51 Reiter disease, and pityriasis rubra pilaris; non-infectious papular, pruritic conditions such as eosinophilic pustular folliculitis,52 severe xerotic dermatitis, papular dermatitis of AIDS, papular urticaria, and atopic dermatitis; disorders of blood vessels, including vasculitis, idiopathic thrombocytopenic purpura, hyperalgesic pseudothrombophlebitis, diffuse facial and truncal telangiectasia, and erythema elevatum diutinum; photoaggravated and photoinduced disorders, including chronic actinic dermatitis, porphyria cutanea tarda, photoexacerbated drug eruptions, and photoexacerbated rosacea; drug eruptions; and neoplasms both epithelial and mesenchymal. It is beyond the scope of this chapter to discuss each of these because many of them have been addressed elsewhere. HISTOPATHOLOGIC FEATURES OF CUTANEOUS MANIFESTATIONS OF HIV INFECTION The histopathologic findings of folliculitis generally include collections of neutrophils within infundibula of hair follicles and a mixed perifollicular inflammatory cell infiltrate. When rupture of follicles occurs, there is often a perifollicular granulomatous infiltrate with fibrosis. Botryomycosis is characterized by a diffuse inflammatory cell infiltrate in the dermis associated with colonies of grampositive bacteria forming grains in the skin. These generally appear bluish-purple on hematoxylin and eosin (H&E)–stained sections. Ecthyma is manifested histologically as a deep ulcer that often extends into the subcutaneous fat with extensive degeneration of dermal collagen. There is a mixed inflammatory cell infiltrate of neutrophils, eosinophils, and histiocytes. Histopathologic findings in bacillary angiomatosis are characterized by a lobular proliferation of capillaries associated with enlarged epithelioid-appearing endothelial cells. The background stroma is usually edematous in superficial lesions and more compact in deeper ones. Neutrophils and leukocytoclasis are often seen in the interstitium between vessels. The presence of neutrophils in the body of lesions is a valuable finding that permits distinction from ulcerated pyogenic granulomata that may have similar histologic features, although neutrophils are present primarily under areas of ulceration. Granular amphophilic aggregates are characteristically seen adjacent to vessels, often in association with neutrophils,

representing masses of Bartonella organisms. These appear black after staining with the Warthin-Starry stain. Electron microscopy is confirmatory. Although the diagnosis usually can be made on the basis of microscopic examination of routine H&E-stained tissue sections, on occasion, atypia of endothelial cells may be marked, causing histologic confusion with angiosarcoma. Part of this atypia is an unusual vasoformative proliferative response. The histopathology of cutaneous syphilis is usually similar to that of immunocompetent hosts, demonstrating the characteristic superficial and deep psoriasiform lichenoid pattern of inflammation associated with plasma cells and histiocytes. On the other hand, unusual histologic findings may be seen, including vasculitis as well as very sparse inflammatory infiltrates with minimal numbers of plasma cells and abundant spirochetes. Cutaneous mycobacterial infections may assume classic patterns of suppurative granulomatous infiltrates in the dermis associated with pseudocarcinomatous hyperplasia, although other unusual patterns may also be observed, including dense areas of suppuration with minimal granulomatous infiltrate. Conversely, some cases are characterized by an exuberant lichenoid and granulomatous response without any neutrophils In crusted scabies, there is usually a superficial and middle to deep perivascular and interstitial infiltrate of lymphocytes with numerous eosinophils. The epidermis is hyperplastic with prominent crusting, and many mites are visible in the cornified layer. In patients with postscabetic id reactions, a spongiotic dermatitis may be noted, and in nodular scabies, a dense mixed inflammatory infiltrate with numerous eosinophils in a nodular configuration resembling a pseudolymphoma may be seen. In nodular scabies, the number of mites is few. Demodicidosis characteristically shows abundant Demodex mites within follicular infundibula associated with a mixed infiltrate of neutrophils and eosinophils within and around the infundibula of hair follicles. P. carinii in the skin has an appearance similar to that in the lung, with a diffuse infiltrate of foamy-appearing cells that, when stained with Gomori methenamine silver or Steiner stains, highlights the microorganisms, resulting in the “teacup and saucer” appearance. Acanthamebiasis shows a diffuse infiltrate of amebic cysts and trophozoites throughout the skin, especially around blood vessels and in the subcutaneous

fat. Careful inspection is required because these may appear similar to histiocytes or other normal-appearing structures in the skin. Erythrophagocytosis may be noted. Non-infectious inflammatory skin diseases appear similar histologically to those seen in immunocompetent hosts with the exception that individually necrotic keratinocytes are present with greater frequency. Eosinophilic folliculitis differs from other forms of folliculitis because in prototypical cases, there is a dense infiltrate of eosinophils within the follicular ostia of affected hair follicles. In many cases, however, lesions are biopsied late in their evolution, so only perifollicular fibrosis and granulomatous inflammation may be seen. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other viral exanthemata, such as those caused by EBV, parvovirus, measles, and rubella. Drug eruptions must also be excluded, especially because HIV-infected patients may be under treatment with numerous medications. The diagnosis is based on the presence of a characteristic clinical picture in an individual with risk factors for the development of HIV infection. Blood tests that reveal either positive anti-HIV antibody titers by the enzyme-linked immunosorbent assay method and Western blot assay or circulating p24 antigen are confirmatory. Other possible viral disorders should be excluded by obtaining acute and convalescent viral titers. The differential diagnosis of cutaneous manifestations of HIV infection is vast. The histologic findings are usually characteristic of the disorder in question, especially in the case of infectious illnesses.

Infectious Mononucleosis Infectious mononucleosis is caused by the EBV, which is a member of the human herpesvirus family. It is an enveloped icosahedral DNA virus that grows well in B-lymphocytes, leading to their immortalization. Infections typically develop in teens and young adults between ages 17 and 25 years.53 Infections occur less commonly in young children and are seen rarely before age 1 year or after age 40 years. There is a long incubation period of between 30 and 50 days. CLINICAL FEATURES An initial prodrome of 3 to 5 days manifests as headache, malaise, myalgia, and fatigue. The classic clinical triad is pharyngitis, fever, and cervical adenopathy, which is seen in over

HISTOPATHOLOGIC FEATURES The pathology of the cutaneous exanthem is similar to that observed with other viral exanthemata and includes a sparse infiltrate of lymphocytes with slight spongiosis and parakeratosis (see Table 22-1). Atypical lymphocytes may be present coincidentally in the infiltrate, a manifestation of the circulating atypical cells. Biopsies of enlarged lymph nodes most commonly demonstrate reactive lymphoid hyperplasia, although marked immunoblastic proliferation with cytologic atypia of lymphocytes may simulate immunoblastic lymphoma or Hodgkin disease. Histologic findings in the ampicillinassociated eruption are more florid than those of the primary EBV-induced exanthem. In addition to the perivascular infiltrate of lymphocytes, vacuolar interface and spongiotic changes may occur. There is often a denser infiltrate of inflammatory cells in the dermis that may be accompanied by scattered neutrophils and eosinophils.

A pityriasis lichenoides-like exanthem may also arise due to EBV infection. The histopathologic features of these lesions include a thickened epidermis with necrotic keratinocytes and parakeratosis as well as lymphocytic infiltrate along the dermoepidermal junction and around the superficial vessels.55 DIFFERENTIAL DIAGNOSIS CMV infection, toxoplasmosis, streptococcal pharyngitis, tularemia, viral pharyngitis, diphtheria, acute leukemia, acute infectious lymphocytosis, infectious hepatitis, and drug eruptions must be distinguished. Clinical findings coupled with serologic studies are usually adequate in establishing a definitive diagnosis.

Other Viral Exanthems A number of other viruses may result in exanthems and should be kept in mind when evaluating the cause of a febrile illness associated with a cutaneous eruption. Some of these include the echoviruses 2, 4, 5, 6, 9, 11, 16, 18, 25, and 30; coxsackieviruses A4, A5, A6, A9, A10, A16, B2, B3, and B5; adenovirus and reoviruses types 1 and 2; enterovirus 71; and the hepatitis viruses A, B, and C. These eruptions develop most commonly in young children and infants. The viruses are distributed widely. A large number of arthropod-borne viral illnesses may have cutaneous findings, most of which are associated with the development of hemorrhagic fevers. Some of these may produce morbilliform eruptions. These include togaviruses such as Chikungunya, O’Nyong-Nyong, Sindbis, Ross River and Bharma forest; bunyaviruses; arenaviruses such as Lassa, Junin, and Machupo; filoviruses such as Marburg and Ebola; and hantaviruses. West Nile virus, a single-stranded RNA virus of the flavivirus family, has been known to produce morbilliform eruptions.56 CLINICAL FEATURES The exanthem associated with coxsackievirus A9 is prototypical and has received the most attention. Typically, there is a prodrome with fever sometimes as high as 39.6°C (103°F), malaise, sore throat, and cervical adenopathy. After several days of fever, an eruption often develops on the face with progression to the neck and trunk, followed by the extremities and occasionally the palms and soles. There is minimal pruritus. Individual lesions are pinkish to red macules and small papules ranging in size from 2 to 13 mm. Small vesicles and petechiae may be

seen. Other findings include conjunctivitis, muscle weakness, orchitis, hepatosplenomegaly, myocarditis, diarrhea (echovirus 4), pleurodynia (coxsackieviruses B2 and B5), and meningitis (coxsackievirus A9 and echovirus 9). Hepatitis A virus has been reported to cause a generalized morbilliform eruption similar to other viral exanthemata. Hepatitis B virus has been associated with both a directly induced urticarial eruption and a secondary chronic urticaria that may occasionally be associated with lupus erythematosus.57 In addition, Giannotti Crosti papular acrodermatitis of childhood is a distinct papular dermatitis involving the face, buttocks, and extremities associated with hepatitis infection. However, any virus such as pox virus and parvovirus B19 may be associated with this distinctive eruption There may be accompanying lymphadenopathy and fever. Polyarteritis nodosa also has been associated with hepatitis B.58 Hepatitis C virus may be associated with porphyria cutanea tarda and a small- to medium-sized vessel vasculitis. The latter may be thromboocclusive secondary to cryoglobulinemia or a typical leukocytoclastic vasculitis with purpuric papules mediated by immune complexes.59 Viral hemorrhagic fevers are typified by erythematous macules, petechiae, purpura, and widespread intracutaneous and visceral hemorrhage. These manifestations are a consequence of thrombocytopenia, diminished coagulation factors, platelet dysfunction, disseminated intravascular coagulation (DIC), and direct vascular injury.

CHAPTER 22 ■ VIRAL INFECTIONS

80% of patients. Fever may be as high as 39°C (102.2°F) and may persist for 7 to 10 days. Other symptoms may include nausea, anorexia, headache, muscle pain, weakness, arthralgias, rhinitis, and ocular pain. Tender, firm lymphadenopathy is seen in virtually all cases and may be generalized. Splenomegaly is quite common, being present in 50% to 60% of patients, and may be accompanied by hepatomegaly. An absolute and relative lymphocytosis, sometimes up to 50,000 cells/dL, develops, and there may be up to 20% atypical lymphocytes. Mucocutaneous findings include small petechiae at the junction of the hard and soft palate in 20% to 30% of cases. Eyelid petechiae and periorbital edema also may be seen. An exanthem develops in 10% to 15% of patients, usually on days 4 to 6 of the illness. Pinkish macules and fine papules appear initially on the trunk and upper arms, with spread to the face and forearms and occasionally to the thighs and legs (see Table 22-1). The eruption may be morbilliform, scarlatiniform, or urticarial and usually fades after 3 to 4 days. Administration of ampicillin and, less commonly, penicillin, cephalosporins, or tetracycline leads to the development of an exanthematous eruption that is usually more widespread and erythematous than the primary eruption.54 It usually develops 7 to 10 days after institution of the antibiotic. Periorbital edema is present in 25% to 30% of patients. Occasionally, jaundice, arthritis, and pneumonitis may be seen.

HISTOPATHOLOGIC FEATURES The findings are similar to those described earlier and are not specific for any infection. The histologic features of disorders induced by hepatitis viruses are similar to those induced by other agents and are discussed elsewhere. Viral hemorrhagic fevers are associated with abundant intradermal hemorrhage and, in the case of DIC, marked thrombosis of vessels and secondary ischemic necrosis. DIFFERENTIAL DIAGNOSIS The differential diagnosis is similar to that for other viral exanthems. In many cases, because acute and convalescent viral titers are not determined, the diagnosis is never confirmed. Nevertheless, the diagnosis of a viral exanthem should be considered in any instance in which a patient develops an acute febrile illness associated with a cutaneous eruption.

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HERPES SIMPLEX

PART III ■ INFECTIONS

Infection with human herpesvirus hominis is one of the most common mucocutaneous viral infections of human beings. Eight herpesviruses have now been defined. For the purposes of this discussion, only types 1 and 2 will be discussed.

504

CLINICAL FEATURES HSV infection is characterized by an acute eruption of tense, umbilicated, grouped vesicles on an erythematous base, usually at or near a mucocutaneous junction (Table 22-3). The onset is usually preceded by a prodrome of burning and itching a few hours before onset of the eruption.

Table 22-3 Herpes Simplex

 FIGURE 22-2 Herpes simplex infection. Scanning magnification shows a multiloculated intraepidermal vesicle.

Clinical Features Localized clusters of vesicles usually on the lip (type 1) or genital mucosa (type 2) Prodrome of burning a few hours before eruption Primary and recurrent lesions HSV type 1 usually above the waistline; HSV type 2 usually below the waist Herpetic folliculitis Herpetic whitlow (involvement of fingers) Generalized and chronic localized herpes, often in immunocompromised hosts Histopathologic Features “Steel gray” nuclei of keratinocytes Margination of chromatin and multinucleated epithelial giant cells Eosinophilic intranuclear inclusions with clear halo Intracellular edema and ballooning degeneration Reticular degeneration and rupture of cell walls of epithelial cells Acantholysis Multiloculated intraepidermal vesicle formation Lymphoid infiltrates, often rather dense in dermis Infiltration of nerve twigs by infiltrate Occasional lymphocytic and leukocytoclastic vasculitis Differential Diagnosis Other viral exanthems Erythema multiforme Drug eruptions Pityriasis lichenoides Graft-versus-host reaction Radiation dermatitis Impetigo Syphilitic chancre Chancroid Aphthae Traumatic ulcerations

The vesicles appear in groups, are of pinhead size, and often later become seropurulent. Primary genital HSV infection occurs most commonly in young adults. It is transmitted through sexual contact and presents as a painful, erosive balanitis, vulvitis, or vaginitis. Individuals who have a primary attack are prone to recurrent attacks, which may have their onset shortly after the primary infection or may be delayed for months to years. There may be a “latency” period of variable duration between recurrences. A complication of recurrent HSV is the secondary development of erythema multiforme. HSV also occurs commonly as a folliculitis; may involve distinctive sites such as the fingers or hands (herpetic whitlow), the cervix of the female genital tract (herpes cervicitis), the cornea and conjunctiva (herpes keratoconjunctivitis), and the low back and buttocks (recurrent lumbosacral herpes); and may become generalized or chronic at a local site (chronic ulcerative herpes), particularly in immunocompromised individuals. Kaposi varicelliform eruption or eczema herpeticum refers to secondary, usually widespread involvement of a primary dermatosis such as atopic dermatitis, Darier disease, pemphigus foliaceus, or other dermatitides by HSV. Lesional skin or skin previously involved by the dermatitis is preferentially affected by typical vesicles of HSV.

there is pallor and swelling of the cytoplasm of keratinocytes, imparting a “steel gray” appearance of nuclei (Figs. 22-2 to 22-4). The nuclei also show margination of chromatin (see Table 22-3). Infected keratinocytes may fuse, forming characteristic multinucleated epithelial giant cells (Fig. 22-5). Eosinophilic inclusion bodies usually surrounded by a clear halo may be observed in the nuclei of infected cells. Spongiosis and intracellular edema are also present in the epidermis and the epithelium of hair follicles. Infected keratinocytes characteristically develop intracellular edema, leading to ballooning degeneration, which is feature of viral vesicles. Epithelial cells showing ballooning degeneration lose intercellular adhesions and thus become acantholytic. Intracellular edema also results in reticular degeneration and the rupture of cell walls. The latter phenomenon and acantholysis eventuate in multiloculated intraepidermal vesicles. In time, keratinocytes become necrotic and develop pyknotic nuclei and dense eosinophilic cytoplasm. There is a variably dense inflammatory infiltrate in the dermis consisting of lymphocytes, neutrophils, and eosinophils. Associated lymphocytic or leukocytoclastic vasculitis and inflammation are often within and around nerve twigs.

HISTOPATHOLOGIC FEATURES The earliest change occurs in the epidermis, in which

Varicella is one of the most common childhood infections. The disease is caused by

Varicella (Chickenpox) and Herpes Zoster

 FIGURE 22-3 Herpes folliculitis. Edema and ballooning degeneration of follicular epithelial cells with vesicle formation are seen. Table 22-4 Varicella (Chickenpox) the varicella-zoster virus, which is a double-stranded DNA virus and a member of the family Herpesviridae. Airborne droplet infection is the usual route of transmission, although direct contact is

another mode of spread. It is one of the most contagious of all infections. Herpes zoster represents reactivation of latent varicella infection that resides in sensory ganglia.60

CHAPTER 22 ■ VIRAL INFECTIONS

CLINICAL FEATURES The incubation period ranges from 11 to 20 days and is followed by a prodrome of mild fever and malaise, often accompanied by photophobia (Table 22-4). The eruption is characterized by crops of erythematous macules and papules on the trunk and face that evolve rapidly into vesicles of 1 to 3 mm in size with clear serous fluid surrounded by narrow red halos. “Dew drops on a rose petal” is a description that has been given to the vesicular eruption. The number of vesicles varies, ranging from only a few to several hundred. Older lesions crust and begin to heal usually within 1 week to 10 days. Herpes zoster is manifest as a painful eruption of vesicles and occasionally papules on erythematous bases that develops within a sensory dermatome, usually on the trunk, but in some cases, the face, neck, or scalp may be involved (Table 22-5). Usually, older individuals are affected, although patients with immunocompromise such as those with HIV infection also commonly develop

Clinical Features Incubation period of 11-20 days Mild fever, photophobia “Dew drops on rose petal” vesicular eruption on face and trunk Histopathologic Features Same as HSV Differential Diagnosis Miliaria crystallina Id reaction Other viral exanthems

Table 22-5 Herpes Zoster

 FIGURE 22-4 Herpes simplex infection. An intraepidermal vesicle shows prominent intracellular edema of keratinocytes, acantholysis, reticular degeneration, and occasional eosinophilic inclusion bodies within nuclei. The inclusion bodies are surrounded by a clear halo.

Clinical Features Unilateral painful eruption of vesicles within a sensory dermatome Ophthalmic branch of trigeminal nerve commonly involved May be disseminated in immunocompromised patients Histopathologic Features Same as herpes simplex Differential Diagnosis Same as herpes simplex Dermatomal herpes simplex Angina pectoris Early glaucoma

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Table 22-6 Human Papillomavirus

PART III ■ INFECTIONS

Condyloma acuminatum HPV-6, -8, -11, -16, and -18 Verruca vulgaris HPV-1, -2, -3, and -4 Verruca plana HPV-3 Verruca plantaris and palmaris HPV-2 Epidermodysplasia verruciformis HPV-3, -5, -12, -17, -19, and -29 Bowenoid papulosis HPV-16, -18 Verrucous carcinoma HPV-61, -11

 FIGURE 22-5 Herpes virus infection. The intraepidermal vesicle shows striking multinucleate giant cells. The nuclei within these giant cells exhibit molding and prominent ground-glass alteration of chromatin. There is also prominent reticular degeneration, resulting in the intraepidermal vesicle.

the condition. Zoster in HIV-infected patients may assume a number of unusual manifestations, especially persistent crusted, verrucous lesions.61 HISTOPATHOLOGIC FEATURES As in the case of HSV infection, the changes are within the epidermis, with steel-gray nuclei, margination of chromatin, multinucleated giant cells, acantholysis, and intraepidermal vesiculation (see Table 22-3). No significant differences have been observed between zoster and varicella, although biopsy specimens from immunocompromised patients with zoster often demonstrate extensive infection of the epidermis with marked necrosis and involvement of cutaneous adnexal structures such as the hair follicles, sebaceous glands, and eccrine sweat units. Chronic granulomatous vasculitis, palisading and interstitial granulomas resembling granuloma annulare, and florid and atypical lymphoid infiltrates after herpes zoster infection have been documented.62

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DIFFERENTIAL DIAGNOSIS HSV infection may be identical histopathologically. The clinical findings and the results of viral cultures, immunohistochemical staining, in situ hybridization, and polymerase chain reaction assays can help distinguish these entities.63,64 Most cases of HSV infection appear as localized clusters of vesicles on erythematous bases, usually on the lip or a mucosal surface. Occasionally, a zosteriform

distribution may be observed, which is of great importance in cases involving the maxillary branch of the facial nerve because treatment of the two diseases differs significantly. Late-stage necrotizing ulcers in immunocompromised patients must be distinguished from other causes of ulcers, including serious opportunistic infections caused by other viruses, fungi, or bacteria. Verrucous herpesvirus infections may simulate neoplastic disorders as well as other infections. Biopsies may be required to define the nature of these lesions. Relatively few widespread vesicular eruptions should not be confused with varicella, although miliaria crystallina and widespread spongiotic dermatitis, such as an id reaction, conceivably could appear similar.65-67 The differential diagnosis of herpesvirus infection in general includes other viral infections and exanthems, erythema multiforme, drug reactions, graft-versus-host reaction, pityriasis lichenoides, radiation dermatitis, and connective tissue disease. Identification of the characteristic viral cytopathic changes, culture, immunostaining for the virus, or use of other techniques is necessary to distinguish herpes from the entities listed previously.

HUMAN PAPILLOMAVIRUS INFECTIONS HPV infection is an extremely prevalent disorder and is one of the most common viral infections of human beings.68

The causative agents are small doublestranded DNA viruses that are 50 to 55 nm in diameter. More than 100 different strains have now been described (Table 22-6).69 HPV is transmitted by close, repeated contact that is often sexual in nature, although patients may inoculate themselves and thus spread lesions from one body site to another. These viruses all have a tropism for epithelial cells. After internalization, the virus enters the nucleus, eventuating in either productive infection or a period of latency. Once infected, the host almost always remains infected for life, irrespective of whether clinical lesions develop or not. In active infections, transcription of HPV takes place primarily in basal cells, and virion production occurs in the more differentiated layers of the epithelium. Thus, only the surface epithelium contains infectious viral particles. In addition to causing verrucae and papillomata, HPV infection may lead to carcinoma. Proteins produced by the oncogenic HPVs bind p53, a tumor suppressor gene product, resulting in unregulated cell growth and neoplasia. Particular HPV types tend to cause predictable lesions, but there is considerable overlap. Whereas types 6 and 11 generally induce benign lesions, types 16, 18, 31, and 33 are associated with potential for malignancy, especially types 16 and 18. Use of a quadrivalent HPV vaccine for types 6, 11, 16, and 18 has been shown to reduce the incidence of HPV-associated anogenital disease in young women.70 CLINICAL FEATURES Condyloma acuminatum, also known as genital warts, is the most common venereal disease in the United States and poses a public health problem of major magnitude (Table 22-7). The annual incidence of this disorder has been reported to be as

Table 22-7 Human Papillomavirus Infection HISTOPATHOLOGIC FEATURES

DIFFERENTIAL DIAGNOSIS

Condyloma acuminata Anogenital areas Soft sessile lesions smooth or digitated surface 3-5 mm Often multiple

Condyloma acuminata Polypoid configuration Epidermal hyperplasia Focal parakeratosis in invaginations of epidermis Koilocytes Dyskeratosis Verruca vulgaris Hyperkeratosis Focal parakeratosis overlying epidermal papillomatosis Digitated epidermal hyperplasia Hypergranulosis Vacuolization of upper Malpighian layer with prominent keratohyaline granules Dilated vessels in dermal papillae Verruca plana Basket-weave hyperkeratosis Often absence of parakeratosis Slight or no papillomatosis Hypergranulosis Vacuolated keratinocytes (Bird’s-eye cells) in upper Malpighian layer Verruca plantaris Hyperkeratosis Prominent papillomatosis Vacuolization of keratinocytes Prominent eosinophilic cytoplasmic inclusions at periphery of cell Rounded deeply basophilic nuclei

Condyloma acuminata Bowenoid papulosis Squamous papilloma Verrucous carcinoma

Verruca vulgaris Exposed skin Fingers, hands, dorsal aspects; face Hyperkeratotic papules, plaques Solitary or grouped lesions Filiform variants on face Mosaic variants on palms and soles Verruca plana Face, extremities Skin-colored or brown, slightly elevated papules Barely palpable 1-3 mm Usually multiple or numerous

Verruca plantaris Soles, particularly ball of foot Solitary often Firm papules or plaques Often marked hyperkeratosis

high as 106.5 per 100,000, or about 0.1% of the entire population. The incubation period varies from 3 weeks to 8 months, averaging 2.8 months. Men and women

A

Verruca vulgaris Epidermal nevus Seborrheic keratosis

Verruca plana Seborrheic keratosis Stucco keratosis

Verruca plantaris Punctate keratosis Verrucous carcinoma

are affected similarly, and the median age of infection with anogenital HPV is 22 to 25 years. In men, the most common sites of involvement are the penis;

CHAPTER 22 ■ VIRAL INFECTIONS

CLINICAL FEATURES

urethra; scrotum; and perianal, anal, and rectal areas.71 Types 6, 8, 16, and 18 HPV are the most common viral isolates from anogenital condylomata (Figs. 22-6 and 22-7). Clinically, lesions are usually manifest as soft, sessile tumors with surfaces that may be either smooth or markedly digitated with numerous fingerlike projections. Penile condylomata are usually 3 to 5 mm in diameter and often occur in groups of three to four. In women, the spectrum of clinical disease induced by HPV may be quite broad.72 Classic exophytic lesions of the external genitalia generally are readily recognized, although detection of other forms of HPV infection requires colposcopic and sigmoidoscopic examination. Vulvar condylomata acuminata appear as soft, whitish, sessile tumors with papillae or fine, fingerlike projections seen most commonly in moist areas such as the introitus and labia. Cervical condylomata occur in 20% of women with HPV infection involving other areas of the genital tract. Papillary epithelial projections are usually present at the cervical transformation zone and involve the squamous epithelium on colposcopic examination. Verrucae vulgares, or common warts, are the most common manifestation of HPV infection, occurring most frequently on the dorsal aspects of the fingers and hands (see Table 22-7). Clinically, they present as circumscribed, firm papules or plaques with a rough surface. They may occur singly or in groups and are caused most commonly by HPV types 1, 2, 3, and 4. Filiform warts are more slender and elongated, commonly localized to the eyelids and beard region. Verruca plana, or flat warts, are 1 to 3 mm, slightly elevated, skin-colored or

B

 FIGURE 22-6 Human papilloma virus (HPV). (A) In situ hybridization study for HPV detection demonstrates very focal staining of keratinocytes for the low-risk HPV strains 6 and 11. (B) Light microscopic appearance of the lesion, which corresponds to a benign papillary epidermal hyperplasia with features reminiscent of a seborrheic keratosis.

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PART III ■ INFECTIONS

and 10, in which patients have an abnormal propensity to develop cutaneous squamous cell carcinoma after ultraviolet irradiation. Epidermodysplasia verruciformis may be familial or sporadic. Familial cases usually demonstrate autosomal recessive inheritance, although an X-linked inheritance has also been reported.74 Affected individuals develop numerous red, flat to skin-colored, wartlike papules on sun-exposed surfaces. Malignant transformation is common.

508

 FIGURE 22-7 Human papilloma virus (HPV). In situ hybridization study for HPV detection demonstrates very focal staining of keratinocytes for the high-risk HPV strains 16 and 18. The light microscopic appearance of the lesion is one of high-grade squamous dysplasia.

slightly brownish papules. They are usually well demarcated and exhibit a minimally hyperkeratotic surface. They are often multiple and commonly involve the face or extremities. Warts on the soles (verruca plantaris) are variants of verrucae vulgares, most commonly occurring as solitary lesions on the ball of the foot, and they typically exhibit a markedly thickened cornified layer. Mosaic warts are coalesced clusters of warts on the sole; they are not generally as elevated as other plantar verrucae, possibly because of constant weight bearing. They tend to recur after removal, and because of the massive number of viral particles being shed from them, they tend to be more infectious than other verrucae. Plantar warts may lead to severe pain with walking and often pose a difficult therapeutic problem. Bowenoid papulosis refers to a localized form of squamous cell carcinoma in situ that develops as a consequence of infection by oncogenic HPVs, especially types 16 and 18. Lesions may appear identical to condylomata acuminata but usually consist of small, brown, flattopped papules involving the genital and perigenital areas. The condition is seen in both sexes but is more common in men. Lesions may become confluent and hyperplastic, and in some cases they may progress to fully developed squamous cell carcinoma.73 The shaft of the penis is involved more commonly than the glans. Giant HPV-induced verrucous carcinomas are large, vegetating tumors

developing most commonly in the genital and perigenital areas. These lesions are similar clinically to the BuschkeLowenstein variant of verrucous carcinoma. Epidermodysplasia verruciformis clinically may simulate widespread warts or, in some cases, other forms of erythroderma or widespread erythematous scaly dermatoses. Epidermodysplasia verruciformis refers to a cutaneous eruption caused by specific subtypes of HPV, especially types 3, 5,

HISTOPATHOLOGIC FEATURES Infection with HPV characteristically causes squamous epithelial proliferation. Histologically, the condyloma acuminatum is a papular or nodular lesion with prominent acanthosis and often koilocytosis (see Table 22-7). Lesions are usually gently papillated (Fig. 22-8), although they may be digitated. One variant has a striking resemblance to seborrheic keratosis. The epithelial retia are bulbous and branching and may simulate pseudocarcinomatous hyperplasia in some cases. The cells of the upper portion of the epithelium have perinuclear vacuolization and round or “raisinoid” (crinkled) hyperchromatic nuclei (Fig. 22-9). The latter cytopathic alteration is characteristic of HPV and constitutes koilocytosis. Often anisokaryosis of keratinocytes and dyskeratotic cells are present as well. In many cases, increased mitoses are also observed. The dermis or lamina propria appears edematous with dilated blood vessels and a variably intense lymphocytic infiltrate.

 FIGURE 22-8 Condyloma acuminatum. The lesion shows hyperkeratosis, a polypoid configuration, and slight papillomatosis.

Verrucae vulgares generally show epidermal hyperplasia with acanthosis, papillomatosis, dilated blood vessels in the papillary dermis, intraepidermal hemorrhage, and parakeratosis (Fig. 22-10).

The koilocytes of verrucae contain enlarged, clumped keratohyaline granules that appear intensely basophilic. Vertical columns of parakeratosis are also present at the tips of individual digitations. There

 FIGURE 22-10 Verruca vulgaris. The epidermis shows striking papillomatosis with overlying hyperkeratosis. Hypergranulosis and vacuolization of keratinocytes can also be observed.

DIFFERENTIAL DIAGNOSIS Condylomata acuminata may be confused with hymenal papillomatosis in women, pearly penile papules in men, seborrheic keratoses, and bowenoid papulosis. Verrucae may be confused with seborrheic keratosis, keratoacanthoma, solar keratosis, and squamous cell carcinoma. Plantar verrucae must be distinguished from clavi and carcinoma cuniculatum, a variant of verrucous squamous cell carcinoma. Epidermodysplasia verruciformis may simulate morbilliform exanthemata. 19 With all of these conditions,

CHAPTER 22 ■ VIRAL INFECTIONS

 FIGURE 22-9 Condyloma acuminatum. This field shows koilocytes with the characteristic distortion of nuclear outlines.

is often hemorrhage within the cornified layer at the tips of individual digitations. These changes are more pronounced in relatively early, well-developed lesions; however, involuted or older lesions often lack these characteristic features and rather demonstrate compact ortho- and parakeratosis with wedge-shaped hypergranulosis, slight papillomatosis, and acanthosis. Verruca plana are only slightly elevated and show less pronounced or no papillomatosis compared with common verruca (Fig. 22-11). In general, the stratum corneum has a basket-weave pattern of hyperkeratosis with little or no parakeratosis. Perhaps the most striking finding is the presence of vacuolated koilocytes (so-called “bird’s-eye” cells) in the superficial malpighian layer of the epidermis. Histologically, plantar verrucae show features similar to verruca vulgaris, although there is minimal papillomatosis because the lesions tend to be endophytic. Parakeratosis is minimal, and the cornified layer has a basket-weave appearance with subjacent markedly thickened granular layer (Fig. 22-12). Koilocytic cells, if present, are located in the upper portion of the epidermis, especially the granular layer. Bowenoid papulosis demonstrates architectural features similar to condyloma acuminatum, but cytologically, the changes of atypical keratinocytic proliferation and features of squamous cell carcinoma in situ are seen (Figs. 22-13 and 22-14). Individual keratinocytes are large, hyperchromatic, and pleomorphic and are closely crowded together, and they fail to demonstrate normal maturation from the basal cell layer to the granular cell layer. Epidermodysplasia verruciformis demonstrates papillomatosis, large vacuolated cells in the epidermis, and variable keratinocytic atypia. In some cases, there is an unusual form of dyskeratosis with corps rondlike bodies in the basket-weave stratum corneum.

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Pityriasis Rosea

 FIGURE 22-11 Verruca plana. The lesion demonstrates hyperkeratosis, hypergranulosis, slight acanthosis, and the characteristic vacuolated or “bird’s-eye” cells in the upper spinous layer.

histologic evaluation should facilitate distinction.

Human Herpesvirus Human herpesviruses 6, 7, and 8 (HHV-6, -7, and -8) have received a great deal of

attention regarding possible association with lymphoproliferative, inflammatory, and neoplastic processes. Although there are conflicting reports, there has been no direct association of HHVs with lymphoproliferative disorders such as lymphomatoid papulosis or cutaneous T-cell lymphoma.75

A number of factors suggest an infectious etiology for pityriasis rosea. Some of these include case clustering within households or other closely quartered communities such as military personnel; prodromal symptoms of upper respiratory infection in many patients; seasonal prevalence in the spring and fall; the presence of a primary lesion that evolves to multiple secondary lesions; and a low rate of recurrence. Evidence indicates that pityriasis rosea is not associated with CMV, EBV, parvovirus B19, picornavirus, parainfluenza, or influenza viruses. The role of HHV-7 and HHV-6 remain controversial. Although some studies have reported the detection of HHV-7 and HHV-6 in patients with pityriasis rosea, subsequent studies failed to confirm this.76,77 Thus, pityriasis rosea is more likely either a multifactorial process representing a cutaneous manifestation of several agents or possibly an infection by a still undiscovered virus. The biopsy findings are those defined by a low-grade eczematous dermatitis associated with focal parakeratosis. The parakeratotic scale is typically detached from the epidermis, often angled at 45 degrees from the long axis of the epidermis. Focal dyskeratosis is noted. There is directed migration of lymphocytes into the suprapapillary plates. A moderately dense angiocentric lymphocytic infiltrate surrounds the superficial vascular plexus, including the dermal papillae capillaries.

Kaposi Sarcoma Kaposi sarcoma is a multisystem vascular neoplasm characterized by purple mucocutaneous lesions. It is now known to be caused by HHV-8, which is found predominantly in individuals infected with HIV-1. This is entity is discussed in Chapter 31.

Cytomegalovirus

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 FIGURE 22-12 Verruca plantaris. The lesion exhibits hypergranulosis with prominent vacuolization of keratinocytes, many of which contain large keratohyalin granules.

CMV is an enveloped DNA virus measuring 110 nm in diameter that is a member of the herpesvirus group. The virus is widespread, and subclinical infections are prevalent because most of the population at large demonstrates CMV antisera. Transmission is via body fluids, including saliva, blood, urine, semen, breast milk, and cervical secretions. Viral secretion may persist for years. Individuals at risk for clinical infections are those immunocompromised for one reason or another, such as those with HIV infection,78 transplant recipients, those undergoing chemotherapy, and pregnant women.

Table 22-8 Cytomegalovirus Infection

 FIGURE 22-13 Bowenoid papulosis. The proliferative epidermis shows full-thickness atypia of keratinocytes.

CLINICAL FEATURES Although most cases are subclinical, a mononucleosis syndrome that is similar to that caused by EBV may develop (Table 22-8). Affected patients develop fever, malaise, myalgias, lymphadenopathy, hepatosplenomegaly, and a sore throat without exudate. An exanthem manifest by an eruption of erythematous macules and papules that may be either urticarial or petechial may develop. The eruption may be precipitated by administration of ampicillin, as with infectious mononucleosis. A vasculitis with palpable purpura also has

been reported.79 In patients with AIDS, CMV may cause chronic perineal and lower extremity ulcerations, chorioretinitis, gastroenteritis, pneumonia, and other visceral involvement.80 Fetal infection with CMV results in significant, often fatal developmental abnormalities. As with congenital rubella, extramedullary hematopoiesis may be seen in the skin as purplish papules and nodules. HISTOPATHOLOGIC FEATURES The acute exanthem of CMV infection generally appears histologically similar to other viral

exanthemata, with the possible exception of scattered enlarged fibroblasts or endothelial cells in the dermis. There is characteristically a sparse infiltrate of lymphocytes around blood vessels in the upper dermis with slight spongiosis. CMV does not infect keratinocytes, so epidermal changes are usually minimal. Virally infected cells in the dermis are characteristically enlarged one- to threefold and contain purplish crystalline inclusions in the cytoplasm and nuclei. These latter inclusions result in the characteristic “owl’s eye” appearance of the cells (Fig. 22-15). CMV vasculitis is a manifestation of endothelial cell infection with swelling, inflammation, and secondary vascular compromise. Ulcerations in immunocompromised hosts are usually not caused by CMV itself but by another agent such as herpesvirus with secondary colonization.

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Clinical Features “Mononucleosis syndrome” similar to that caused by EBV Exanthem of macules and papules Histopathologic Features Sparse spongiotic perivascular dermatitis Characteristic “owl’s-eye” viral inclusion in endothelial cells Vasculitis Differential Diagnosis Toxoplasmosis Infectious mononucleosis Listeriosis Other viral exanthemata

DIFFERENTIAL DIAGNOSIS Infectious mononucleosis, toxoplasmosis, listeriosis, other viral exanthemata, infectious hepatitis, and drug eruptions must be ruled out. CMV vasculitis is similar to other forms of vasculitis and should be excluded by clinical and serologic information. Histologic visualization of infected cells is diagnostic. Viral culture, immunoperoxidase staining, direct immunofluorescence, DNA in situ hybridization, and polymerase chain reaction assays may aid in the diagnosis of difficult cases.

POXVIRUS INFECTIONS

 FIGURE 22-14 Bowenoid papulosis. Higher magnification demonstrating parakeratosis, absence of the granular layer, and atypia of keratinocytes in the spinous layer.

Poxviruses are the largest animal viruses and are the only viruses that are visible by light microscopy (Table 22-9). Three groups affect humans: orthopoxviruses such as variola and vaccinia, which are ovoid and 300 by 250 nm in diameter;

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 FIGURE 22-15 Cytomegalovirus (CMV) infection.This cell shows classic cytopathic changes of CMV infection. The cell appears large, and there is a prominent “owl’s eye,” brightly eosinophilic intranuclear inclusion.

parapoxviruses such as those which cause orf and milker’s nodule, which are cylindrical and 260 by 160 nm in diameter; and the molluscum contagiosum virus, which has an oval bullet shape and is 275 by 200 nm in diameter. Humans may also be affected by tanapox, which is somewhat similar to the parapoxviruses. These are complex DNA viruses that replicate in the cytoplasm and are adapted to proliferation in keratinocytes. Spread is primarily by direct contact with infectious material from an infected individual or animal or via fomites, although variola is spread via aerosolized droplets. CLINICAL FEATURES All of the poxvirus infections have prominent cutaneous manifestations. Although smallpox vaccination is no longer routine except in military settings, occasional infections with vaccinia are encountered. The most important manifestation is eczema vaccinatum, which represents a widespread eruption of edematous, inflamed lesions in individuals with altered cutaneous barrier function, such as those with

Table 22-9 Poxvirus Infections

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Orthopoxviruses Variola Vaccinia Cowpox Parapoxviruses Orf Milker nodule Tanapox Virus of molluscum contagiosum

atopic dermatitis. These patients usually have a high fever and lymphadenopathy. The condition may be fatal, and there is a 5% mortality rate. Animal poxviruses may affect humans. Human monkeypox is indistinguishable clinically from smallpox, although there is more pronounced lymphadenopathy.81 Cowpox is primarily a disease of cattle, although humans may be infected on occasion. After an incubation period of 5 to 7 days, a papule develops that vesiculates, becomes pustular, and then ulcerates. The pustule, which is often umbilicated, is surrounded by a zone of erythema and edema. There is characteristically lymphangitis and lymphadenitis with fever, myalgia, and constitutional symptoms. Lesions heal over 3 to 4 weeks. Lesions are most commonly present on the hands, arms, or face and may be multiple.82 Orf is caused by a parapoxvirus that is widespread in sheep and goats, affecting mainly lambs and kids. Human lesions are caused by direct inoculation of infected material and are common among shepherds, veterinary surgeons, and other individuals with exposure to these animals.83 There is an incubation period of 5 to 6 days, after which a small, firm, red or reddish-blue papule enlarges to form an umbilicated hemorrhagic pustule or bulla. The lesion enlarges to up to 3 to 5 cm in diameter and becomes crusted. A grayish to violaceous ring is surrounded by a zone of redness and warmth. The lesions are usually solitary or few in number and are located most commonly on the fingers, hands, or forearms. There may be tenderness and associated lymphangitis and regional adenitis with mild fever.

Spontaneous recovery usually occurs within 3 to 6 weeks. Milker’s nodule is also caused by a parapoxvirus that most commonly leads to infection of the teats and mouths of cattle so that milkers, farmers, and veterinarians are accidental hosts. The infection may be transmitted by contaminated fomites in some cases. There is an incubation period of 5 days to 2 weeks, after which a small, red papule develops that enlarges and becomes violaceous, firm, and slightly tender over the course of 1 week.84 The epidermis becomes opaque and grayish, and soon after, a crust develops centrally. As with other poxvirus infections, central umbilication is usually present. There is a surrounding zone of erythema, and there may be lymphangitis. Lesions resolve over 4 to 6 weeks without scarring. In contrast to orf, lesions are usually multiple and number between two and five but may be more numerous. The most common sites of involvement are the hands and fingers. Rarely, a more widespread papulovesicular eruption of the hands, arms, legs, and neck may develop. Tanapox is an acute febrile illness associated with a localized nodular skin lesion caused by the Tanapox virus, a member of the genus Yatapoxvirus.85,86 The infection was first seen in the Tana River area of Kenya and is probably widely distributed in tropical Africa. The virus affects monkeys and humans and is acquired by inoculation through abraded skin. Affected individuals have mild preeruptive fever accompanied by headache and backache. The lesion begins as a localized zone of erythema and induration that develops into a nodule over the course of 2 weeks. The limbs are involved most commonly. There is usually accompanying localized lymphadenopathy that is often painful. The nodule ulcerates in the third week and heals slowly with a scar over 6 weeks. Most cases are characterized by a solitary lesion, although lesions may be multiple. Molluscum contagiosum is the most common human disease induced by poxviruses. Infection occurs after contact with infected individuals and fomites. It is common in childhood, although it is rare under the age of 1 year. In children, the face, limbs, and trunk are involved commonly. A second peak occurs in young adults due to sexual transmission, with involvement of the genital and perineal skin. The face is involved commonly in HIV-infected patients. Any body site may be involved, including the mucous membranes. The incubation period ranges from 14 days to 6 months. The individual lesion is a translucent, skin-colored to whitish

B

 FIGURE 22-16 Smallpox. (A) This biopsy of smallpox shows a hemorrhagic necrolytic blister associated with striking acantholysis and marked epithelial degeneration. Although clinically the lesions may have a pustular appearance, the vesicles are actually composed of serum and necrotic cellular debris. (B) Higher power magnification reveals prominent intracytoplasmic and intranuclear inclusions with multinucleation. dome-shaped papule that is characteristically umbilicated with a central pore. Lesions range from 1 to 10 mm and may be significantly larger, sometimes resembling keratoacanthoma, especially in immunocompromised hosts. Small lesions may coalesce to form plaques. In time, the lesions may become inflamed, suppurative, and crusted before eventual resolution. Most cases are self-limited and resolve within 6 to 9 months, although some may persist for as long as 3 or 4 years. HISTOPATHOLOGIC FEATURES The acute inflammatory poxvirus infections all have similar histologic features and usually exhibit prominent spongiosis, ballooning degeneration, dermal edema, and acute inflammation. Individual lesions demonstrate changes that are distinct and permit differentiation in many cases. In vaccinia and cowpox, the basal layer of the epidermis contains large, eosinophilic cytoplasmic inclusions. There is necrosis of the epithelium with spongiosis; pallor of keratinocytes; and a dense infiltrate consisting mostly of neutrophils, lymphocytes, and some eosinophils. There are also extravasated erythrocytes in the dermis with prominent papillary dermal edema (Fig. 22-16). Orf demonstrates marked inter- and intracellular edema, vacuolization, and ballooning degeneration (Fig. 22-17). A dense infiltrate is seen in the dermis that has a characteristic architecture, consisting mainly of histiocytes and macrophages centrally with lymphocytes and plasma cells at the periphery. Characteristically, there are very few neutrophils. There is also prominent vascularity with an increased number of

small blood vessels, many of which show swelling and proliferation of endothelial cells. Ultrastructural studies show viral particles within the cytoplasm of degenerating epidermal cells. Milker nodule is characterized by multilocular vesicle formation in the epidermis that is strikingly acanthotic. There is characteristically less ballooning degeneration

than in orf. There is often marked parakeratosis, and eosinophilic cytoplasmic and intranuclear inclusions are seen commonly. The dermis is edematous, and there is an infiltrate of mononuclear cells that may be granulomatous (Fig. 22-18). The molluscum contagiosum virus initially enters basal keratinocytes and is accompanied by an increase in cell

 FIGURE 22-17 Orf. High magnification shows spongiosis and intracellular edema of the keratinocytes. Eosinophilic inclusions are noted in the cornified layer.

CHAPTER 22 ■ VIRAL INFECTIONS

A

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A

B

C  FIGURE 22-18 Milker nodule. (A) Low-power view of a lesion of a Milker nodule shows a striking mononuclear cell dominant infiltrate with prominent vascularity and vascular ectasia. (B) and (C) Prominent intracytoplasmic and nuclear eosinophilic inclusions are seen within the epidermal keratinocytes.

turnover, leading to epidermal proliferation (Figs. 22-19 and 22-20). The basal layer remains intact, and cells at the core of the lesion become enlarged as a

514

consequence of the accumulation of masses of viral material and appear as large, purplish red bodies (molluscum bodies) that are up to 25 μm in diameter.

 FIGURE 22-19 Molluscum contagiosum. Scanning magnification shows the characteristic lobular architecture of epithelium infected by molluscum contagiosum.

The proliferation has a distinct lobulated character with formation of a central crater that corresponds to the central umbilication observed clinically. Lesions typically have an exo- or endophytic appearance. Inflammatory changes in the dermis are usually minimal but may be pronounced when lesions rupture and discharge their contents.87 DIFFERENTIAL DIAGNOSIS Each of the inflammatory poxvirus illnesses must be distinguished from the others by clinical setting, number of lesions, histologic findings, and electron microscopy. Other acute inflammatory infections such as primary tuberculosis and sporotrichosis, acute foreign body granulomatous reactions, pyogenic granulomas, pronounced inflammatory reactions with dermal edema such as Sweet syndrome, and polymorphous light eruption must also be differentiated from poxvirus infections based on clinical and histologic findings.

Polyoma Virus Infections Polyoma viruses are small doublestranded DNA viruses. Polyoma viruses can promote tumors in animal models. Recently, sequences of a previously unknown polyoma virus dubbed the Merckle cell polyoma virus were found in eight of 10 cases of Merckle cell carcinoma. In six of the eight Merckle cell virus positive cases, the viral DNA was incorporated into the tumor genome in a clonal fashion, suggesting that Merckle cell virus integration may contribute to Merckle cell carcinoma pathogenesis.88

ACKNOWLEDGMENT We would like to acknowledge the contributions of Dr. R. Wesley Wetherington and Dr. Zafar M. Khan.

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CHAPTER 22 ■ VIRAL INFECTIONS

 FIGURE 22-20 Molluscum contagiosum. The epithelial cells contain the characteristic eosinophilic cytoplasmic inclusion bodies. The nuclei are pushed to the periphery of the cell by the inclusion body.

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seminated cutaneous histoplasmosis in a patient infected with human immunodeficiency virus. J Am Acad Dermatol. 1993; 29:311-313. Rosenthal D, LeBoit PE, Klumpp L, Berger TG: Human immunodeficiency virus-associated eosinophilic folliculitis: a unique dermatitis associated with advanced human immunodeficiency virus infection. Arch Dermatol. 1991;127: 206-209. Andiman WA: The Epstein-Barr virus and EB virus infections in childhood. J Pediatr. 1979;95:171-182. Pullen H, Wright N, Murdoch JM: Hypersensitivity reactions to antibacterial drugs in infectious mononucleosis. Lancet. 1967; ii:1176-1178. Klein P, Jones E, Nelson J, et al: Infectious causes of pityriasis lichenoides: a case of fulminant infectious mononucleosis. J Am Acad Dermatol. 2003;49(suppl):S151S153. Anderson R, Horn K, Hoang M, et al: Punctate exanthem of West Nile virus infection: report of 3 cases. J Am Acad Dermatol. 2004;51:820-823. McElgunn PSJ: Dermatologic manifestations of hepatitis B virus infection. J Am Acad Dermatol. 1983;8:539-548. Michalak T: Immune complexes of hepatitis B surface antigen in the pathogenesis of periarteritis nodosa: a study of seven necropsy cases. Am J Pathol. 1928;90:619-632. Caroli J: Serum sickness-like prodromata in viral hepatitis: Caroli’s triad. Lancet. 1972;i:964-965. Juel-Jensen BE, MacCallum FO: Herpes Simplex, Varicella and Zoster. London: Heinemann; 1972. Gilson IH, Banett JH, Conant MA, et al: Disseminated ecthymatous herpes varicella-zoster virus infection in patients with acquired immunodeficiency syndrome. J Am Acad Dermatol. 1989;20: 637-642. Carlson J, Chen K: Cutaneous vasculitis update: neutrophilic muscular vessel and eosinophilic, granulomatous, and lymphocytic vasculitis syndromes. J Am Acad Dermatol. 2007;29:32-43. Nikkels A, Delvanne P, Sadzot-Delvaux C, et al: Distribution of varicella zoster virus and herpes simplex virus in disseminated fatal infections. J Clin Pathol. 1996;49:243-248. Kennedy P, Grinfield E, Gow J: Latent varicella-zoster virus is located predominantly in neurons in human trigeminal ganglia. Proc Natl Acad Sci USA. 1998; 95:4658-4662. Peto TEA, Juel-Jensen BE: Varicella zoster virus disease, in Monk BE, GrahamBrown RAC, Sarkany I (eds). Skin Disorders in the Elderly. Oxford, UK: Blackwell Scientific Publications; 1988: 80-96. Nahmias AJ, Keyserling HL, Kerrick GM: Herpes simplex, in Remington JS, Klein JO (eds). Infectious Diseases of the Fetus and Newborn Infant, 2d ed. Philadelphia: Saunders; 1983:636. Corey L: First-episode, recurrent and asymptomatic herpes simplex infections. J Am Acad Dermatol. 1988;18:169-172. Beutner KR, Becker TM, Stone KM: Epidemiology of HPV infections. Dermatol Clin. 1991;9:211-218.

69. Brown C, Kowalczyk A, Taylor E, et al: p53 represses human papillomavirus type 16 DNA replication via the viral E2 protein. Virology Journal. 2008;5:5 70. Garland S, Hernandez-Avila M, Wheeler C, et al: Quadrivalent vaccine against human papilloma virus to prevent anogenital diseases. N Engl J Med. 2007;356:19281943. 71. Syrjanen SM, von Krogh G, Syrjanen KJ: Anal condylomas in men: 1. Histopathological and virological assessment. Genitour Med. 1989;65:216-224. 72. Campion MJ: Clinical manifestations and natural history of genital human papillomavirus infection. Obstet Gynecol Clin North Am. 1987;14:363-388. 73. Rütlinger R, Buchmann P: HPV 16-positive bowenoid papulosis and squamous cell carcinoma in an HIV-positive man. Dis Colon Rectum. 1989;32:1042-1045. 74. Hu W, Nuovo G, Willen M, Somach S: Epidermodysplasia verruciformis in two half brothers with HIV infection. J Cutan Med Surg. 2004;8:357-360. 75. Kempf W, Kadin M, Kutzner H, et al: Lymphomatoid papulosis and human herpesviruses: a PCR-based evaluation for the presence of human herpesvirus 6, 7 and 8 and related herpesviruses. J Cutan Pathol. 2001;28:29-33. 76. Kempf W, Burg G: Pityriasis rosea: a virus-induced skin disease? An update. Arch Virol. 2000;145:1509-1520. 77. Chuh A, Chan H, Zawar V: Pityriasis rosea—evidence for and against an infectious aetiology. Epidemiol Infect. 2004;132: 381-390. 78. Jacobson MA, Mills J: Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1988;108:585-594. 79. Lin CS, Pinha PD, Krishnan MN, et al: Cytomegalic inclusion disease of the skin. Arch Dermatol. 1981;117:282-284. 80. Feldman PS, Walker AN, Baker R: Cutaneous lesions heralding disseminated cytomegalovirus infections. J Am Acad Dermatol. 1982;7:545-548. 81. Jezek Z, Szczeniowski M, Paluku KM, et al: Human monkeypox: clinical features of 282 patients. J Infect Dis. 1987;156: 293-298. 82. Casemore DP, Emslie ES, Whyler DK, et al: Cowpox in a child, acquired from a cat. Clin Exp Dermatol. 1987;12:286-287. 83. Gill MJ, Arlette J, Buchan KA, et al: Human orf. Arch Dermatol. 1990;126: 356-358. 84. Leavell UW, Phillips IA: Milker’s nodules. Arch Dermatol. 1975;111:1307-1311. 85. Jezek Z, Arita I, Szczeniowski M, et al: Human tanapox in Zaire: clinical and epidemiological observations on cases confirmed by laboratory studies. Bull WHO. 1985;63:1027-1035. 86. Nazarian s, Barrett J, Frace M: Comparative genetic analysis of genomic DNA sequences of two human isolates of tanapox virus. Virus Res. 2007;129:11-25. 87. Kwittken J: Molluscum contagiosum: some new histologic observations. Mt Sinai J Med. 1980;47:583-588. 88. Feng H, Shuda M, Chang Y: Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319: 1096-1100.

CHAPTER 23 Protozoal and Algal Infections Ann Marie Nelson Paul Hofman Freddye Lemons-Estes

LEISHMANIASIS Leishmaniasis is a spectrum of diseases caused by various species of the dimor-

phic protozoa Leishmania and is prevalent in tropical and neotropical areas of more than 70 countries throughout Asia, Africa, the Americas, and the Mediterranean, with up to 1.5 to 2.0 million new cases each year.19,20 The incidence and spread of the disease has increased due to global climate changes, migration and tourism, urbanization, and deforestation, as well as increased drug resistance.20-25 Approximately one-third of the world’s HIV-infected population lives in zones endemic for leishmaniasis.26 Dogs, cats, and rodents typically serve as reservoirs. Humans acquire the infection from the bite of infected female sandflies carrying the flagellated promastigote forms in their gastrointestinal (GI) tract. The infective promastigotes enter at the inoculation (bite) site and invade reticuloendothelial cells. There they transform into aflagellate amastigotes and proliferate intracellularly until the cell ruptures.27 Although macrophages are the primary cells that harbor the parasites, phagocytosis by fibroblasts in the dermis and regional lymph nodes also occurs and may provide an important reservoir of organisms in latent disease.28,29 The incubation period for cutaneous leishmaniasis varies from 2 to 8 weeks but may be several months or years depending on the size of the inoculum and the immunologic status of the host.20,27,30 Leishmania subgenera include Leishmania (which develop in the midgut and foregut of the sandfly) and Viannia (which develop in the hindgut and migrate to the mid and foregut).27 Three serologically and biochemically distinct species of Leishmania—L. tropica, L. aethiopica, and L. major—are responsible for Old World leishmaniasis. They are transmitted by sandflies of the genus Phlebotomus.20,27 New World leishmaniasis with predominately cutaneous involvement is caused by multiple species of L. (Viannia)—L. (V). braziliensis, L. (V.) guyanensis, L. (V.) peruviana, L. (V.) panamensis, and L. (V.) columbiensis and by L. (L.) mexicana, L. (L.) amazonensis, and other minor species. All of which are transmitted by sandflies of the genus Lutzomyia. L. (V.) braziliensis is the etiologic agent of mucocutaneous leishmaniasis and is also transmitted by the genus Lutzomyia. Visceral leishmaniasis is caused by L. donovani, L. infantum/L. chagasi and L. (L.) amazonensis.27 Because of new genetic techniques and field testing, the taxonomy of Leishmania genera, subgenera, species, and subspecies is in flux.20,27 CLINICAL FEATURES Old World leishmaniasis (eg, Baghdad boil, Biskra button,

CHAPTER 23 ■ PROTOZOAL AND ALGAL INFECTIONS

Protozoa are unicellular parasites that infect hundreds of millions of people each year. Infections are often latent but may progress to active disease when the host-parasite balance shifts in favor of the parasite. Parasite burden (at the initial infection or later), host immunity, and other factors influence this balance. International travel, extension of vector habitats, and increased numbers of immunocompromised hosts (patients undergoing chemotherapy, organ transplant recipients, HIV-infected individuals) have increased the pool of susceptible hosts. Protozoa may cause cutaneous lesions as a primary, secondary, or incidental site. Leishmaniasis, the most common form of protozoal dermatitis, affects millions of people in the tropical and subtropical belts of the world. Up to 1 billion people carry Entamoeba histolytica, but cutaneous lesions are rare and occur as secondary complications of chronic diarrhea or fistulas. Lesions may develop at the inoculation site of visceral infections (ie, kala-azar or Chagas disease). Iatrogenic and HIV-associated immune suppression have resulted in an increase in toxoplasmosis and acanthamebiasis. Cutaneous lesions in these patients often represent a manifestation of disseminated disease. Many protozoal diseases cause cutaneous immune reactions in the absence of cutaneous organisms. Algae (both chlorophyllic and achlorophyllic) cause infections in wild and domestic animals but rarely cause disease in humans. Classically, protozoal infections of the skin are diagnosed by clinical correlation with skin smears; routine histology; and in some cases, microbiologic cultures. Molecular assays increase the specificity and in some instances may increase the sensitivity of histopathologic tests.1 In this regard, molecular methods of detection may be particularly useful when protozoa are undetectable by means of histochemical methods, are present in low numbers,

stain poorly, are uncultivable, or exhibit an atypical morphology. Free trophozoites and protozoa present in large necrosis areas may be impossible to be distinguish from apoptotic nuclei. In some cases, molecular methods are important for the rapid; specific; and more rarely, quantitative detection of protozoa.1,2 After the use of traditional histochemical stains, these special techniques are the next step in the diagnosis of protozoa by means of histopathologic testing. These special techniques include immunohistochemistry; in situ hybridization (ISH); and nucleic acid amplification technologies, mainly polymerase chain reaction (PCR).1-6 After histochemical staining, immunohistochemistry is the most commonly used ancillary diagnostic technique for the diagnosis of protozoa in histologic sections.7-12 This technique uses monoclonal or polyclonal antibodies directed against specific protozoa antigens. The specificity of this method is dependent on the specificity of the antigen binding (Fab) portion of the immunoglobulin molecule used.12 Whereas immunofluorescent immunohistochemistry is usually performed for detection protozoa on fresh, frozen tissue, immunoperoxidase methods are usually performed to detect protozoa on formalin fixed, paraffin-embedded tissues. ISH has many of the same advantages as immunohistochemistry. However, this method uses the complementary nature of protozoa nucleic acids, rather than an antibody raised against a protozoal antigen, to impart specificity. The nucleic acid probe, which may be labeled by a variety of methods, anneals to a specific target sequence in the protozoa DNA or RNA.13-17 A signal is generated by methods similar to those used in immunohistochemistry. PCR has revolutionized the detection of infectious agents.1,3 This allows for the detection of protozoa that are difficult to culture or are not cultivable and may be used to quantify the amount (load) of protozoa present.18 Nucleic acid amplification methods that use tissue sections include in situ PCR and conventional amplification using tissue extracts. These methods can then reveal the specific identify of the protozoa. Currently, there are very few applications for routine diagnosis of cutaneous protozoa; these are discussed by specific disease. Further development and integration into traditional morphologic pathology are required.

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Leishmania tropica, Lahore sore, bouton d’orient or Oriental sore) is characterized by two types of lesions, moist (rural) and dry (urban) (Table 23-1). Moist lesions present as a slowly growing, indurated red papule that may be intensely pruritic; multiple lesions are common. The papules enlarge in a few months to form nodules with an indurated border and dusky discoloration. These nodules tend to ulcerate within a few weeks, forming ulcers up to 5 cm in diameter with depressed granulating centers and raised indurated margins. Secondary bacterial infection is common after ulceration. Spontaneous healing usually occurs within 6 months,

Table 23-1 Leishmaniasis

Clinical Features Spectrum of disease caused by multiple species of Leishmania Old World cutaneous (L. tropica, L. major, L aethiopica) Middle East, Africa, Asia, Mediterranean Rural (moist), multiple, progress from papules to ulcer with spontaneous healing in 6 months Urban (dry), single, on face, protracted course of up to 2 years or more New World cutaneous and mucocutaneous (L. braziliensis, L. tropica) Bay sore usually visceral (L. donovani) Histopathologic Features Ulceration often Histiocytic infiltrates with varying admixtures of lymphocytes, neutrophils, and plasma cells Epithelioid granulomas on occasion (with greater immunity) Intracellular organisms (amastigote forms– Leishman-Donovan bodies) varied in number depending on age of lesion and immunologic status of host Amastigotes with round basophilic nucleus and small basophilic rodlike kinetoplast Giemsa stain – nucleus purple and kinetoplast intense red or reddish-purple Laboratory Evaluation Giemsa, PAS, silver stains Culture on NNN or Schneider Drosophila medium Differential Diagnosis American trypanosomiasis Histoplasmosis Rhinoscleroma Granuloma inguinale Leprosy Atypical mycobacteriosis

leaving a characteristic depressed, flattened white or pink cribriform scar. Dry lesions have a similar presentation but follow a more protracted course. Lesions are often single and occur primarily on the face. Progression to the nodular form does occur; however, the lesions do not ulcerate for several months. Healing may be delayed up to 2 years.31 New World leishmaniasis encompasses several clinical entities. The “bay” sore typically occurs on the face as one or occasionally multiple erythematous plaques that typically do not ulcerate. “Apple jelly” nodules resembling lupus vulgaris are sometimes seen. The “Chiclero” ulcer is similar but is more often a single erythematous plaque that ulcerates; it affects the ear in 40% of patients and may cause extensive destruction of the cartilage. “Uta” presents as one or several papules on exposed sites; lesions usually ulcerate and are self-healing. In “pian bois,” the patient has a single skin ulcer. Lymphatic spread may occur and result in widespread ulceration, but mucocutaneous involvement is extremely uncommon. Leishmaniasis recidivans (lupoid leishmaniasis) is a relapsing form of the disease that may occur with any of the cutaneous leishmaniases but is usually secondary to L. tropica infection. Most cases are in Iran and Iraq. Typically arising months to years after the primary lesion has healed, the disease presents as erythematous, sometimes circinate papules with a whitish scale. Lesions begin on the face, often at the edge of healed scars, and spread on an erythematous base. Patients are hypersensitive with good humoral and cellular immune (skin test) responses but are unable to completely eliminate the parasites. As the central lesion heals, active peripheral ones continue to form. The course is chronic and often relentless, lasting 20 to 40 years in some patients. Other reported atypical forms include sporotrichoid, paronychial, erysipeloid, eyelid lesions, psoriasiform, mycetomatous, chancriform, zosteriform, whitlow, palmar or plantar, discoid lupus erythematosus (DLE)-like, verrucous (carcinomalike), and eczematous.24 Disseminated cutaneous leishmaniasis presents as a single ulcer, nodule, or plaque on the face and other exposed areas. Nodular or plaquelike satellite lesions develop from the primary lesion and may disseminate over the entire body. Patients are anergic to leishmanial antigens and do not mount a specific cellular immune response to the infection. The organisms proliferate indefinitely, forming many lesions teeming with parasites.32

The ulcerative cutaneous lesions of mucocutaneous leishmaniasis develop exactly as those seen in Old World leishmaniasis but are more frequently multiple and tend to become extremely large. Cutaneous lesions may extend to involve mucosal surfaces, but lymphatic and hematogenous spread of parasites is the usual route for mucosal involvement. Mucocutaneous leishmaniasis tends to occur in patients with untreated or poorly healing primary lesions. Although mucosal membrane involvement is uncommon in Central America, it is present in up to 80% of affected persons in Brazil and has a predilection for the nasopharynx. Visceral leishmaniasis (kala-azar) presents infrequently with cutaneous lesions. The reticuloendothelial system is the primary target of the parasite, and disease generally is characterized by fever, weight loss, hepatosplenomegaly, and pancytopenia. On rare occasions, an initial papule or nodule (leishmanoma) arises at the site of the infecting bite. Later in the course of the disease, melanin deposition may result in hyperpigmented patches on the forehead, over the temples, periorally, and on the midabdomen. Post–kala-azar dermal leishmaniasis (dermal leishmanoid) occurs predominantly in India but is also seen in Africa. Approximately 2% of patients in Africa and up to 50% in Sudan27,33 develop the syndrome shortly after treatment, but 5% to 10% in India develop lesions up to 10 years after treatment.27 The disease can present as hypopigmented or hyperpigmented macules predominantly on the face (often in a butterfly distribution) or as warty papules or nodules. The nodules are rarely greater than 1 cm in size and are found primarily on the face (especially around the mouth and nose) and to a lesser extent on the trunk and extremities. The lesions are chronic and may occur as a single type or in combination. In HIV-infected hosts, visceral leishmaniasis is the predominant clinical presentation of this protozoal disease.34 Purely cutaneous and mucosal manifestations of leishmaniasis in HIV coinfection are rare. The skin and mucosal lesions in this setting are similar to those seen in non–HIVinfected persons but are more frequently multiple at the time of presentation.35 Dissemination of the parasite through the lymphatic system may produce sporotricoid-like lesions.24,33 On rare occasions, a dermatomyositis-like eruption occurs. However, there is no associated proximal symmetric muscle weakness, elevated muscle enzymes, or myopathic changes on electromyogram.36 Organisms have

been reported in nonlesional skin.37 Treatment failure and relapse are also common. Death during the first episode of visceral leishmaniasis has been reported in up to 19% of patients.26 Effective host response depends on both innate and adaptive immunity. Th1 (interferon-γ)-induced macrophage activation is required to kill the intracellular parasites. The Th2 (IL-4) response blunts tissue damage but promotes intracellular infection and increases the susceptibility to diffuse cutaneous (anergic) disease.20,27,38 In mucocutaneous disease, there is a mixed Th1/Th2 response with increased delayed-type hypersensitivity.20

 FIGURE 23-1 Cutaneous leishmaniasis. Skin biopsy showing numerous round to oval amastigotes in histiocytes. The nucleus is easily seen in most organisms; the smaller rodlike kinetoplasts are more difficult to identify.

generally more prevalent in these lesions than in the pigmented variety. Nodular and warty lesions have variable degrees of epithelial hyperplasia. A dense dermal infiltrate of histiocytes and epithelioid cells admixed with lymphocytes and plasma cells extends into the subcutaneous fat. A narrow grenz zone may separate the infiltrate from the epidermis. Organisms are abundant in some lesions and difficult to find in others. Ulcerated mucosal lesions show nonspecific inflammatory infiltrates in areas of ulceration; varying degrees of epithelial hyperplasia; and a dense dermal infiltrate of histiocytes, lymphocytes, and plasma cells. New lesions may have neutrophils admixed. Tubercle-type granulomas and Langhans-type giant cells also may be observed. Lesions in which organisms cannot be identified in histologic sections require additional studies. Species-specific PCR assays for the detection of Leishmania species have been developed and can be used with a number of specimens.40-45 The specificity and sensitivity of the current PCR technology generally exceed those of culture methods46,47 and histologic detection of parasites.48 The sensitivity of cultures and PCR for Leishmania species in ulcerated skin lesions may be improved by selecting material from both the edge of the active indurated margin and the base of the ulcer.49,50 An aspirate, scrapings, or homogenate of tissue from the lesion can be plated on Novy-MacNeal-Nicolle (NNN)

medium or Schneider Drosophila medium for a specific diagnosis. The spindled flagellated promastigotes, which measure 10 to 15 μm, usually grow in 1 to 2 weeks, but cultures should not be considered negative for 4 weeks. Direct smears of material obtained from the edge of an ulcer and stained with Giemsa may reveal organisms that are somewhat larger (2 to 4 μm) than those seen in fixed tissue.51 Recently, some centers have developed immunohistochemistry for the diagnosis of leishmaniasis. Anti-leishmaniasis immunolabeling can confirm the diagnosis showing numerous parasites in macrophages. Moreover, this immunolabeling can allow this diagnosis when a very small number of amastigotes are present or are extracellular in the connective tissue or in areas of necrosis.11 Immunolabeling in tissue sections with specific anti-Leishmania antibodies is a valuable tool for identifying organisms in unusual histopathological manifestations of leishmaniasis. Extracellular parasites can be noted free in the connective tissue or in capillary lumens. Rarely, Leishmania species can be detected inside epithelial or endothelial cells.52 This immunostaining may be useful in leishmanial spindle cell pseudotumor of the skin with presence of parasites within eccrine ducts or in leishmanial infection of endothelial cells in Kaposi sarcoma.53,54 DIFFERENTIAL DIAGNOSIS The histopathologic differential diagnosis includes

CHAPTER 23 ■ PROTOZOAL AND ALGAL INFECTIONS

HISTOPATHOLOGIC FEATURES The diagnosis of leishmaniasis ultimately depends on isolation or identification of the organism from tissue. Common to all leishmanial lesions are dermal infiltrates of large histiocytes and varying numbers of organisms. The histiocytes range from 20 to 30 μm in diameter and have abundant cytoplasm. Organisms vary in number depending on the age of the lesion and the immunologic status of the host. They are more numerous in early lesions and those arising in immunocompromised hosts. Amastigote forms (Leishman-Donovan bodies) are generally found intracellularly, singularly or in great numbers. In routine hematoxylin and eosin (H&E)-stained sections, amastigotes are 1 to 3 μm in diameter, round to oval, and nonencapsulated with a distinct cytoplasmic membrane (Fig. 23-1). Amastigotes have a round basophilic nucleus approximately 1 μm in diameter and a small basophilic rodlike kinetoplast. In Giemsa-stained sections, the nucleus is purple, and the kinetoplast is an intense red or reddish purple. Various admixtures of lymphocytes, neutrophils, and plasma cells are also present. Areas of ulceration may have pseudoepitheliomatous hyperplasia (PEH) at the edge of the ulcer and show predominantly nonspecific inflammatory infiltrates. As the lesions age, there tends to be a gradual reduction in the number of both organisms and histiocytes. A granulomatous infiltrate containing epithelioid cells and multinucleated giant cells develops; caseous necrosis is notably absent.39 The pigmented lesions show varying amounts of melanin deposition with admixtures of lymphocytes, histiocytes, and plasma cells in the upper dermis. Organisms are sparse and may not be found in some lesions. Erythematous macular lesions tend to have a more cellular dermal infiltrate with a prominent plasma cell component. Organisms are

519

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American trypanosomiasis, histoplasmosis, penicilliosis, rhinoscleroma, granuloma inguinale, leprosy, and atypical mycobacteriosis. Each of these entities is characterized by an infiltrate of parasitized histiocytes admixed with chronic inflammatory cells. However, Leishmania amastigotes generally can be differentiated histologically from other organisms. Differentiation of Leishmania amastigotes from those of Trypanosoma cruzi may be quite difficult. T. cruzi amastigotes are larger (3 to 5 μm) and round to oval with a distinct cytoplasmic membrane, a round nucleus, and a basophilic kinetoplast.55 Unlike Leishmania and Histoplasma species, Trypanosoma species are able to invade mesenchymal cells and are often seen in myocytes. The diagnostic feature of histoplasmosis is the presence of yeast cells of Histoplasma capsulatum within histiocytes and occasionally within giant cells. In sections stained with H&E stain, yeast cells appear as 2- to 4-μm round to oval bodies surrounded by clear spaces. The yeast of Penicillium marneffii are elongated ovals 2 to 4 μm that divide by transverse septae. Spores of both fungi are better visualized with methenamine silver stain. They are positive to periodic acid-Schiff (PAS). In rhinoscleroma, the histiocytes (Mikulicz cells) range from 10 to 100 μm in diameter and have pale vacuolated cytoplasm containing the gram-negative bacilli Klebsiella pneumoniae rhinoscleromatis. The bacilli are 2 to 3 μm in length, appear round to oval in cross-section, and stain poorly with routine H&E staining. The organisms are much better visualized with Warthin-Starry (WS) silver impregnation. The inflammatory infiltrate is rich in plasma cells with prominent Russell bodies. The intracytoplasmic inclusions (Donovan bodies) in histiocytes of granuloma inguinale are small coccobacilli (1 to 2 μm in length). The multivacuolated histiocytes may be 20 μm or more in diameter. Vacuoles contain organisms (best seen with WS). The accompanying inflammatory infiltrate is rich in plasma cells with fewer lymphocytes and scattered neutrophils. The histologic spectrum seen in leprosy varies with the type of disease. Histiocytes have abundant foamy or vacuolated cytoplasm, may be epithelioid, and are often separated from the epidermis by a narrow grenz zone. The histiocytes may be scattered among other inflammatory cells in the dermis or form granulomas. The granulomas tend to be elongated and course along

nerves. Organisms stain poorly with Ziehl-Neelsen stain and are best seen with a Fite-Faraco acid-fast stain. They appear as red-staining bacilli measuring approximately 0.5 by 5.0 μm, primarily within histiocytes. Atypical mycobacteriosis also has a varied histologic appearance. Earlier lesions show dermal infiltrates of histiocytes, lymphocytes, and neutrophils with occasional microabscess formation. As the lesions age, epithelioid and tuberculoid type granulomas as well as Langhans giant cells are noted. Epithelial hyperplasia and hyperkeratosis may also be present. Variable numbers of organisms primarily within histiocytes are seen in acid-fast–stained sections. Anti-leishmaniasis immunohistochemistry can differentiate Leishmania species from T. cruzi, H. capsulatum, P. marneffei, and Toxoplasma gondii. Although H. capsulatum, P. marneffei, and T. gondii lack the characteristic kinetoplast found in Leishmania species, the kinetoplasts are sometimes difficult to identify on paraffin sections and are not observed in every parasite because of the plane of section. In the absence of immunohistochemical analysis using specific antibodies, it may be difficult to distinguish the trophozoites of T. gondii from the amastigotes of Leishmania species.

TRYPANOSOMIASIS Trypanosomiasis in humans is caused by two distinctly different species of the genus Trypanosoma. T. brucei gambiense and T. brucei rhodesiense are the etiologic agents of African sleeping sickness in western, eastern, and central Africa. T. cruzi is responsible for American trypanosomiasis (Chagas disease) and extends from the southern parts of the United States through Mexico and Central America and as far south as Argentina. The highest prevalence is in Brazil. During the past decade, effective eradication programs have drastically reduced vector transmission of T. cruzi in many previously endemic areas.56,57 African trypanosomiasis is transmitted by the bites of male and female tsetse flies of the genus Glossina. Glossina palpalis and G. tachinoides most frequently transmit T. brucei gambiense; G. pallidipes and G. morsitans are the usual vectors for transmission of T. brucei rhodesiense. T. brucei gambiense is limited by the habitat of its vectors to forest belts, especially along rivers in tropical west and central Africa, and has no known animal reservoirs. The vectors of T. brucei rhodesiense are game-feeding

tsetse flies that breed along lightly covered brush. The Rhodesian disease is typically confined to eastern Africa in the savanna areas where cattle are raised. T. brucei rhodesiense has several animal reservoirs (bushbuck, hartebeest, domestic ox, sheep). Humans are incidentally infected.56 In the African forms of the disease, trypanosomes ingested by the fly during a blood meal reproduce in the midgut. Infective trypomastigotes are passed into the bite wound when the fly feeds and proliferate locally in the dermis. From there, they enter the dermal lymphatics or general circulation. T. brucei gambiense and T. brucei rhodesiense do not directly invade most tissue cells but produce injurious effects on almost every tissue and organ in the body. American trypanosomiasis is transmitted by various species of the triatomid bugs (reduviid bug, “kissing bug,” or “assassin bug”). A number of mammalian hosts, including domestic animals (especially dogs and cats), rodents, armadillos, bats, and raccoons, serve as reservoirs. The reduviid bug ingests trypomastigotes while feeding on an infected animal. The parasite multiplies and matures in the GI tract of the insect. The infective trypomastigotes are located in the hindgut and are passed in the feces that are stimulated as the insect feeds. The infective feces contaminate the insect’s bite site, conjunctivae, mucous membranes, or breaks in skin. Trypomastigotes are engulfed by histiocytes or actively invade histiocytes, adipose cells, and muscle cells immediately below the inoculation site. Intracellularly, they transform into aflagellate amastigotes and proliferate until the host cells rupture. Parasites are released to invade other cells and to enter the lymphatics or bloodstream and travel to distant sites.56 Congenital transmission may occur in both African and American trypanosomiasis but is extremely uncommon at any stage in the African forms of disease. Transmission of disease by contaminated blood products and laboratory accidents also occurs.58,59 CLINICAL FEATURES There are two distinct clinical forms of African trypanosomiasis (Table 23-2). Gambian disease is characterized by prominent lymph node involvement, late invasion of the central nervous system (CNS), and a chronic progressive course that may last years before death ensures. Rhodesian disease is usually acute, with chancre, fever, and involvement of the CNS within 3 to 4 weeks. There are prominent cardiac

Table 23-2 Trypanosomiasis

symptoms and death within 3 to 6 months if the disease is untreated. In Africans, the incubation period in Gambian disease varies from a few days to several months but is typically short in Rhodesian disease and in cases involving nonAfricans. Patients are asymptomatic during the incubation period. A primary lesion, the trypanosomal chancre, may appear at the bite site within 5 to 15 days. It is more common in Rhodesian disease and in nonAfricans.60 The painful chancre appears as a red-purple nodule 2 to 5 cm in diam-

Chagas disease may pursue an acute, subacute, or chronic course. Acute disease is usually a mild febrile illness characterized by malaise, edema of the face and lower extremities, and generalized adenopathy. Amastigotes may be found in any enlarged lymph node and are most abundant in the regional nodes draining the chagoma. The acute phase resolves in 4 to 8 weeks and is followed by a latent or subacute phase of variable duration that is characterized by parasitemia and antibodies to many antigens of T. cruzi. Years to decades later, 10% to 30% of infected individuals develop the cardiac or GI symptoms of chronic Chagas disease.62 T. cruzi may also invade the CNS, and in rare cases, it cause meningoencephalitis, especially in immunocompromised hosts, including those with HIV coinfection.34 HISTOPATHOLOGIC FEATURES Definitive diagnosis of both African and American trypanosomiasis depends on demonstration of the organism in blood or tissue (biopsy or aspiration material from bone marrow, enlarged lymph nodes, and primary skin lesions). Centrifuged cerebral spinal fluid (CSF) is also a source of organisms when the CNS is affected. Trypomastigotes of T. brucei gambiense and T. brucei rhodesiense are morphologically identical and exhibit pleomorphism in human blood and CSF. Typical slender flagellates (15 to 30 μm by 1.5 to 3.5 μm) exhibit a flagellum at the anterior end and have a pointed posterior end. They have a large central nucleus, a small discrete subterminal kinetoplast, and an 8- to 30-μm flagellum that passes along the edge of an undulating membrane and projects from the anterior end. Their cytoplasm is pale and usually contains minute refractile volutin granules. Short or stumpy forms approximately 20 μm by 3.5 μm with a shorter flagellum are also noted. The nucleus and kinetoplast stain dark with a pale cytoplasm when using Giemsa, Wright, and Romanovsky stains.55 The trypanosomal chancre is characterized histologically by an intense inflammatory infiltrate of histiocytes, plasma cells, and lymphocytes with marked interstitial edema and tissue damage. There is typically vasculitis with endothelial cell proliferation, vasodilatation, perivascular mononuclear cell infiltrate with prominent plasma cells, and fibrosis. Trypomastigotes multiply within the interstitium but are difficult to visualize in routine sections stained with H&E stain.63 Overstained Giemsa sections are the preferred means of identification.

CHAPTER 23 ■ PROTOZOAL AND ALGAL INFECTIONS

Clinical Features Caused by Trypanosoma gambiense and Trypanosoma rhodesiense: African forms of the disease (Gambian and Rhodesian forms) Trypanosomal chancre—painful red-purple nodule 2-5 cm at site of bites of tsetse flies Evanescent circinate eruption resembling erythema multiforme Urticaria, erythema nodosum, painful edemas Lymphadenopathy Caused by Trypanosoma cruzi: American forms of the disease (Chagas disease) Chagoma—erythematous indurated nodule at site of bite of reduviid bug Acute, subacute, or chronic course Fever, malaise, edema of face and extremities Histopathologic Features Trypanosomal chancre and chagoma Epidermal ulceration and hyperplasia Infiltrate of histiocytes, plasma cells, and lymphocytes Vasculitis Trypomastigotes with nucleus and kinetoplast that stain with Giemsa Multiply in interstitium in cancer and intracellularly in chagoma Laboratory Evaluation Giemsa, Wright, Romanovsky stains Culture T. brucei gambiense and T. brucei rhodesiense on Tobie and Weinnan media or T. cruzi on NNN medium Differential Diagnosis Trypanosomal chancre Syphilis Chagas disease Leishmaniasis Histoplasmosis Rhinoscleroma Granuloma inguinale

eter. It is well circumscribed and indurated and may have a surrounding white halo; ulceration may occur. The lesion persists for 2 to 3 weeks and subsides spontaneously. Trypanosomes can be in aspirates from the chancre and are seen in blood films at the end of the incubation period. The infection is sometimes abortive and terminates without development of symptoms. In active disease, parasites invade lymphatic tissues with accompanying febrile attacks. Generalized lymphadenopathy occurs as the disease progresses in both Gambian and Rhodesian disease but is much less pronounced in the latter. Prominent enlargement of the posterior cervical nodes is characteristic of Gambian disease and is known as Winterbottom sign. It may not develop in Rhodesian disease. Trypanosomes are in aspirates from enlarged lymph nodes. Cutaneous signs are more common in Rhodesian disease. An irregular, circinate, evanescent rash resembling erythema multiforme appears in up to 50% of patients. It is seen commonly in nonAfricans and is typically associated with fevers. The lesions occur primarily on the trunk, shoulders, and thighs. The rash is fairly transient, lasting only a few hours, and may be associated with underlying edema and pruritus. The rash is thought to represent a type III hypersensitivity reaction. Other less common lesions include urticaria; erythema nodosum; and transient painful edemas of the hands, feet, and eyelids. Deep hyperesthesias (Kerandel sign) are reported in 20% of Europeans but are uncommon in Africans.32 The incubation period for American trypanosomiasis and Chagas disease is approximately 5 to 17 days. Organisms proliferate at the site of the infecting bite and typically produce a single primary lesion or chagoma. Hematogenous dissemination may result in multiple lesions on the trunk and extremities. The chagoma is an erythematous indurated nodule with a scale that eventually ulcerates. It attains a size of several centimeters within a few days and becomes very painful. Trypomastigotes or amastigotes may be aspirated from the chagoma in the early stages of disease. The lesion subsides gradually over 2 to 3 months. Infections occasionally occur via the conjunctival route, resulting in unilateral lacrimal sac inflammation, conjunctivitis, edema, and erythema (Romaña sign); an oculoglandular syndrome may develop. Allergic reactions to Triatoma bites may result in local erythema and, in some cases, anaphylaxis.61

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Varying degrees of epithelial hyperplasia and ulceration with associated acute inflammatory changes may also be seen. Histologic examination of enlarged lymph nodes shows follicular hyperplasia with sinus histiocytosis and infiltration by plasma cells, lymphocytes, and pale-staining mononuclear cells. Trypomastigotes develop antigenic characteristics very different from organisms in blood. Lymphocyte depletion occurs as the infection progresses.62 T. cruzi appear in blood as trypomastigotes approximately 10 days after onset of infection and in tissue as amastigotes. The trypomastigotes range from 15 to 22 μm in length. They are characteristically C or S shaped. The nucleus is usually centrally located and has a large oval kinetoplast at the extreme posterior end. The flagellum arises near the kinetoplast and passes through the margin of a delicate undulating membrane and proceeds anteriorly for approximately one-third of the body length. Amastigotes of T. cruzi are small oval bodies 3 to 5 μm in diameter. They have a discrete cytoplasmic membrane, a round to oval nucleus, and a small rodshaped kinetoplast. Amastigotes are predominantly intracellular and have a predilection for cells of mesenchymal origin; however, practically every organ of the body may be invaded. Histologically, the chagoma consists of an intense inflammatory reaction with invasion of histiocytes, adipose cells, and adjacent muscle cells by amastigotes proliferating at the inoculation site. Varying amounts of epithelial hyperplasia and ulceration may also be seen. As the parasitized host cells rupture, there is an infiltrate of neutrophils and mononuclear cells, predominantly histiocytes (Fig. 23-2). In this case of Chagas disease, there is a predominance of mononuclear cells with epidermal hyperplasia and a suggestion of an ensuing interface dermatitis (Fig. 23-3). Higher power magnification reveals structures highly reminiscent of those encountered in leishmaniasis. Note the small, rounded morphology with a discrete centrally positioned nucleus and vertically oriented kinetoplast. A lipogranuloma eventually forms after spread of organisms to regional nodes. The lymph nodes show reactive follicular hyperplasia; sinus histiocytosis; and infiltrates of plasma cells, lymphocytes, and mononuclear cells. Organisms are often difficult to find in blood and CSF in both African and American trypanosomiases. They may be present in tissue in patients with

 FIGURE 23-2 Chagas disease. In this case of Chagas disease, a predominance of mononuclear cells with epidermal hyperplasia and a suggestion of an ensuing interface dermatitis are observed. (Courtesy of Claudia I. Vidal, MD, PhD, Fellow, Dermatopathology, Mount Sinai School of Medicine.)

Chagas disease but almost never in those with African disease. T. cruzi can be cultivated on NNN medium and T. brucei gambiense and T. brucei rhodesiense on Tobie and Weinnan media. Diagnosis is

also made by inoculation of laboratory animals and xenodiagnosis. Note that small laboratory animals are less susceptible to T. brucei gambiense. Serologic techniques are available for detection of

 FIGURE 23-3 Chagas disease. Higher power magnification reveals structures highly reminiscent of those encountered in leishmaniasis. Note the small, rounded morphology with discrete centrally positioned nuclei and vertically oriented kinetoplasts. (Courtesy of Claudia I. Vidal, MD, PhD, Fellow, Dermatopathology, Mount Sinai School of Medicine.)

disease and have variable sensitivities and specificities.63-65 Species-specific PCR analysis is available and has shown to be both specific and sensitive in the molecular detection of organisms. However, these techniques have not been adapted for use in the field.66,67

TOXOPLASMOSIS T. gondii is an obligate intracellular coccidian parasite that is transmitted to humans as infective oocysts from feline feces or by ingesting the undercooked meat of infected animals68 (Table 23-3). Toxoplasmosis is a worldwide zoonosis; it is estimated that up to 50% of the adult population in some areas of the United States is infected. T. gondii is able to actively invade target cells, where it may cause cell lysis or form cysts.69,70 In immunocompetent hosts, the infection is usually arrested in the cyst stage, but cysts may persist for life. Infection may progress to active disease in immunocompromised patients (eg, HIV infection, chemotherapy, hematologic malignancies, and after organ transplantation). Reactivation rather than newly acquired infections is the major source of disease.69-71 CLINICAL FEATURES Acute infection is often asymptomatic or mild. Symptoms vary, but most patients have fever and lymphadenopathy. Cutaneous lesions are less common but have been reported in up to 10% of patients (both acute and reactivation disease).72,73 The frequency

Clinical Features Caused by Toxoplasma gondii Cutaneous manifestations in <10% of acute infections, increased in immunocompromised individuals Recurrent infections rarely presenting as cutaneous dissemination Most common presentation is a maculopapular, erythematous rash over the trunk Case reports of nodular, pustular, lichenoid, vegetative forms Histopathologic Features Nonspecific, perivascular lymphoid infiltrates Necrosis and hemorrhage variable Organisms cannot be identified in ≥ 50% of cases Diagnostic forms include: Tachyzoites, round to crescentic, 4-8 μm, intra- or extracellular Pseudocysts, intracellular Cysts, spherical, filled with bradyzoites (PAS positive) Laboratory Evaluation IgG and 1gM, toxoplasma titers (eg, Sabin-Feldman, IFA, agglutination) Differential Diagnosis Other causes of mononucleosis-like syndromes (eg, Epstein-Barr, cmv) Leishmaniasis and cutaneous trypanosomiasis (reaction, lack of kinetoplast in T. gondii) Histoplasmosis (staining characteristics)

is higher in severe or disseminated cases and those in immunocompromised hosts. Approximately 1% of cases of acute mononucleosis-like syndrome are due to acute toxoplasmosis. The most common cutaneous manifestation is a maculopapular, erythematous rash involving the trunk. When the extremities are involved, the palms and soles are usually spared. Other lesions described in documented cases include nodular, purpuric, papulopustular, lichenoid, vegetative, erythema multiforme-like dermatitidis72,73 and one case of panniculitis74 in an AIDS patient. Dermatomyositis and polymyositis are serologically linked to toxoplasmosis. HISTOPATHOLOGIC FEATURES The histologic features vary with the clinical presentation. Findings in the maculopapular rash are nonspecific, consisting of a

perivascular and periadnexal lymphocytic infiltrate; vasculitis with necrosis and hemorrhage are reported in isolated cases. The case of panniculitis showed mixed septal and lobular infiltrate of lymphocytes and histiocytes with scattered neutrophils.74 Some immunocompromised patients have little or no inflammatory response. Definitive diagnosis requires visualization of the characteristic tachyzoites, pseudocysts, or cysts in tissue. Diagnosis is frequently based on identification of organisms from other sites such as brain (the most common site of infection), bone marrow, or lung or by serology (although not, specific, IgM may indicate acute infection).75 Although rare, epidermotropic toxoplasmosis has been described; the histology of the papular purpuric nodules showed acanthosis and dyskeratosis with tachyzoites and pseudocysts identified in all levels of the epidermis.72 Tachyzoites actively enter cells, especially those of the reticuloendothelial system, and are found intracellularly or in areas of necrosis. They measure 4 to 8 μm by 2 to 3 μm on touch preparations but are smaller and more rounded in fixed tissue. H&E staining is usually adequate, although tachyzoites may be difficult to identify. Tachyzoites are only weakly PAS positive and are not argyrophilic. Pseudocysts are intracellular colonies of zoites that fit the contour of the parasitized cells, giving them an irregular shape. Pseudocysts measure from 8 to 30 μm in greatest dimension. True cysts are spherical in most tissue but elongate in muscle. They contain hundreds of tightly packed bradyzoites; the cyst membrane is thin, slightly eosinophilic, and argyrophilic. Bradyzoites appear as small blue structures with little visible cytoplasm; they are strongly PAS positive. Immunohistochemical techniques using antitoxoplasmic antibodies greatly increase the sensitivity and specificity of light microscopy.9,10,76,77 Because free parasitic forms can be confused with cellular or nuclear debris on H&E stain, immunolabeling may be required to demonstrate the trophozoites, particularly in unusual localizations,77-79 but even with this method, diagnostic forms of T. gondii are detectable in fewer than half of cutaneous biopsies. Electron microscopy identifies the diagnostic structures of T. gondii, but tachyzoites are difficult to find in light infections. PCR has been used for the identification of T. gondii in formalin-fixed, paraffin-embedded tissue but seems to be less specific than immunohistochemistry.80,81

CHAPTER 23 ■ PROTOZOAL AND ALGAL INFECTIONS

DIFFERENTIAL DIAGNOSIS The vascular changes seen in the trypanosomal chancre resemble those in secondary syphilis. Endothelial proliferation, vasodilatation, and prevalent plasma cells in the perivascular infiltrate are seen in both diseases. Organisms also may be difficult to see in both and require special stains. A Giemsa stain helps identify trypanosomes, and a WS silver impregnation is necessary for identification of spirochetes. Syphilis serologies should be reactive. The differential diagnosis for American trypanosomiasis includes leishmaniasis, histoplasmosis, rhinoscleroma, and granuloma inguinale. The special features of each of these entities have already been discussed. The presence of a kinetoplast distinguishes T. cruzi from organisms lacking this structure. Differentiating American trypanosomiasis from leishmaniasis may be difficult, but T. cruzi is larger than Leishmania species and inhabits different tissues.

Table 23-3 Toxoplasmosis

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DIFFERENTIAL DIAGNOSIS Clinically, cutaneous lesions of toxoplasmosis must be differentiated from the myriad other maculopapular rashes of various etiologies. Acute seroconversion, positive titers indicative of acute infection or recrudescence, and identification of diagnostic organisms in other tissues are supportive of the diagnosis of toxoplasmosis.70,75 In most cases, the histologic findings are also nonspecific. When organisms are identified, they must be differentiated from other protozoa (Leishmania or Trypanosoma species). The host response in leishmaniasis and trypanosomiasis is sufficiently different to eliminate misdiagnosis in most cases (see previous discussion); the zoites of T. gondii also lack kinetoplasts. H. capsulatum has a similar size and infects reticuloendothelial cells but, unlike T. gondii, it usually elicits a granulomatous reaction in immunocompetent hosts. Yeast forms of H. capsulatum are surrounded by a small halo (shrinkage artifact) and are Gomori methenamine silver (GMS) positive, which are features not seen in toxoplasmosis. Intracytoplasmic inclusions of cytomegalovirus (CMV) may mimic pseudocysts; if diagnostic intranuclear inclusions of CMV are not seen, immunohistochemical stains may be used for differential diagnosis. CMV inclusions are argyrophilic.

ACANTHAMEBIASIS Acanthamoeba species (eg, A. castellani, A. culbertsoni, A. polyphaga, A. palestinensis, A. rhysodes A. astronyxis, and rarely A. lenticulata) and Balamuthia mandrillaris (formerly known as Leptomixid), are freeliving amoebae found in soil and water throughout the world. Species that are able to tolerate temperatures above 37°C are most likely to cause human disease. Most infections are caused by three or four genotypes; T4 is the most common genotype in the environment and causes most cases of corneal and cutaneous infections.82 Multiplication occurs in the trophozoite stage by binary fission. Both cyst and trophozoite stages exist in nature and are identifiable in tissue sections. Transmission occurs via the respiratory mucosa or contamination of skin lesions; spread is hematogenous. Acanthamoeba and Balamuthia infections are increased in contact lens wearers and immunocompromised hosts.83-89

524

CLINICAL FEATURES Granulomatous meningoencephalitis and keratoconjunc-

tivitis are the classic clinical presentations, but chronic skin lesions may occur before or coincidental with CNS disease in a significant percentage of patients (Table 23-4). Infections have been limited to the skin in patients with AIDS. Skin lesions start as papules and nodules (cutaneous and subcutaneous), are usually multiple as well as multifocal, and may appear in crops. Lesions may be painful or nontender, indurated, violaceous to erythematous, and may progress to draining pustules and ulcers. The ulcers are poorly demarcated; have elevated borders; often with an eschar; and eventually heal. Reported sites have included the trunk, face, and extremities; several cases were disseminated and have occurred in transplant patients; secondary bacterial infection is also reported.88-94 HISTOPATHOLOGIC FEATURES In papular lesions, the epidermis is usually intact (see Table 23-4). Mild perivascular inflammation with lymphocytes and scattered histiocytes may progress to

Table 23-4 Acanthamebiasis

Clinical Features Caused by Acanthamoeba species and leptomixids (Balamuthia mandrillaris) Most cases in immunocompromised (HIV-infected) hosts Papules, ulcers, and nodules (cutaneous and subcutaneous) Variably painful Hematogenous dissemination with multiple, sometimes generalized eruptions Can involve trunk, face, and extremities Histopathologic Features Granulomatous inflammation or ulcers and abscesses Vasculitis, sometimes leukocytoclastic Trophozoites measure 8-25 μm, have characteristic “bull’s-eye” karyosome Cysts have wrinkled ectocyst (argyrophilic) Immunohistochemical and electron microscopy aid in identification of species Laboratory Evaluation Culture on nonnutrient agar Smears and aspirates can be used for wet-mount examination Differential Diagnosis Granulomatous and ulcerative infections in the immunocompromised host Blastomyces dermatitidis infection Other amebic infections

necrotizing granulomatous inflammation. A neutrophilic infiltrate may be present in the pustules, acute ulcers, and abscesses. Deep dermal and subcutaneous lesions are characterized by a marked cellular response consisting of histiocytes, lymphocytes, plasma cells, eosinophils, and scattered giant cells, often with a leukocytoclastic vasculitis. There may be an associated lobular or necrotizing panniculitis.92 Skin lesions in severely immunocompromised hosts show an altered response with lack of giant cells and only poorly formed granulomas. Variable numbers of organisms are seen throughout the lesion and often surround dermal vessels. Acanthamoeba and Balamuthia trophozoites measure 15 to 45 μm in tissue. Both trophozoites and cysts are seen on H&E staining. Cysts have a double-contoured wall, or ectocyst, that is wrinkled after fixation (Fig. 23-4). The ectocyst is best seen with silver impregnation, PAS, or calcofluor white stain. Acanthamoeba have a large nucleus with a single prominent central karyosome (nucleolus) that has a bull’s-eye appearance. Balamuthia also have a large nucleus that frequently contains two karyosomes. The genus and species cannot be determined by morphologic features; immunohistochemical stains, electron microscopy, culture, or PCR (gene amplification) is required, although they are rarely used in routine clinical settings.86,93-96 DIFFERENTIAL DIAGNOSIS In immunocompromised hosts, Acanthamoeba infection must be differentiated from other papulonodular and ulcerative lesions, including many parasitic, fungal, bacterial, and viral infections. Most of these can be ruled out by biopsy, direct examination, or culture of material from the lesion. E. histolytica produces painful ulcers that are seen most often in the perineal or perianal areas rather than on the face or extremities. The trophozoites of E. histolytica overlap in size with Acanthamoeba and Balamuthia species, but they have a smaller nucleus with a barely perceptible karyosome and do not produce cysts in tissue. Acanthamoeba cysts may be confused with Blastomyces dermatitidis; the yeast are slightly smaller and have broad-based budding and multiple nuclei and lack the prominent karyosome of the amoebae. The zygospore of Basidiobolus ranarum, when seen in isolation in tissue, can mimic the appearance of trophozoites of Acanthamoeba or Balamuthia species; the differential diagnosis requires identification of the other fungal elements. Other

Table 23-5 Entamebiasis

protozoa, deep fungi, and mycobacteria can be ruled out based on the size and morphology of the organisms; many fungal infections show PEH and dermal microabscesses. The deep dermal abscesses may be confused clinically with furunculosis, but the latter is centered on the hair follicle rather than blood vessels. Macrophages may be confused with trophozoites, but nuclear morphology and immunohistochemical stains can be used as diagnostic aids.

AMEBIASIS E. histolytica is a pathogenic intestinal amoeba that is usually acquired via the fecal–oral route through ingestion of cysts. Prevalence rates are highest in areas where sanitation is poor, such as developing countries. Most infected individuals are asymptomatic cyst passers; the parasite resides in the colon but does not invade the mucosal tissues. Risk factors for disease include very young age (neonates); pregnancy and postpartum states; corticosteroids; and immunosuppression due to malnutrition, malignancy, chemotherapy, and HIV/AIDS.97 In most symptomatic patients, E. histolytica causes colitis or proctitis, but severe cases may spread to the liver, lung, skin, or subcutaneous tissue. Cutaneous involvement results from several mechanisms, including direct extension of a bowel infection to the anogenital region; at sites of perforation or fistulization of hepatic, pleural, or enteric abscesses; and as a consequence

of surgical interventions. Genital (cervical, vulvovaginal, or penile) ulcers may also occur, especially in patients who practice anal-receptive intercourse or have poor hygiene. Rare cases of primary inoculation of the skin of the orbit, face, and legs are reported from contact with contaminated material.68,97-100 CLINICAL FEATURES Anogenital lesions present as serpiginous or spreading ulcers with well-demarcated, raised borders that are frequently undermined (Table 23-5). The ulcer crater contains necrotic slough, a sanguinopurulent exudate, and granulation tissue. Ulcers are often painful and have a variable course (weeks to years). Rapid, fatal spread has been reported in young patients and those with compromised immune status. Some patients develop granulomas (amebomas), polypoid lesions, or marked PEH resembling a condyloma (which may be clinically mistaken for carcinoma). Infection and malignancy may coexist, and secondary bacterial infection occurs. Superficial lesions usually have concomitant visceral lesions with contiguous spread or perforation.98 HISTOPATHOLOGIC FEATURES The lesions themselves are nonspecific. E. histolytica, as the name implies, cause tissue lysis with ulceration. The ulcer has a necrotic base with acute and chronic inflammation, granulation tissue, and edema (see Table 23-5). In chronic lesions, granulomas and fibrosis may be prominent.

Superficial lesions show spongiosis, PEH, liquefaction necrosis, ulceration, and fissures with invasive trophozoites. Varying degrees of acanthosis and papillomatosis are present at the epithelial margin. Deep lesions have deep dermal and subcutaneous liquefaction necrosis with suppuration and vasculitis.98-101 Trophozoites are seen in the areas of inflammation or at the interface between necrotic and viable tissue. They measure 15 to 25 μm, have fine granular cytoplasm and phagocytized erythrocytes, and are usually isolated from the surrounding tissue by a small space (shrinkage artifact). The nucleus is small and round with a uniform blue ring of chromatin along the nuclear membrane; it may not be visible in all sections. The nucleus contains a single tiny karyosome that frequently is not observed. For the experienced observer, the organisms are seen easily with H&E staining (Fig. 23-5) but may be easier to locate using PAS stain. Material from the ulcer edge can also be examined directly using iron hematoxylin or trichrome stain. DIFFERENTIAL DIAGNOSIS The ulcers must be differentiated from other anogenital or cutaneous ulcers (eg, syphilis, chancroid, or herpes) by biopsy or direct

CHAPTER 23 ■ PROTOZOAL AND ALGAL INFECTIONS

 FIGURE 23-4 Acanthamoebiasis. Trophozoites and cysts are present. Note the wrinkled ectocyst and the prominent nuclear karyosome.

Clinical Features Caused by Entamoeba histolytica Increased frequency in patients with poor hygiene, severe dysentery, or immunosuppression Due to direct extension of invasive intestinal disease (most common), rupture or fistulization of hepatic or pleural abscesses, direct contamination (rare) Painful, necrotic ulcers Epithelial hyperplasia common Histopathologic Features Ulcerative dermatitis with acute and chronic inflammation Granulomata, marked pseudoepitheliomatous hyperplasia may be present Trophozoites easily identified in tissues, ≥15-25 μm Typical nuclear structure with smooth rim of chromatin on nuclear membrane Laboratory Evaluation Direct smears stained with iron-hematoxylin or trichrome Serologic tests are often nondiagnostic Differential Diagnosis Genital ulcer diseases

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Table 23-6 Protothecosis and Chlorellosis

 FIGURE 23-5 Entamoeba histolytica. On oil immersion, multiple trophozoites can be seen. Note the lack of cohesion, the thin rim of nuclear chromatin, and the erythrophagocytosis.

smear. Pseudoepitheliomatous lesions can mimic carcinomas or condylomas. Trophozoites of E. histolytica can be differentiated from macrophages by their nuclear configuration; the nuclei of macrophages are convoluted and have an irregular distribution of chromatin.

PROTOTHECOSIS AND CHLORELLOSIS Protothecosis is a rare exogenous, nontransmissible infection caused by the achlorophyllic algae Prototheca wickerhamii and P. zopfii. Both species are ubiquitous in soil, contaminated water, and vegetation.102 The index case of human protothecosis was reported in a rice farmer from Sierra Leone in 1964.103 There are now more than 100 cases recorded in the world literature104-107; they have come from almost all continents in both tropical and temperate climates. Cases have been reported in HIV-infected individuals.105,108-110 Chlorella species are chlorophyllic or green algae. Although chlorellosis has been described in several animal species, there is only one published report involving a human.102

526

CLINICAL FEATURES Three clinical syndromes are associated with Prototheca infection: a localized infection of the olecranon bursa in patients with normal immunity and an eczematoid dermatitis or disseminated disease in immunocompromised individuals (Table 23-6). Disseminated infections have involved

subcutaneous tissue, lymph nodes, deep organs, and meninges (in an HIVinfected individual). Use of topical steroids may predispose some individuals to a localized skin lesion.107 Many infections have been associated with trauma or contact with contaminated water, but the source of the infection is often unknown. Protothecosis of the olecranon bursa develops several weeks after injury to the elbow. There is local swelling or thickening of the bursa, development of draining sinuses, and epithelial hyperplasia. Systemic symptoms are not reported. In the cutaneous and subcutaneous forms, single or multiple lesions are seen, usually over an exposed surface of the body such as the face or limbs. The lesions develop slowly, spread centrifugally, and do not resolve. Typical lesions are indurated and maculopapular with an overlying crust and may have focal ulceration. Other reported presentations included verrucous, herpetiform, pyoderma-like, and chromomycosis-like eruptions.107-113 HISTOPATHOLOGIC FEATURES In olecranon bursitis, the histopathologic changes include areas of caseation necrosis surrounded by granulation tissue, Langhans giant cells, and fibrosis (see Table 23-6). Prototheca organisms are scattered throughout the areas of caseation. In cutaneous lesions, the inflammatory response varies from minimal to necrotizing granulomas and appears related to the depth of the invasion. The organisms

Clinical Features Caused by Prototheca wickerhamii or Prototheca zopfii Rare, ≈100 reported cases worldwide Majority of cases in adults, men slightly > women Associated with contaminated water or soil Two syndromes: Olecranon bursitis in immunocompromised host Chronic eczematoid dermatitis Histopathologic Features Granulomatous inflammation, may have caseous necrosis in bursa Severity of skin lesions related to depth of invasion Organisms in areas of necrosis Diagnostic features include Size (P. wickerhamii, 2-12 μm; P. zopfii 10-25 μm) Septation and morula formation Stain well with fungal stains Species identification by immunofluorescence Confirmation by electron microscopy Laboratory Evaluation Culture on Sabouraud medium Sugar assimilation Differential Diagnosis Olecranon bursitis is clinically unique Granulomatous dermatitides (eg, fungal, mycobacterial) Chromomycosis

may be in any or all layers of the skin and may be single or in clusters, extracellular, or within giant cells. Although the organisms are usually apparent on routine staining with H&E stain, they are much better seen with fungal stains such as GMS, PAS, and Gridley fungus. These spherical, unicellular organisms with hyaline sporangia reproduce asexually by internal septation and cytoplasmic cleavage. P. wickerhamii is smaller and measures from 2 to 12 μm in diameter; P. zopfii measures from 10 to 25 μm. P. wickerhamii divides to form characteristic morulas (Fig. 23-6), a form usually not produced by P. zopfii. Fluorescence immunoassay aids in determining the species; specific antisera for each of the Prototheca species are available and can be used on either fresh or formalin-fixed tissue. Chlorella species are similar to Prototheca species but can usually be differentiated in tissue sections by immunohistochemical staining or the presence of chloroplasts (seen with the GMS and PAS

methods or on electron microscopy). Material from skin scrapings, biopsies, and aspirates can be cultured on Sabouraud medium and require 1 to 2 days for growth. Differentiation is done by sugar assimilation tests. DIFFERENTIAL DIAGNOSIS Protothecosis of the olecranon bursa is quite specific clinically and can be confirmed by biopsy, wet mount, or culture. Cutaneous protothecosis must be differentiated from other granulomatous diseases; biopsy or culture is required. Prototheca species are distinguished from Cryptococcus neoformans, Coccidioides immitis, B. dermatitidis, and other fungi by the type of division. In rare cases mimicking chromomycosis113 or if typical morula or septate forms are not seen, immunofluorescence studies can be performed.

MICROSPORIDIOSIS There have been only a few reported case of cutaneous microsporidiosis. One lesion presented as a nodular skin lesion overlying osteomyelitis in a patient with AIDS. The patient had disseminated Encephalitozoon intestinalis; protozoa were found in the skin nodule.114 Brachiola algerae was identified in the dermis of a child with leukemia.115 A number of genera of Microsporidans cause keratitis,116 but these are not discussed here. The organisms are seen with H&E staining, but tissue Gram stains (Brown-Hopps or Brown-Brenn) or WS stain is preferred. Electron microscopy and immunostaining

are required to determine the genus and species.116,117

GIARDIASIS Giardiasis is the most common cause of protozoal diarrhea in humans, accounting for 2 to 8 million infections annually. Skin infections are not described, but some patients develop urticaria, angioedema, atopic dermatitis, lichen-planus-like skin and mucocutaneous eruption, and erythema nodosa. These conditions may be due to a Th2 response.118

RHINOSPORIDIOSIS Rhinosporidium seeberi, previously considered a fungus, has been reclassified as a Mezomycetozoa, a clade between the fungi and protozoa.119 It has been reported to cause disseminated granulomatous disease.120

REFERENCES 1. Ehrlich GD, Alexa-Sirko D: PCR and its role in clinical diagnostics, in Ehrlich GD, Greenberg SI (eds). PCR-Based Diagnosis in Infectious Disease. Boston: Blackwell Scientific Publications; 1994:3. 2. Figueroa ME, Rasheed S: Molecular pathology and diagnosis of infectious diseases. Am J Clin Pathol. 1994;95:21. 3. Fredricks DN, Relman DA: Applications of polymerase chain reaction to the diagnosis of infectious diseases. Clin Infect Dis.1999;29:475. 4. Naber SP: Molecular pathology: diagnosis of infectious disease. N Engl J Med. 1994;331:1212.

CHAPTER 23 ■ PROTOZOAL AND ALGAL INFECTIONS

 FIGURE 23-6 Prototheca wickerhamii. Gomori methenamine silver impregnation of olecranon bursa biopsy reveals the pleomorphic organisms. Note the classic morula or “daisy” form.

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42. Harris E, Kropp G, Belli A, et al: Singlestep multiplex PCR assay for characterization of New World Leishmania complexes. J Clin Microbiol. 1998;36:1989. 43. Cruz I, Canavate C, Rubio JM, et al: A nested polymerase chain reaction (Ln-PCR) for diagnosing and monitoring Leishmania infantum in patients coinfected with human immunodeficiency virus. Trans R Soc Trop Med Hyg. 2002;96(suppl 1):S185. 44. Ramos A, Maslov DA, Fernandes O, et al: Detection and identification of human pathogenic Leishmania and Trypanosoma species by hybridization of PCR-amplified miniexon repeats. Exp Parasitol. 1996;82:242. 45. Adhya S, Hassan MQ, Mukherjee S, et al: Visceral leishmaniasis in India: promises and pitfalls of PCR-based blood test. Trans R Soc Trop Med Hyg. 2002;96(suppl 1):179. 46. Saltoro P, Sreenivas G, Pogue GP, et al: Development of a species-specific PCR assay for detection of Leishmania donovani in clinical samples from patients with kala-azar and post-kala-azar dermal leishmaniasis. J Clin Microbiol. 2001; 39:849. 47. Rodriguez N, De Lima H, Aguilar CM, et al: Molecular epidemiology of cutaneous leishmaniasis in Venezuela. Trans R Soc Trop Med Hyg. 2002;96(suppl 1): S105. 48. Medeiros AC, Rodrigues SS, Roselino AM: Comparison of the specificity of PCR and the histopathological detection of Leishmania for the diagnosis of American cutaneous leishmaniasis. Braz J Med Biol Res. 2002;35:421. 49. Ramieriz JR, Agudelo S, Muskus C, et al: Diagnosis of cutaneous leishmaniasis in Columbia: the sampling site within lesions influences the sensitivity of parasitologic diagnosis. J Clin Microbiol. 2000;38:3768. 50. Robinson RJ, Agudelo S, Muskus C, et al: The method used to sample ulcers influences the diagnosis of cutaneous leishmaniasis. Trans R Soc Trop Med Hyg. 2002;96(suppl 1):S169. 51. Evans TG: Leishmaniasis. Infect Dis Clin North Am. 1993;7:3:527. 52. Hofman V, Marty P, Perrin C, et al: The histological spectrum of visceral leishmaniasis caused by Leishmania infantum MON-1 in acquired immune deficiency syndrome. Hum Pathol. 2000;31:75-84. 53. Perrin C, Michiels JF, Bernard E, et al: Cutaneous spindle-cell tumors due to Mycobacterium gordonae and Leishmania infantum. An immunophenotypic study. Am J Dermatopathol. 1993;15:553. 54. Abajao P, Buezo GF, Fraga J: Leishmaniasis and Kaposi’s sarcoma in HIV-infected patient. Am J Dermatopathol. 1997;19:101. 55. Conner DH, Neafie RC, Dooley JR: African trypanosomiasis, in Binford CH, Connor DH (eds). Pathology of Tropical and Extraordinary Diseases. Washington, DC: Armed Forces Institute of Pathology; 1976:252. 56. Kirchhoff LV. Trypanosoma species, in Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas and Bennett’s Principles and Practice of Infectious Disease, 6th ed, vol 2. New York: Churchill Livingstone; 2005:3156. 57. Sabino EC, Goncalez TT, Salles NA, et al: Trends in the prevalence of Chagas’

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90. May L, Sidhu G, Buchness M: Diagnosis of Acanthamoeba infection by cutaneous manifestations in a man seropositive to HIV. J Am Acad Dermatol. 1992;26:352. 91. Torno MS, Babapour R, Gurevitch A, et al: Cutaneous acanthamoebiasis in AIDS. J Am Acad Dermatol. 2000;42:351. 92. Rosenberg AS, Morgan MB: Disseminated acanthamoebiasis presenting as lobular panniculitis with necrotizing vasculitis in a patient with AIDS. J Cutan Pathol. 2001;28:307. 93. Paltiel M, Powell E, Lynch J, et al: Disseminated cutaneous acanthamebiasis: a case report and review of the literature. Cutis. 2004;73:241. 94. Deetz TR, Sauwyer MH, Billman G, et al: Successful treatment of Balumuthia amoebic encephalitis: presentation of 2 cases. Clin Infect Dis. 2003;37:1304. 95. Schroeder JM, Booton GC, Hay J, et al: Use of subgenic 18S ribosomal DNA PCR and sequencing for genus and genotype identification of acanthamoebae from humans with keratitis and from sewage sludge. J Clin Microbiol. 2001;39:1903. 96. Lehmann OJ, Green SM, Morlet N, et al: Polymerase chain reaction analysis of corneal epithelial and tear samples in the diagnosis of Acanthamoeba keratitis. Invest Ophthalmol Vis Sci. 1998;39:1261. 97. Ravdin J, Stauffer WM: Entamoeba histolytic (Amebiasis), in Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas and Bennett’s Principles and Practice of Infectious Disease, 6th ed, vol 2. New York: Churchill Livingstone; 2005:3097. 98. Ramdial PK, Calonje E, Singh B,, et al: Amebiasis cutis revisited. J Cutan Pathol. 2007;34:620. 99. Connor DH, Neafie RC, Meyers WM: Amebiasis, in Binford CH, Connor DH (eds). Pathology of Tropical and Extraordinary Diseases. Washington, DC: Armed Forces Institute of Pathology; 1976:308. 100. Jackson TFHG, Gathiram V: Amebiasis, in Strickland TG (ed). Hunter’s Tropical Medicine, 8th ed. Philadelphia: Saunders; 2000:577. 101. Magaña M, Magaña ML, Alcantara A, Perez-Martin MA. Histopathology of cutaneous amebiasis. Am J Dermatopathol. 2004;26:280. 102. Chandler FW, Watts JC: Protothecosis and infections caused by green algae, in Pathologic Diagnosis of Fungal Infections, 2d ed. Chicago: American Society of Clinical Pathologists; 1987:43. 103. Davies RB, Spencer H, Wakelin PV: A case of human protothecosis. Trans R Soc Trop Med Hyg. 1964;58:448. 104. Nelson AM, Neafie RC, Connor DH: Cutaneous protothecosis and other extraordinary “aquatic-borne” cutaneous infections, in Mandojano RM (ed). Clinical Dermatology (Aquatic Dermatology). Philadelphia: Lippincott; 1987:76. 105. Wirth FA, Passalacqua JA, Kao G: Disseminated cutaneous protothecosis in an immunocompromised host: a case

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report and literature review. Cutis. 1999;63:185. Naryshkin S, Frank I, Nachamkin I: Prototheca zopfii isolated from a patient with olecranon bursitis. Diagn Microbiol Infect Dis. 1987;6:171. Chao S-C, Hsu MM-L, Lee JY-Y: Cutaneous protothecosis: report of five cases. Br J Dermatol. 2002;146:688. Woolrich A, Koestenblatt E, Don P, et al: Cutaneous protothecosis and AIDS. J Am Acad Dermatol. 1994;31:920. Laeng RH, Egger C, Schaffner T, et al: Protothecosis in an HIV-positive patient. Am J Surg Pathol. 1994;18:1261. Kaminaski ZC, Kapila R, Sharer LR, et al: Meningitis due to Prototheca wickerhamii in a patient with AIDS. Clin Infect Dis. 1992;15:704. Tyrin SK, Lee PC, Walsh P, et al: Papular protothecosis of the chest: immunologic evaluation and treatment with a combination of oral tetracycline and topical amphotericin B. Arch Dermatol. 1989; 125:1249. Kuo TT, Hsueh S, Wu JL, et al: Cutaneous protothecosis: a clinicopathologic study. Arch Pathol Lab Med. 1987;111:737. Mcanally T, Parry EL: Cutaneous protothecosis presenting as recurrent chromomycosis. Arch Dermatol. 1985;121:1066. Kester KE, Turiansky GW, McEvoy PL: Nodular cutaneous microsporidiosis in a patient with AIDS and successful treatment with long-term oral clindamycin therapy. Ann Intern Med. 1998;128:911. Visvesvara GS, Moura H, Leitch GJ, et al: Public health importance of Brachiola algerae (Microsporidia)—and emerging pathogen of humans. Folia Parasitol. 2005;52:82. Weiss LN: Microsporidiosis, in Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas and Bennett’s Principles and Practice of Infectious Disease, 6th ed, vol 2. New York: Churchill Livingstone; 2005:3237. Schwartz DA, Sobottka I, Leitch GJ, et al: Pathology of microsporidiosis: emerging parasitic infections in patients with acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1996; 120:173. Pietrzak A, Chodorowska G, Urban J, et al: Cutaneous manifestation of giardiasis—case report. Ann Agric Environ Med. 2005;12:299. Pfaller MA, Diekema DJ: Unusual fungal and pseudofungal infections of humans. J Clin Microbiol. 2005;43:1795. Tolat SN, Gokhale NR, Belgaumkar VA, et al: Disseminated cutaneous rhinosporidiomas in an immunocompetent male. Indian J Dermatol Venereol Leprol. 2007;73:343.

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76. Budka H, Costanzi G, Cristina S, et al: Brain pathology induced by infection with the human immunodeficiency virus (HIV). A histological, immunocytochemical and electron microscopy study of 100 cases. Acta Neuropathol. 1987;75:85. 77. Brouland JP, Audouin J, Hofman P, et al: Bone marrow involvement by disseminated toxoplasmosis in acquired immunodeficiency syndrome: the value of bone marrow trephine biopsy and immunohistochemistry for the diagnosis. Hum Pathol. 1996;27:302. 78. Hofman P, Quintens H, Michiels JF, et al: Toxoplasma cystitis associated with acquired immunodeficiency syndrome. Urology. 1993;42:589. 79. Jautzke G, Sell M, Thalmann U, et al: Extracerebral toxoplasmosis in AIDS. Histological and immunohistological findings based on 80 autopsy cases. Pathol Res Pract. 1993;189:428. 80. Tsai MM, O’Leary TJ: Identification of Toxoplasma gondii in formalin-fixed, paraffin-embedded tissue by polymerase chain reaction. Mod Pathol. 1993;6:185. 81. Weiss LM, Chen YY, Berry GJ, et al: Infrequent detection of Toxoplasma gondii genome in toxoplasmic lymphadenitis. A polymerase chain reaction study. Hum. Pathol. 1992;23:154. 82. Booton GC, Visvesvara GS, Byers TJ, et al: Identification and distribution of Acanthamoeba species genotypes associated with non-keratitis infections. J Clin Microbiol. 2005;43:1689. 83. Visvesvara GS, Stehr-Green JK: Epidemiology of free-living ameba infections. J Protozool. 1990;37(suppl):25S. 84. Culbertson CG: Amebic meningoencephalitides, in Binford CH, Connor DH (eds). Pathology of Tropical and Extraordinary Diseases. Washington, DC: Armed Forces Institute of Pathology; 1976:317. 85. Ma P, Visvesvara S, Martinez A, et al: Naegleria and Acanthamoeba infections: review. Rev Infect Dis. 1990;12:506. 86. Gutierrez Y: The free-living amebae: Naegleria and Acanthamoeba, in Gutierrez Y (ed). Diagnostic Pathology of Parasitic Infections with Clinical Correlations. Philadelphia: Lea & Febiger; 1990:80. 87. Singh U: Free-living amebas, in Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas and Bennett’s Principles and Practice of Infectious Disease, 6th ed, vol 2. New York: Churchill Livingstone; 2005: 3111. 88. Helton J, Loveless M, White CR Jr: Cutaneous Acanthamoeba infection associated with leukocytoclastic vasculitis in an AIDS patient. Am J Dermatopathol. 1993;15:146. 89. Tan B, Linne-Weldon M, Rhone DP, et al: Acanthamoeba infection presenting as skin lesions in patients with the acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1993;117:1043.

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CHAPTER 24 Helminthic Diseases

PART III ■ INFECTIONS

Kapil Gupta Franz von Lichtenberg Skin lesions caused by endemic worm infections continue to plague millions of people in tropical rural regions. Skin lesions caused by helminth species domestic to the United States and Europe have always been uncommon but do crop up occasionally, as do imported cases. When biopsied, such specimens are usually sent to a helminthologist for consultation, yet because such specimens fit within a small set of specific morphologic criteria, with information on patient exposure or travel, any knowledgeable pathologist should be able to arrive at a precise etiologic diagnosis, as will be outlined in this chapter. The life cycles of parasitic worms may be complex and varied, but humans can only be infected in three manners: ingestion of eggs or larvae (eg, cysticercosis), skin penetration of larvae (eg, strongyloidiasis), or a bite or sting of an insect vector (eg, bancroftian filariasis). Many vector-borne helminths are linked to a specific environment or geographic area (eg, snail-borne schistosomiasis hematobia); other helminths are

obligate parasites of nonhuman hosts that act as their reservoirs (eg, larva migrans). Therefore, helminth-infected patients should always be asked three questions: (1) Where have you been (Unde venis)?, (2) What have you eaten (Quod edisti)?, and (3) What contacts have you had with vectors and wild or domestic animals (Quod tetigisti)? At a minimum, these questions should help to clarify whether a given helminth infection is likely to have been acquired in a temperate zone or in the tropics. When a suspected helminth structure is seen microscopically, whether intact or damaged, one should first exclude the possibility of confusion with insect or plant material (Fig. 24-1). Plant cells can be recognized easily by their stiff, refringent, angular cell walls and prominent glycogen granules; insect cuticles are chitinous, thick, and pigmented and may show elaborate appendages (eg, legs or mandibles). Nevertheless, distinction between a partially destroyed worm or helminth egg and other kinds of partly digested foreign body material can sometimes be difficult. Both may appear fragmented and birefringent under polarized light and therefore distinguishable only by virtue of their microscopic contour. The most critical decision to be made regarding helminth structures in the skin concerns taxonomy, that is whether a given nematode structure belongs to the order of roundworms (nematodes),

Rule out insect material Myasis, tunga, tick part

Nematode

Adult

Temperate Dirofilaria Lagochilascaris

530

Tropical Dracunculus Onchocerca Wuchereria Brugia Mansonella Loa Loa

1. Adult nematodes in the skin can range in length from a barely visible 2 mm to 35 cm and are round and slender in contour; they have a nonsegmented body with a true collagenous epicuticle surrounding a coelomic cavity that contains their sexually differentiated reproductive organs, as well as a digestive tract with a distinct proximal

Helminth structure in skin

Rule out foreign body Splinter, mineral, plastic

Cestode

Larva

Temperate Ankylostoma

tapeworms (cestodes), or flukes (trematodes) (Fig. 24-1). In dermatopathology, that decision is relatively simple because adult tapeworms and their eggs are restricted to the gut lumen, and the only cestode life stage found in the human skin is thus a cystic larva. Second, all roundworm (nematode) species whose adult specimens are able to dwell in cutaneous tissue are viviparous (ie, they can spawn larvae but not eggs). By the same token, when noncystic helminth larvae are found in the skin, they most likely belong to a roundworm (nematode). The only skin lesion caused by trematode larvae is a transitory and rarely biopsied rash known as swimmers’ itch. Finally, adult trematodes have short life spans when arrested in ectopic sites, such as subcutaneous tissue, and therefore are seldom found intact; instead, they can usually be identified by the characteristics of their residual eggs (see Paragonimiasis). The following histologic criteria are useful for assigning specimens to each of the three helminth orders:

Cystic larva

Tropical Onchocerca Mansonella Gnathostoma

Temp-trop Cysticercus Spargasnum Coenurus

Trematode

Larva or adult

Temp-trop Schistosoma Fasciola

 FIGURE 24-1 Speciating algorithm. Algorithm proposed for speciating helminth material found in tissue sections.

Egg

Temp-trop Schistosoma Paragonimus Fasciola

from which the definitive diagnosis is then chosen by applying species-specific criteria. If the characteristics of the parasite differ from those of any listed species, consultation is advised because rare and new helminthic infections of humans are discovered from time to time and by all means should be reported.1

NEMATODE INFECTIONS

Onchocerciasis

By following the algorithmic sequence outlined in Figure 24-1 (ie, the successive definition of helminth life stage, taxonomic order, and likely site of patient exposure), the differential diagnosis of parasitic helminths can be narrowed down to a small number of possibilities

CLINICAL FEATURES Onchocercal nodules are discrete, movable, up to 5 cm across in size, and are often located close to bony prominences. Endemic onchocercal dermatitis is intensely itchy; predominantly papular and lichenoid; and if severe and untreated, may lead to cachexia and death

 FIGURE 24-2 Cross-section of an adult nematode (Enterobius vermicularis). Note the thick collagenous epicuticle (with paired alae), empty-appearing coelomic cavity, and prominent esophageal bulb (hematoxylin and eosin stain).

esophageal segment (Fig. 24-2), and with both buccal and anal openings. Invasive nematode larvae are at least one order of magnitude smaller than their corresponding adults, measuring up to 500 μm in length but no more than 10 to 30 μm in cross-section (see Strongyloidiasis). They lack sexual differentiation and show tiny, basophilic, dot-like nuclei. 2. Tapeworm larvae in the skin range in size from 1 to 10 cm. They form rounded cysts bound by a hyaline wall and contain an inwardly protruding embryo lined by a noncollagenous syncytial absorptive tegument with a brush border (“gastrodermis”). When a scolex or scolices are present (Fig. 24-3), they possess arrays of sucker plates and rostella studded with sharktoothshaped hooklets. 3. Adult trematodes (flukes) found in the skin are leaf shaped. They are nonsegmented worms with a syncytial, noncollagenous tegument showing specializations, for example, spines or tubercles, ventral sucker plate(s), a primitive gut ending in two blind bifurcations (ceca), and either hermaphroditic or sexually dimorphic reproductive organs with prominently granulated vitellaria (Fig. 24-4). Trematode eggs can have round or elliptical shells and can measure up to 140 μm in greatest diameter. Fragmented or calcified eggs, of course, are smaller. Skin-penetrating Trematode larvae, similar to those of nematodes, are

 FIGURE 24-3 Cystic cestode larva (Cysticercus cellulosae) showing scolex with hooklet bearing rostellum and internal gastrodermis (hematoxylin and eosin stain).

CHAPTER 24 ■ HELMINTHIC DISEASES

of microscopic size, but instead of a true cuticle, they have a syncytial, noncollagenous tegument, and their nuclei are larger and more distinct than those of roundworm larvae.

Synonyms: Onchocerciasis, river blindness, sowda Onchocerciasis is a chronic dermatitis accompanied by progressive keratitis, uveitis, and loss of sight (river blindness) caused by the filarial nematode Onchocerca volvulus, which is transmitted by the bite of blackflies (Simulium species). Onchocerciasis is endemic to the savannahs and rainforests of subequatorial Africa and in Yemen, Central America, and the Amazon basin of South America. The skin and eye lesions are elicited by numerous tissue-invading microfilariae spawned by relatively few adult worms dwelling in scattered subcutaneous inflammatory nodules that are walled off by dense fibrous tissue.

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PART III ■ INFECTIONS

but degenerate larvae can evoke focal microabscesses followed by granuloma formation as the dead microfilariae are broken down. Treatment with DEC results in epidermotropism and synchronized death of microfilariae and a marked systemic flareup of the skin and eye lesions (Mazzotti reaction) with eosinophilic microabscesses forming around the dying larvae. In advanced stages of eoncocerciasis, secondary skin changes appear (eg, acanthosis, parakeratosis, depigmentation, pigment phagocytosis). Finally, progressive scarring of the dermis may ensue with deposition of hyaline collage and concomitant epidermal atrophy.

 FIGURE 24-4 Adult trematode (Fasciola hepatica). Note the syncytial tegument and paired, pigmentcontaining ceca plus the egg-filled uteri (hematoxylin and eosin stain). (Courtesy of Dr. H. Zaiman.)

from intercurrent infection. Lesions are most often generalized; less frequently, especially in Yemen and the savannah regions of Africa, they are limited to a single extremity (sowda).2 Depending on their duration, the lesions can be spottily depigmented (“leopard skin”), scaly and atrophic (“lizard skin”), or thickened and hyperkeratotic (“elephant skin”). In advanced disease, patients may also have lymphedema of the groin (“hanging groin”). Onchocerciasis acquired by travelers to endemic regions is seen up to 2 years later as an itchy rash with marked peripheral eosinophilia, sometimes affecting one extremity only, as in sowda.

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HISTOPATHOLOGIC FEATURES Onchocercal nodules contain several long, tangled, and coiled worms of both sexes. In crosssection, they measure up to 450 μm in diameter, making them one of the largest human parasitic filariae (Fig. 24-5). The female worms show prominent bicornual uteri containing maturing microfilariae that are unsheathed, measuring up to 350 μm in length by 9 μm in width. In patients treated with ivermectin or diethyl carbamazine (DEC), adult worms appear largely intact, but their uteri are empty of microfilariae. Adult worms are embedded in dense granulation tissue and in mixed inflammatory cells, including macrophages and multinuclear giant cells of the foreign body type. These aggregates, in turn, are surrounded by thick layers of collagen bundles encapsulating the nodules. Microfilariae in transit toward the epidermis and cornea can be spotted

insinuating themselves between collagen fibers. Because of their slender width, microfilariae seen in cross-section may be confused with host cell nuclei. Early epidermal changes in patients with onchocerciasis may be minimal, with variable numbers of microfilariae concentrated in the papillary dermis and clusters of macrophages, plasma cells, and eosinophils surrounding vessels and adnexa. Little or no inflammation is seen around intact microfilariae (Fig. 24-6),

DIFFERENTIAL DIAGNOSIS In endemic West Africa, Mansonella streptocerca may cause epidermal lesions closely mimicking those of onchocerciasis. Indeed, Mansonella microfilariae, similar to those of Onchocerca species, are unsheathed and are found in the skin rather than the blood, but adult Mansonella worms are smaller (40 to 85 μm across) and are found singly or in pairs in nonencapsulated inflammatory foci in the reticular dermis, smaller than the prominent nodules found in oncocerciasis.3 The Calabar swellings of loiasis are itchy, localized to the extremities, and show intense eosinophil infiltration, but they evidence few epidermal changes and are fleeting in duration. Moreover, microfilariae can seldom be detected histologically in these lesions. Serodiagnosis may be useful in

 FIGURE 24-5 Onchocerca volvulus worms. Section of subcutaneous nodule containing several coiled adult O. volvulus worms that appear empty after treatment with ivermectin. Note the broad collagenous capsule (hematoxylin and eosin stain).

 FIGURE 24-6 Intact Onchocerca volvulus microfilariae in human dermis accompanied by sparse inflammatory infiltrates and mild edema (hematoxylin and eosin stain). (Courtesy of Dr H. Zaiman.)

travelers who have returned from endemic areas for differentiating early onchocerciasis from nonparasitic dermatoses associated with eosinophilia. Currently, the Centers for Disease Control and Prevention uses an enzyme-linked immunosorbent assay (ELISA) for IgG4 antibodies followed by Western blotting against a cocktail of recombinant Onchocerca antigens.4

Only a minority of heavily and repeatedly infected individuals manifest the skin pathology described here. CLINICAL FEATURES Sterile abscesses elicited by filariae are localized in the subcutis along the lymphatics draining the extremities or genitals and may be red,

HISTOPATHOLOGIC FEATURES Biopsies of subcutaneous filarial abscesses or granulomas are taken rarely, and only about half or fewer show intact worms. When present, coiled segments of W. bancrofti measure up to 150 μm in diameter; those of Asian filariae measure less than 100 μm. Intact gravid females contain bicornual uteri packed with microfilarial progeny in various stages of development (Fig. 24-7). Alternatively, only fragments of partly or totally destroyed worms may

CHAPTER 24 ■ HELMINTHIC DISEASES

hot, and painful or erupt through the skin much like bacterial abscesses. Episodes of acute lymphedema may be accompanied by fever, peripheral eosinophilia, and patient anxiety or depression; filarial fevers are fleeting but tend to recur, with lymphedema or hydrocele eventually turning chronic. Unless hygienic precautions are taken, chronic filarial lymphedema can then become superinfected by bacteria or fungi, resulting in marked enlargement of the extremity with verrucous epidermal change, hyperkeratosis, and a thickened fibrotic dermis, a condition known as elephantiasis. Filarial skin lesions tend to be bilateral but asymmetric; the external genitalia and lower extremities are affected most often, except in Pacific foci, in which lymphedema of the arm and mammary region is frequent.

Lymphatic Filariasis Synonyms: Bancroftian filariasis, Malayan filariasis Lymphatic filariasis is defined as infection by one of the mosquito-borne filarial species Wuchereria bancrofti, Brugia malayi, B. pahangi, or B. timori, whose long and threadlike adult worms dwell inside human lymph vessels, or nodes, or both while their microfilariae circulate in the bloodstream. The skin lesions caused by these filariae may be due to (1) focal inflammation around adult worms located in dermal lymphatics (filarial abscess, granuloma, or both); (2) lymph stasis and edema elicited by these worms or their antigens, with or without bacterial or fungal superinfection (filarial lymphedema, elephantiasis); or (3) systemic allergic responses to worm or microfilarial antigens (tropical eosinophilia, occult filariasis). Of the four lymphatic filariae, W. bancrofti is the most widely distributed throughout the wet tropics, with multiple strains of varying diurnal or nocturnal microfilarial periodicity; the other three species are focalized to the western Pacific and Asia.

 FIGURE 24-7 Wuchereria bancrofti. Intact female W. bancrofti in an inguinal lymphatic vessel. Note the maturing intrauterine microfilariae and the surrounding eosinophil-enriched inflammatory exudate (hematoxylin and eosin stain).

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PART III ■ INFECTIONS

be found after serial sectioning. These are typically birefringent and strongly periodic acid-Schiff–positive; occasionally, both intact and disintegrating worm segments may coexist. Microfilariae must be diligently searched for, especially when adult worms cannot be found; their number is usually small, and their profile in cross-section can be as narrow as 7 μm. Indeed, their minute, speckled nuclei do mimic host nuclear chromatin. Microfilariae are found only rarely outside small vessels and can also be seen scattered in the lumina of venules in the skin of asymptomatic individuals without any host inflammatory reaction at all. If a skin lesion shows neither macronor microfilariae detectable by histology, certain features can still suggest filarial infection, such as the presence of 20 percent or more eosinophils with Charcot-Leyden crystals in an abscess or granuloma surrounded by a wide halo of inflammatory edema and by lymph vessels showing either extensive ectasia or endolymphangitis of the polypoid or occlusive type 5 (Fig. 24-8). However, older filarial lesions evolving toward healing and scarring may show few or no distinctive histologic markers even when clinical evidence clearly points to filariasis. In essence, the histologic features mentioned in the few existing descriptions of chronic filarial lymphedema and elephantiasis are similar to those of nonfilarial lymphedema and elephantiasis. The histologic features include lymphangiectasia

and tortuosity of lymph vessels, sparse chronic inflammation with lymphocytic predominance, and various degrees of epidermal acanthosis, hyperplasia, and hyper- and parakeratosis. The distinctive form of polypoid endolymphangitis seen in early filariasis may persist in chronic lesions, but filarial worms are found rarely because most are located upstream from edematous skin close to the groin or the axillary lymph nodes. Recent studies indicate that the cells infiltrating skin with significant filarial lymphedema are predominantly CD-3, CD-8+ T-lymphocytes.5 The landmark lesion of occult filariasis or tropical eosinophilia is the MeyersKouvenaar (MK) body (ie, a nonviable or degenerate microfilaria enveloped by a sunburst-like eosinophilic semihyaline precipitate, surrounded, in turn, by a small eosinophilic abscess or eosinophilenriched epithelioid cell granuloma). MK bodies are usually found in lymph nodes or in lung tissue rather than in the skin, accompanied by high peripheral eosinophilia and sometimes by asthma or a transient eczematoid skin rash.6

residents of the tropics. They may be accompanied by systemic symptoms and eosinophilia and may mimic fevers caused by lymphatic filariae. Loa loa microfilariae, similar to those of W. bancrofti, circulate in the bloodstream and are sheathed, but the two species can be distinguished by the number of nuclei in their tail ends. In addition, migration of adult filariae to serosal cavities or to the cornea of the eye is typical of loiasis but is extremely rare in lymphatic filariasis. Conversely, in the absence of geographic and clinical information, involuting filarial granulomas of the subcutis or lymph nodes without detectable cuticular residua can mimic mycobacterial or fungal infection. Also, testing for microfilaremia may not reliably distinguish chronic filarial from nonfilarial lymphedema because false-negative results are common in the late stages of infection; in such cases, an IgG4 antibody ELISA can be helpful. For current information on medical or surgical treatment, a recent monograph should be consulted.7

DIFFERENTIAL DIAGNOSIS In areas endemic for multiple filarial species, onchocercal hanging groin can mimic filarial lymphedema but is always accompanied by systemic dermatitis or eye lesions. Also, in contrast to O. volvulus microfilariae, those of W. bancrofti and B. malayi are sheathed and blood-borne. The Calabar swellings of loiasis typically occur in expatriates and tourists rather than in

Synonyms: Zoonotic filariasis, Dirofilaria conjunctivae infection Dirofilariasis of the skin is distinct from lung infection caused by the dog heartworm, Dirofilaria immitis. In Florida and adjacent southeastern US states, the causal agent of cutaneous dirofilariasis is D. tenuis,8 a natural parasite of raccoons; on the eastern seaboard, it is D. ursi, a parasite of bears; in Europe, it is D. repens, whose reservoirs are domestic dogs and cats. All three species are transmitted by unknown mosquito vectors. Because human beings are an accidental, nonpermissive host for dirofilariae, worms do not reach sexual maturity, and microfilariae are not generated. By the same token, skin lesions are limited to a solitary inflammatory nodule surrounding a fourthstage (larval) to fifth-stage (adult) worm.

Cutaneous Dirofilariasis

CLINICAL FEATURES The usual history is the finding of a small, newly arisen subcutaneous nodule anywhere on the body, including the extremities, eye, or genitals, that is nonpainful at first but later becoming inflamed with further growth over several weeks but without any systemic symptoms. Eosinophilia, if present, is usually mild. The nodule, labeled with miscellaneous diagnoses, is eventually excised, resulting in a permanent cure.

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 FIGURE 24-8 Polypoid endolymphangitis distal to a degenerating filarial worm. The infiltrate is rich in lymphoid cells and eosinophils (hematoxylin and eosin stain).

HISTOPATHOLOGIC FEATURES An eosinophilenriched abscess is seen surrounding multiple cross-sections of a coiled filarial

childhood disease caused by Toxocara that infects dogs and cats. Narrowly defined, cutaneous larva migrans is an acute, linear, wavy, inflammatory skin track left behind by the penetration and burrowing of larvae of the animal hookworm Ankylostoma caninum or A. braziliense, natural parasites of dogs and cats, respectively. It should be noted, however, that similar streaky skin eruptions can also be caused by other larval nematodes and even by insect larvae.

worm measuring about 200 to 350 μm across. The worm is more often degenerate than intact and has a thick, laminated cuticle with prominent bilateral internal ridges characteristic of the Dirofilaria genus (Fig. 24-9). Females show paired uteri, and males show a sex tube adjacent to the gut, but mature oocytes or sperm are never present. The abscess cavity containing the worm is walled off by granulation tissue rich in eosinophils and, in older lesions, by fibrosis, giant cells, and granulomas. DIFFERENTIAL DIAGNOSIS Before biopsy, dirofilariasis is diagnosed only if the worm is visible beneath the conjunctiva,8 but after the microscope shows a filaria with internal cuticular ridges, the diagnosis cannot be missed. Of the few adult nematodes known to infect the skin in nontropical countries, only Lagochilascaris is of comparable size, but its lesions contain multiple worms and are large and fistulizing. For the differential diagnosis of other migratory cutaneous larvae.

Dracontiasis Synonyms: Guinea worm diseases, Dracunculus infection Dracontiasis is a chronic subcutaneous inflammatory lesion caused by the stringlike but nonfilarial nematode Dracunculus medinensis. Adult guinea worms shed larvae into water by emerging through a hole in the skin; the larvae enter crustaceans of the genus Cyclops, in which they mature

to their infective stage. Humans then drink the Cyclops-infested water and thus complete the infectious cycle. Formerly a disease of many millions, today it is much reduced, even in subequatorial Africa, and has been nearly eradicated on the Indian subcontinent.1 CLINICAL FEATURES After a year-long incubation, lesions start as a single, localized reddish swelling on the leg, especially the ankle or foot; they then blister and open, permitting the head of the 15-cm-long worm to protrude. The abscess underlying the swelling is painful and incapacitating. If the worm is not removed by gradually rolling it onto a wooden stick (the caduceus), it eventually dies and calcifies, thus perpetuating the inflammation and scarring. HISTOPATHOLOGIC FEATURES AND DIFFERENTIAL DIAGNOSIS When guinea worm lesions have matured, their gross appearance is pathognomonic, and biopsies are rarely taken, except to document ectopic locations. Centrally, there are collections of neutrophils and eosinophils forming abscesses surrounded by granulation tissue and inflamed scar tissue. Worm segments, when present, can measure up to 2 mm in diameter.

Cutaneous Larva Migrans Synonyms: Creeping eruption, zoonotic hookworm infection Cutaneous larva migrans is distinct from visceral larva migrans, a systemic

HISTOPATHOLOGIC FEATURES There is no need to take a biopsy. It is known that animal hookworm larvae migrate between the basal and spinous epithelial layers in the noninflamed part of the epidermis, far ahead of the inflamed portion of the track from which biopsies usually are taken. One therefore usually visualizes only an empty intraepidermal space containing sparse exudate and surrounded by a rich neutrophilic and eosinophilic infiltrate (Fig. 24-10). Scratching of the lesion and bacterial superinfection, of course, can worsen the histologic picture markedly. DIFFERENTIAL DIAGNOSIS Cutaneous larva migrans due to animal hookworms is a self-healing condition and should be differentiated from helminthic diseases with chronic or systemic manifestations requiring treatment. These include (1) invasion of the skin by human hookworm larvae in an infected hypersensitive host; (2) larva currens (ie, skin burrowing of invasive Strongyloides larvae during chronic infection or hyperinfection), and (3) skin manifestations of Gnathostoma spinigerum, a nematode endemic in eastern Asian countries. Differential diagnostic tests should include a search for ova and larvae in excreta and the use of appropriate serologic tests. Botfly larvae invading the skin are relatively large and are usually in a superficial location; therefore, they can often be visualized directly or extracted. As a general rule, any larva found in the skin is best preserved for identification intact rather than embedded and sectioned. Streaky intraepidermal

CHAPTER 24 ■ HELMINTHIC DISEASES

 FIGURE 24-9 Dirofilaria tenuis. Segments of a fifth-stage D. tenuis embedded in an eosinophilenriched subcutaneous abscess. Note the inner cuticular ridges (hematoxylin and eosin stain).

CLINICAL FEATURES The condition occurs worldwide after skin exposure to pet excreta, often on beaches in the summer. Although the feet are the most common site, any part of the body can be affected. A single raised, itchy, erythematous track of 10 cm or more is the norm, advancing at a rate of 3.5 to 5.0 cm per 24 hours, sometimes disappearing and reappearing but ultimately destined to fade away after a couple of weeks.

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CESTODE INFECTIONS

Cutaneous Cysticercosis

PART III ■ INFECTIONS

Synonyms: Taenia solium cystic larvae, “bladder worm” Cysticerci are the cystic larvae of the tapeworm Taenia solium. Normally, adult T. solium inhabit the gut of humans, their definitive host, and cysticerci infect the tissues of its intermediate host, the pig. Humans acquire cysticercosis by accidentally ingesting T. solium eggs in uncooked food. Both intestinal tapeworm infection and cysticercosis are common in the developing world wherever pigs are raised, but the main target of cysticerci is the central nervous system (CNS), and localizations in the skin occur in only about 6% of individuals. Therefore, when cysticerci are found in the skin or muscle, they are likely to also be found in the brain, but not vice versa. Cysticercosis has a long incubation period; it can also remain asymptomatic for years, and its clinical presentation and outcome are varied and hard to predict.  FIGURE 24-10 Histologic section of a larva migrans tract. A mixed acute inflammatory exudate percolates into the tract left behind by the larva.

tunnels with eosinophilia can also be seen in early incontinentia pigmenti, but that condition occurs almost exclusively in newborns.

Other Nematode Skin Lesions: Cutaneous Strongyloidiasis (Larva Currens), Gnathostomiasis, and Lagochilascariasis

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Chronic strongyloidiasis is widespread in many developing countries. In its course, the skin is occasionally invaded by filaroid larvae entering via the perianal zone. This results in a streaky dermatitis named larva currens, which is characterized by serpiginous, itchy tracts that resemble those caused by animal hookworms (larva migrans), except for the greater speed of Strongyloides larvae (≤5 cm/h). Patients with larva currens are at risk for Strongyloides hyperinfection; careful and repeated stool examinations for larvae therefore are indicated, followed by treatment with thiabendazole. Rare instances of skin lesions due to other strongyloid soil nematodes and animal parasites have also been reported.9,10

The spirurida worm Gnathostoma spinigerum parasitizes the stomach wall of various mammals; its larvae inhabit freshwater fish. Human infection therefore is found principally in Asian countries, where uncooked or undercooked fish dishes are eaten customarily. Skin larvae induce a localized pruritic and erythematous subcutaneous induration known in China as Yangtze River edema. The swelling usually disappears spontaneously after 2 weeks but may recur in a different location. Other, more superficial lesions may resemble the tracts of larva migrans,11 but Gnathostoma larvae, when seen or excised, are considerably larger than those of hookworms. Histologically, the lesions show extensive edema with fibrinous and granulocytic exudation. Intact larvae are identifiable by their quadruple rows of pointed anterior hooklets, but classification based on histologic sections is difficult; any nematode wider than 250 μm in diameter found in the skin of a patient with a history of having ingested uncooked fish can be assumed to be G. spinigerum, and any such patient should be given a complete diagnostic workup in anticipation of surgery to remove the worm(s) if necessary.

CLINICAL FEATURES Cysticerci of the skin occur in patients with or without neurologic symptoms and may be single or multiple. They appear as rounded nodules underlying normal epidermis anywhere on the body. They are firm, elastic to the touch, and movable by lateral pressure but do not seem obviously cystic by palpation. Indeed, they are sometimes confused with small benign tumors (eg, schwannomas or fibrolipomas), but their cystic nature declares itself as soon as the overlying skin is incised. Dermal cysticerci can remain asymptomatic for many years or elicit an inflammatory flareup when the cyst degenerates and begins to leak. When treated with albendazole or praziquantel, dermal cysts become inflamed, followed by shrinkage and virtual disappearance after a couple of weeks. HISTOPATHOLOGIC FEATURES Intact, viable cysticerci elicit remarkably little inflammation. The cyst lining is a relatively thin and flat syncytial tegument with underlying mesenchyme containing myocytes and excretory ducts. The inverted scolex ends in a rostellum bearing a row of delicate birefringent hooklets flanked by two pairs of sucker caps. The inner epithelial lining of its neck is destined to become the adult tapeworm’s absorptive surface (gastrodermis). It is taller than the bladder wall, hyaline in appearance, and has microvilli forming a brush border (see Fig. 24-3). The worm’s mesenchyme is speckled

genus whose adult worms parasitize dogs and cats. Human sparganosis is acquired by ingesting water infested with small crustaceans that function as hosts of first-stage (procercoid) larvae; by ingesting uncooked reptile or fish meat already infected with pleurocercoids; or by applying such meat to the skin for medicinal purposes, as is customary in some Asian countries. Consequently, in some Eastern countries, sparganosis is far more common than coenuriasis, but it is still a rarity in the United States.13 Subcutaneous spargana are the most frequent, followed by CNS localizations.

with ovoid concretions containing central purplish dots, called calcareous bodies, that are found as well in cestodes of other species. In degenerating and dead cysticerci, all of these features are faded or totally obliterated, and the carcass of the scolex may be calcified, but hooklets and calcareous bodies persist for a long time and can usually be found if searched for (Fig. 24-11). As cysticerci degenerate and leak, they may elicit considerable inflammation of the surrounding subcutaneous tissue, with infiltration of neutrophils and eosinophils later shading into a granulomatous pattern. The final result is a centrally calcified scar.

addition, daughter cysts may be present, either swimming in the cyst fluid or budding off in a grapelike fashion from the main cyst (Fig. 24-12).

Sparganosis Synonyms: Spargana, plerocercoid tapeworm larvae Spargana are the second-stage (plerocercoid) larvae of tapeworms of the Spirometra

HISTOPATHOLOGIC FEATURES AND DIFFERENTIAL DIAGNOSIS On histology, several segments of the plerocercoid may be seen, consisting of parvicellular mesenchyma covered by a simple tegument analogous to that lining a cysticercus wall. However, there is no formed scolex other than a vestigial tegumental

CHAPTER 24 ■ HELMINTHIC DISEASES

 FIGURE 24-11 Degenerating cysticercus scolex. Note the purplish calcareous bodies (hematoxylin and eosin stain).

CLINICAL FEATURES Spargana are nonsegmented, ribbon-like worms up to 40 cm long but only 3 mm wide that are actively motile. Subcutaneous nodules rarely exceed 3 cm in width and may disappear and reappear. As long as worms are intact, there is little reaction, but eventually death occurs, causing significant local inflammation and pain and motivating surgical intervention.

DIFFERENTIAL DIAGNOSIS A cystic subcutaneous tapeworm larva of 1 to 4 cm in size bearing a single scolex is considered to be a cysticercus found in the CNS and has not been reported in skin. Larger cysts with either multiple scolices or none at all should raise the possibility of coenuriasis or sparganosis, respectively.

Coenuriasis Synonym: Dog tapeworm larva About 50 cases of coenuriasis of the human CNS or skin have been reported to date. Most represent the intermediate stage of Taenia multiceps, a dog tapeworm, or related wild-animal parasites.12 As in cysticercosis, humans acquire the infection by accidentally ingesting eggs, and the clinical and pathologic features also closely resemble those of cystic-ercosis except that the cysts are larger (≤10 cm in diameter) and contain multiple (≤100) scolices rather than a single scolex. In

 FIGURE 24-12 Gnathostoma spinigerum larva located in the upper dermis. (Reproduced with permission from Pathology of Tropical and Extraordinary Diseases, edited by Chapman H. Binford, MD and Daniel H. Connor, MD, published by the Armed Forces Institute of Pathology, Washington, DC 1976;2;474. Figure 9-14-1.)

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nodules caused by cestode larvae do not contain any eggs at all. Old Paragonimus nodules may be mistaken for mycobacterial lesions if eggs are not searched for carefully in multiple sections.14

PART III ■ INFECTIONS

Fascioliasis

 FIGURE 24-13 Subcutaneous plerocercoid of Spirometra mansonoides (sparganum). Note simple tegument and mesenchyma without scolex formation. The larva is surrounded by eosinophil-enriched exudate (hematoxylin and eosin stain).

duplication at the anterior end of the primitive larva (Fig. 24-13). The host inflammatory changes surrounding the larva vary with the state of the larva and resemble those already described in the section on cysticerci.

TREMATODE INFECTIONS

Paragonimiasis

Intact trematodes are seldom found in these lesions, but there may be residual eggs, which are thin-shelled, birefringent, operculated, and measure 80 to 118 μm in greatest diameter (Fig. 24-14). DIFFERENTIAL DIAGNOSIS Skin nodules caused by Paragonimus can be differentiated from those caused by Fasciola based on the larger egg size of the latter. Skin

Synonym: Liver fluke infection Fasciola hepatica, the common liver fluke, has a cosmopolitan distribution and infects sheep, goats, and other herbivores that consume plants on which metacercariae have been deposited by a snail intermediate host. Humans are accidental hosts, most often acquiring the infection from field-collected herbs such as watercress. During its early migration from the gut to the liver, F. hepatica can track through many sites, including the skin, thus giving rise to ectopic lesions before settling into the lumen of a large bile duct or gallbladder. Similar pathology is caused by F. gigantica, a closely related but larger fluke found mainly in the tropics. CLINICAL FEATURES Early fascioliasis may be accompanied by fever, abdo-minal pain, urticarial rash, and high peripheral eosinophilia. Itchy skin tracks resembling those of cutaneous larva migrans or paragonimiasis may accompany this syndrome. Late disease may resemble chronic calculous cholecystitis or cholangitis, sometimes with painful subcutaneous nodules up to 6 cm in diameter persisting mostly on the abdomen.

Synonym: Lung fluke infection Human paragonimiasis is caused most frequently by Paragonimus westermani, the oriental lung fluke, but at least seven additional species are known to infect humans or animals in Asia, Africa, and Latin America. Worms retained in ectopic sites from which eggs cannot be excreted, such as the skin, tend to die earlier with formation of an abscess and, eventually, a calcified nodule. Whether active or calcified, cutaneous paragonimiasis therefore denotes the likelihood of visceral involvement and the need for systemic clinical and parasitologic patient evaluation.

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CLINICAL AND HISTOPATHOLOGIC FEATURES Early stages of skin involvement, as seen in China, are said to resemble the creeping eruption of cutaneous larva migrans. Later skin lesions present as inflammatory or calcified subcutaneous nodules 2 to 4 cm in diameter, most often in an abdominal site. Histologically, they show variable mixtures of eosinophilia, abscess formation, necrosis, and focal calcification.

 FIGURE 24-14 Egg shell of metagonimus yokogawai containing a foreign body giant cell (hematoxylin and eosin stain).

HISTOPATHOLOGIC FEATURES AND DIFFERENTIAL DIAGNOSIS Fasciolae seen in biopsies of early tracks are immature, lacking vitellaria glands, but show the spined, syncytial tegument typical of trematodes as well as branched ceca (Fig. 24-15). The surrounding tissue may show massive eosinophilia and CharcotLeyden crystals. In chronic lesions, there is a mix of necrosis, granulomatous inflammation, and calcification. Similar to paragonimiasis, worms are likely to be degenerate or absent, but eggs may persist; they are thin-walled, operculated, and measure 140 × 90 μm, making them among the largest helminth eggs found in humans. The larger egg size distinguishes fascioliasis from paragonimiasis, and the absence of a spine differentiates its eggs from those of the schistosomes. This distinction is important because each trematode parasite requires different therapy.

A papular erythematous skin rash called swimmers’ itch occurs after penetration of the human skin by cercarial larvae of bird or animal schistosomes of various species found in snail-infested lakes and ponds worldwide. This rash is selfhealing within hours or days because animal schistosomes exposed to human tissue always die at an early developmental stage. More rarely, a similar rash occurs soon after exposure to cercariae of any of the major human-adapted schistosomes. This rash is usually mild and is

CLINICAL AND HISTOPATHOLOGIC FEATURES Cercarial skin rashes, whether of the swimmers’ itch or the tropical variety, are more often localized than generalized; are erythematous, maculopapular, and intensely pruritic; occur within hours of water contact; and fade within days. Only two biopsy studies of these lesions have been published.15 Similar to animal models, they showed vasodilatation and edema of the reticular dermis, basophil degranulation, and perivascular infiltration by sparse netrophils and eosinophils (Fig. 24-16). Around dying schistosomal, there was

CHAPTER 24 ■ HELMINTHIC DISEASES

 FIGURE 24-15 Section through lateral portion of Fasciola hepatica showing complex branching of ceca and spined tegument (hematoxylin and eosin stain).

seen more frequently in adult travelers to the tropics than in residents of the endemic zone who have been exposed to infection from childhood.15 However, skin penetration by the major human schistosomes is followed within a few weeks by full-scale systemic infection and therefore should be recognized and treated. During its early prepatent stage, schistosomiasis is diagnosable only by serology. ELISA and Western blotting should be used in combination,16 and inquiry about the patient’s travel and water contact should be made. Skin lesions due to ectopic egg laying by established schistosome worms during the chronic phase of infection have also been reported but are truly exceptional, more rare than CNS lesions. Most have been seen in the perianal and scrotal region, but an occasional one has been periumbilical. There is even a solitary report of a nasal skin lesion.

Schistosomiasis Synonyms: Swimmers’ itch, bilharziosis Schistosomiasis is a widespread chronic endemic infection by sexually dimorphic trematodes. Human skin lesions can be caused by (1) schistosomes adapted to animals or birds that cause an abortive infection in humans or (2) by one of the tropical, human-adapted schistosome species, most commonly Schistosoma mansoni, S. haematobium, or S. japonicum, which may cause choreic, potentially severe systemic human disease and are known to infect millions of people in their endemic tropical countries.

 FIGURE 24-16 Schistosomulum of Schistosoma mansoni entering the dermis. Note the degranulating mast cells (Domenici stain).

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PART III ■ INFECTIONS

 FIGURE 24-17 Schistosoma mansoni. Two acid-fast-positive eggs of S. mansoni and a convoy of seven acid-fast-negative eggs of S haematobium in a single histologic field (Ziehl-Neelsen stain).

exocytosis and formation of eosinophilenriched microabscesses. Dermal schistosome egg deposits present as mildly inflamed subcutaneous nodules or tumor-like masses that are tender but not painful with little or no erythema. On histology, they show granulomas of various stages of activity or involution formed around schistosome eggs. These eggs measure up to 120 μm in length. In paraffin-embedded sections, they are too distorted to discern the spines that characterize each species; however, S. mansoni and S. japonicum eggs are acid fast by the Ziehl Neelsen method, S. haematobium eggs are negative (Fig. 24-17). DIFFERENTIAL DIAGNOSIS Differentiation of acute cercarial dermatitis from another

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allergic and pruritic dermatosis must be made on clinical and serologic grounds. Patients with chronic schistosome egg lesions of the skin usually also excrete eggs in the feces or urine or present with clinical evidence of urinary or hepatointestinal schistosome pathology. The only helminth eggs larger in size than those of schistosomes are the operculated ones of Fasciola species.

REFERENCES 1. Gutieserre Y: Introduction to Nematodes in Diagnostic Pathology of Parasitic Infections with Clinical Correlations. Philadelphia: Lea & Febiger; 1990:177-183. 2. Connor DH, Gibson DW, Neafie RC, et al: Sowda: onchocerciasis in North Yemen. A clinicopathologic study of 18 patients. Am J Trop Med Hyg. 1983;32:123-137.

3. Meyers WM, Connor DH, Harman LE, et al: Human streptocerciasis: a clinicopathologic study of 40 Africans (Zairians) including identification of the adult filaria. Am J Trop Med Hyg. 1972;21:528–545. 4. Ramachandran CP: Report on a multicenter effort to develop improved immunodiagnostic tests to monitor onchocerciasis programs. Parasitol Today. 1993;9:76-79. 5. Friedman DO, Horn TD, Silva CME, et al: Predominant CD-8 infiltrate in limb biopsies of individuals with filarial lymphedema and elephantiasis. Am J Trop Med Hyg. 1995;53:633-638. 6. von Lichtenberg F: Inflammatory responses to filarial connective tissue parasites. Parasitology. 1987;94(suppl):S101-S122. 7. Ottesen E: Filarial infections. Infect Dis Clin North Am. 1993;7(3):619-633. 8. Orihel TC, Beaver PC: Morphology and relationship of Dirofilaria tenuis and Dirofilaria conjunctivae. Am J Trop Med Hyg. 1964;14:1030-1043. 9. Ginsbur B, Beaver PC, Wilson ER, et al: Dermatitis due to larvae of the soil nematode, Pelodera strongyloides. Pediatr Dermatol. 1984;2:33-37. 10. Little MD: Dermatitis in a human volunteer infected with Strongyloides of the nutria and raccoon. Am J Trop Med Hyg. 1965;14:1007-1009. 11. Bhaibulaya M, Charoenlarp P: Creeping eruption caused by Gnathostoma spinigerum. Southeast Asian J Trop Med Public Health. 1983;14:266-268. 12. Kurtycz DFI, Alt B, Mack E: Incidental coenurosis: larval cestode presenting as an axillary mass. Am J Clin Pathol. 1983; 80:735-738. 13. Sparks AK, Neafie RC, Connor DH: Sparganosios, in Binford CH, Connor DH (eds). Pathology of Tropical and Extraordinary Diseases. Washington, DC: Armed Forces Institute of Pathology; 1976:534-538. 14. Yokogawa M: Paragonimus and paragonimiasis. Adv Parasitol. 1965;3:99-158. 15. Gonzalez E: Schistosomiasis, cercarial dermatitis, and marine dermatitis. Dermatol Clin. 1984;7:291-300. 16. Tsang VL, Wilkins PP: Immunodiagnosis of schistosomiasis: screen with FASTELISA and confirm with immunoblot. Clin Lab Med. 1991;11:1029-1039.

4 PART

Proliferations—Hamartomas, Hyperplasias, and Neoplasias

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CHAPTER 25 Cutaneous Cysts and Related Lesions Glynis A. Scott

CYSTS WITH AN EPITHELIAL LINING

Cysts Lined by Stratified Squamous Epithelium Cysts lined by stratified squamous epithelium can be conveniently divided into those that contain other structures within the cyst wall, such as steatocystoma, dermoid cysts, and thymic cysts, and those that lack additional structures within the cyst wall, including epidermoid cysts, pilar cysts, vellus hair cysts, milia, follicular hybrid cysts, pigmented

follicular cysts, and proliferating epithelial cysts (PECs).

Epidermoid Cysts Synonyms: Infundibular cyst, epidermal inclusion cyst Epidermoid cysts (ECs) are by far the most common cyst received in the pathology laboratory. They present predominantly on the face, neck, and torso, although ECs of the palms and soles have been reported. ECs have also been termed infundibular cysts, reflecting the belief that they arise from the infundibular portion of the hair follicle. Whereas cysts that arise on acral surfaces of the skin are believed to arise from implantation of epidermis into the dermis through trauma, the more commonly observed cysts on nonacral skin are thought to arise from inflammation of the hair follicle. An EC arising on the right great toe after trauma has also been reported,2 and multiple ECs on the scrotum (Fig. 25-2A) are commonly encountered and frequently become calcified, so-called “scrotal calcinosis.”3 An EC arising from an eccrine duct has been reported.4 Recently described variants of EC include ECs with associated basal cell carcinoma5 and plantar ECs with associated human papilloma virus infection.6 PEC,7 a variant of EC, is discussed in detail under Recently Described Entities at the end of the chapter. HISTOPATHOLOGIC FEATURES ECs are located predominantly in the dermis and

Cyst

Epithelial lining

Stratified squamous

No components in cyst wall Epidermoid cyst Vellus hair cyst Pilar cyst Follicular hybrid cyst Pigmented follicular cyst Milium

Components in cyst wall Steatocystoma Dermoid cyst Thymic cyst

 FIGURE 25-1 Algorithm for diagnosis of cutaneous cysts.

CHAPTER 25 ■ CUTANEOUS CYSTS AND RELATED LESIONS

Cysts are one of the most common specimens received by pathologists. A cyst is any cavity that is lined by an epithelium. Cysts may be found in virtually any organ in the body and are often lined by epithelium that is native to that particular organ. Although cysts may be classified on the basis of several different criteria, the diagnosis of cutaneous cysts is predominantly based on the nature of the epithelial lining. Recognition of the nature of the epithelial cyst wall lining is also important for understanding the histopathogenesis of these lesions, which usually arise from normal counterparts in the skin, predominantly adnexal structures. Classification of cutaneous cysts may be approached in a variety of ways. One may classify them based on their presumed appendage of origin, whether it is hair, eccrine gland, apocrine gland, or salivary gland, or on whether they are developmentally or nondevelopmentally

derived. There is considerable overlap between what one might consider to be a cyst and what one might consider to be an appendageal tumor. For example, several authors classify apocrine and eccrine hidrocystomas as appendageal tumors1 because they arise from apocrine and eccrine glands, respectively. Some authors consider endometriosis and endosalpingiosis to be cutaneous cysts even though they represent heterotopic rests of normal tissue that have implanted at distant sites. Because of the extensive overlap between classification schemes of cutaneous cysts, a simple algorithm for the diagnosis of cutaneous cysts based on the nature of their epithelial lining is presented (Fig. 25-1). Tables 25-1 to 25-5 summarize the clinical and histologic features of cutaneous cysts.

No epithelial lining Digital mucous cyst Pseudocyst of auricle Metaplastic synovial cyst Pilonidal cyst

Nonsquamous

Mixed squamous and nonsquamous ciliated Bronchogenic cyst Branchial cleft cyst Thyroglossal duct cyst Cutaneous ciliated cyst

Pseudostratified columnar Median raphe cyst

Cuboidal Apocrine hidrocystoma Eccrine hidrocystoma

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 25-1 Classification of Cutaneous Cysts

544

Epithelial-lined cysts Stratified squamous Epidermoid cyst (infundibular cyst)a Pilar cyst (trichilemmal cyst) Vellus hair cysta Miliaa Follicular hybrid cysta Pigmented follicular cysta Stratified squamous with components in cyst wall Steatocystoma (simplex and multiplex) Dermoid cyst Thymic cyst Cuboidalb Eccrine hidrocystoma Apocrine hidrocystoma Mixed squamous and nonsquamous ciliated Bronchogenic cyst Branchial cleft cyst Thyroglossal duct cyst Cutaneous ciliated cyst Ciliated cyst of vulva Omphalomesenteric cystb Pseudostratified columnar Median raphe cyst Cysts not lined by an epithelium Digital mucous cyst Mucocele Metaplastic synovial cyst Pilonidal cyst Pseudocyst of auricle New entities Proliferating epithelial cyst

and are distinguished from ECs by the usual lack of communication with the skin surface in ECs and the nature of the epithelial lining, which is acanthotic and displays platelike extensions and budding in pilar sheath acanthoma and in the pore of Winer.

Pilar Cysts Synonyms: Trichilemmal cyst, isthmuscatagen cyst, "sebaceous" cyst Pilar cysts occur predominantly on the scalp (90%)6, but otherwise share clinical features with ECs. There is a strong female preponderance, and pilar cysts are usually solitary, but multiple pilar cysts may occur. Pilar cysts arise from the isthmus of anagen hairs or from the sac surrounding catagen and telogen hairs, areas where the inner root sheath is lacking. Proliferating pilar cysts (proliferating trichilemmal tumor) arise from irritation of pilar cysts and may also be considered an adnexal tumor. Although rare, trichilemmal carcinoma8,9 has been reported to occur in association with pilar cysts. Hereditary pilar cysts have been reported and are linked to chromosome 3p24-p21.2.10

contain abundant laminated orthokeratin in the cyst cavity. The cyst wall consists of a stratified squamous epithelium with a variably thick granular layer (Fig. 25-2B). Rupture of the cyst results in an intense foreign body giant cell reaction, with lymphocytes;, neutrophils;, and, eventually, scar formation. Fragments of keratin may be identified within giant cells in ruptured ECs.

HISTOPATHOLOGIC FEATURES Pilar cysts are usually located in the middle to deep reticular dermis or subcutis and are characterized by a three- to four-layer-thick lining of keratinocytes that exhibits abrupt keratinization into compact homogenous keratin (Fig. 25-3). A characteristic feature of pilar cysts is the apparent absence of intercellular bridges between the keratinocytes and peripheral palisading of nuclei. The cells closest to the cyst cavity are pale and show abrupt transition to homogeneous keratin. Occasional cholesterol clefts can be observed in the keratinous material. When ruptured, a foreign-body giant cell reaction is observed, along with calcification and, occasionally, ossification. It is common to observe some areas of the cyst that contain a granular layer (so-called “pseudohybrid cyst”), but the predominantly trichilemmal type of keratinization establishes the true nature of the cyst.

DIFFERENTIAL DIAGNOSIS ECs can be distinguished from pilar cysts by the presence of a granular layer; the nature of the keratin, which is loose and flaky in ECs and compact and homogeneous in pilar cysts; and the absence of palisading of nuclei in the basal layer. Calcification, commonly present in pilar cysts, is usually absent in ECs. Pilar sheath acanthoma and the pore of Winer are also lined by a keratinizing stratified squamous epithelium

PROLIFERATING PILAR CYSTS (TUMORS) Proliferating pilar tumors arise from pilar cysts that have been irritated and are predominantly located on the scalp of elderly women. The size varies from 0.2 to 10.0 cm, but larger sizes have been reported (≤25 cm). These lesions exhibit lobules and sometimes sheets of cells with areas of trichilemmal keratinization evident throughout the tumor. Squamous eddies are usually easily

a

These cysts arise from the infundibular portion of the hair follicle. b These are discussed in detail in Chapter 18.

identified.11 Proliferating pilar cysts usually fill the dermis and may extend into the subcutis. They often contain abundant compact keratin which fills the cyst cavity. As in pilar cysts, a foreign body giant cell reaction may be observed at the periphery of the lesion. Malignant proliferating trichilemmal tumor (squamous cell carcinoma [SCC]) is extremely rare.12 Patients are middle aged to elderly, and lesions present as solitary nodules, papules, or plaques on sunexposed areas of the body. An association of KID syndrome with malignant proliferating pilar tumor has been reported.13 Characteristic histologic features include a solid growth pattern of highly atypical keratinocytes with easily identifiable mitotic figures as well as lobular and trabecular growth patterns. Lesions are usually confined to the dermis; however, extension into the subcutis may be seen, and ulceration may be present. In some cases, continuity of the tumor with hair follicle epithelium may be observed. Tumor cells are characterized by abundant clear cytoplasm, some containing intracytoplasmic eosinophilic globules.11 Microcysts with keratohyaline plugs may be seen, and tumor lobules are surrounded by stratified squamous epithelium with an outer layer of clear cells with palisading nuclei and subnuclear vacuolization, simulating outer root sheath differentiation.11 In exceptionally rare cases, apparent proliferating trichilemmal tumors with atypia, but lacking sufficient evidence for malignancy, may result in regional lymph node metastases. Therefore, pilar tumors exhibiting atypicality should be managed prudently. DIFFERENTIAL DIAGNOSIS Well-differentiated SCC may be confused with proliferating pilar tumor, but the well-demarcated nature of the lobules, the noninfiltrative borders, and the absence of significant atypia help to distinguish proliferating pilar tumors from SCC. In addition, the presence of clear cells with palisading at the periphery is also a useful distinguishing feature of proliferating pilar tumors. Trichilemmal carcinoma may be indistinguishable from SCC; however, the presence of areas of trichilemmal keratinization and the absence of overlying in situ carcinoma help to establish the diagnosis. In addition, careful inspection may reveal residual areas of benign proliferating pilar tumor.

Vellus Hair Cysts Vellus hair cysts most commonly present as multiple lesions as part of an autosomal

Table 25-2 Clinical and Histologic Features of Cysts Lined by Stratified Squamous Epithelium C YST

C LINICAL F EATURES

H ISTOPATHOLOGIC F EATURES

OTHER F EATURES

Epidermoid inclusion (infundibular cyst)

Solitary or multiple, face, neck, torso; occasionally palms and soles

Rupture associated with foreign body giant cell reaction, inflammation, and scarring

Pilar (trichilemmal)

Usually solitary, may be multiple, head and scalp

Vellus hair

Multiple, autosomal dominant or sporadic; trunk, chest, and extremities, small and may be pigmented

Milium

Small, 1- to 2-mm papules, primary or associated with blistering disorders

Pigmented follicular

Solitary lesions on the face, M> > >F, deeply pigmented

Hybrid

Rare, scalp or face, wide age range

Proliferating epithelial cyst

Rare; 1:1.8 F:M ratio; pelvic, anogenital area, scalp, upper extremities, trunk

Stratified squamous lining with variably thick granular layer; loose, abundant laminated orthokeratin Stratified squamous lining of keratinocytes with poorly defined intercellular bridges Abrupt keratinization to compact keratin No or attenuated granular layer Small, dermally located, thin stratified squamous lining Characteristic presence of multiple vellus hairs in cyst lumen Small cysts arising from infundibulum of vellus hairs, lined by thin stratified squamous lining Stratified squamous epithelium with numerous pigmented hair shafts in lumen Superior portion of cyst lined by stratified squamous epithelium, like an EC; sharp transition to lower portion showing trichilemmal keratinization Acanthotic papillomatous or verrucous stratified squamous lining, atypia, mitotic figures may be present

Proliferating pilar tumor arises from the benign cystic counterpart

Connection to a vellus hair may be identified

Connection to the surface of the epidermis usually observed Hybrid cyst consisting of other combinations of hair follicle derivation may be seen

Carcinomatous change may be seen, local recurrence relatively common, frequent connection with epidermis

Abbreviations: EC = epidermoid cyst; F = female; M = male.

CHAPTER 25 ■ CUTANEOUS CYSTS AND RELATED LESIONS

Milia secondary to scarring or bullous disease probably arise from eccrine ducts

Table 25-3 Clinical and Histologic Features of Cysts Lined by Stratified Squamous Epithelium and Containing Elements within the Cyst Wall CYST

CLINICAL FEATURES

HISTOPATHOLOGIC FEATURES

OTHER FEATURES

Steatocystoma

Simplex (solitary) or multiplex (hereditary), axilla, groin, chest

Sebaceous glands arranged within the outer wall of the cyst

Dermoid

Infants and children; periocular, congenital, firm nodules, 1-4 cm

Thymic cyst

Neck or anterior mediastinum

Ruggated wall lined by very thin stratified squamous lining with glassy pink cuticle overlying the internal surface Unilocular cyst with stratified squamous lining; wall contains various appendageal elements such as hair follicles, sebaceous glands, eccrine glands Unilocular or multilocular, cuboidal epithelium or stratified squamous, occasional ciliated cells

Thymic tissue may be identified in wall Pseudoepitheliomatous hyperplasia or even malignant transformation may occur, although rare

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 25-4 Clinical and Histologic Features of Cysts Lined by Mixed Squamous and Nonsquamous Ciliated Epithelium CYST

CLINICAL FEATURES

HISTOPATHOLOGIC FEATURES

OTHER FEATURES

Bronchogenic

Neck, but may occur on face, back, shoulder, abdomen

Wall may contain smooth muscle or cartilage

Branchial cleft

Jaw and preauricular area in areas of lymph nodes

Ciliated (mucinous) cyst of vulva Cutaneous ciliated

Labia minoris

Ciliated lining with goblet cells, stratified squamous lining in some areas because of metaplasia Pseudostratified columnar epithelium with cilia and areas of stratified squamous epithelium Mucin-containing cells with some cilia

Thyroglossal duct

Midline of neck

Cuboidal or columnar single layer of ciliated cells Cuboidal ciliated epithelium admixed with stratified squamous epithelium

Same origin as ciliated cyst of vulva Characteristic presence of thyroid follicles in cyst wall

Abbreviation: LE = lower extremities.

Table 25-5 Clinical and Histologic Features of Cysts Not Lined by an Epithelium CYST

CLINICAL FEATURES

HISTOPATHOLOGIC FEATURES

OTHER FEATURES

Digital mucous cyst

Dorsum of finger

Pseudocyst of auricle

Asymptomatic swelling of upper pinna of the ear

Metaplastic synovial cyst

Occur in areas of trauma or surgical sites

Pilonidal cyst

Sacrococcygeal area, but any area may be affected

Collagenous wall, lumen that contains acid mucopolysaccharides Cystic space within the cartilage associated with some degenerative changes Villous projections into cystic cavity, lined by fibrinous exudate, epithelioid cells, inflammation Acute and chronic inflammation surrounding sinus tract or cystic cavity, hair shafts often identified

Connected to the interphalangeal joint Most likely represents developmental defect in ear formation exacerbated by trauma Immunocytochemically and histologically similar or identical to synovium May rarely progress to squamous cell carcinoma

A

546

Buttocks, LE, women

Lymphoid follicles are abundant and may be the predominant component Müllerian origin

B

 FIGURE 25-2 Epidermoid cyst. (A) Multiple epidermoid cysts of the scrotum. (B) The cyst is notable for laminated keratin, the presence of a granular layer, and squamous epithelium resembling the epidermis.

Langerhans cells may also be seen within the cyst wall.23 DIFFERENTIAL DIAGNOSIS Steatocystoma is in the differential diagnosis of vellus hair cysts because these two cystic lesions share a similar epithelial lining. In contrast with vellus hair cysts, however, which do not usually contain components within its cyst wall, steatocystoma typically has readily identifiable sebaceous glands in the cyst wall, as well as a pink cuticle on the luminal aspect of the epithelial lining.

Milia

dominant disease termed eruptive vellus hair cysts (EVHCs) or as solitary lesions in a nonheritable form.14-17 In sporadic cases, lesions appear abruptly in the first or second decade of life, but cases appearing in adults have also been reported. Familial cases appear at an earlier age (birth or infancy). EVHCs may be associated with other cutaneous lesions, such as steatocystoma multiplex18-20; trichostasis spinulosa21; or other heritable disorders, such as pachyonychia congenita; and neurologic disorders.19,22 Lesions are small (1 to 3 mm) and may be pigmented with red, brown, gray, and black colors. The most common locations are the anterior chest, abdomen, and extremities; however, face, groin, and neck may also be affected. The pathogenetic mechanism of vellus hair cysts is unknown; however, faulty development of vellus hair infundibulum, evolution from blocked terminal hair follicles, and hamartomatous differentiation toward vellus hair follicles have been postulated. HISTOPATHOLOGIC FEATURES Vellus hair cysts are typically located in the middle to upper dermis and consist of a thinwalled cyst lined by stratified squamous epithelium with an attenuated granular layer (Fig. 25-4). Similar to ECs, vellus hair cysts arise from the infundibular portion of the hair follicle. The cyst wall may contain telogen-like hair follicle

structures. Their most characteristic feature, however, is the presence of multiple vellus hairs cut in cross-section in the cyst cavity along with keratin fragments. While it is unusual to observe other structures within the cyst wall, small arrector pili muscles have been observed attached to the outer cyst wall. Ultrastructural examination of EVHC23 reveals an infundibular type of keratinization. Melanocytes and

HISTOPATHOLOGIC FEATURES Milia are a miniature version of an EC but arise from the infundibular portion of vellus hairs rather than terminal hairs. Their lining is a stratified squamous epithelium and contains a granular layer, and the cyst cavity is filled with keratinous debris. Unlike vellus hair cysts, multiple cross-sections of hair shafts in the cyst cavity are not seen. Often, the cyst wall can be seen arising from a vellus hair. In contrast with primary milia, secondary milia arise from eccrine ducts. In cases in which a connection to a hair or eccrine

 FIGURE 25-4 Vellus hair cyst. The cyst lining resembles an epidermoid cyst but contains fragments of hair shaft.

CHAPTER 25 ■ CUTANEOUS CYSTS AND RELATED LESIONS

 FIGURE 25-3 Trichilemmal (pilar) cyst. The epithelial lining resembles the isthmus of the hair follicle and is remarkable for the formation of amorphous keratin, the absence of a granular layer, and peripheral palisading of nuclei.

Milia present as multiple small superficially located lesions that range from 1 to 2 mm in diameter. They may be primary, usually arising on the face; secondary to bullous disorders such as porphyria, epidermolysis bullosa, and pemphigoid; or secondary to trauma such as dermabrasion.

547

appendage cannot be demonstrated, implantation of epidermis in scar tissue is the probable histogenetic mechanism. DIFFERENTIAL DIAGNOSIS Milia can be distinguished from vellus hair cysts by the lack of hair shafts in the cyst cavity and from steatocystoma by the lack of sebaceous glands in the cyst wall and the lack of a pink cuticle.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Follicular Hybrid Cysts

548

Follicular hybrid cysts, first described by Brownstein in 1983,24 are rare mixed types of cysts in which infundibular keratinization is observed in the upper portion of the cyst and trichilemmal keratinization is seen in the lower portion of the cyst. The face and scalp are the primary sites, and persons of any age may be affected. Requena and Yus25 expanded this concept to include cysts that combine features of both infundibular and pilomatric differentiation, trichilemmal and pilomatric differentiation, and vellus hair cyst and steatocystoma. HISTOPATHOLOGIC FEATURES The originally described hybrid cyst combines infundibular keratinization in the upper portion of the cyst wall with trichilemmal keratinization in the lower portion of the cyst wall. Occasional connection with the overlying epidermis may be observed. To fulfill the requirements of a true hybrid cyst, an abrupt transition from infundibular to trichilemmal keratinization must be observed.

DIFFERENTIAL DIAGNOSIS Pigmented follicular cysts may be confused with vellus hair cysts, but the presence of pigmented hair shafts and connection with the epidermis in pigmented follicular cysts help to distinguish between these two entities.

CYSTS WITH STRATIFIED SQUAMOUS EPITHELIAL LINING AND COMPONENTS WITHIN THE CYST WALL

Steatocystoma Steatocystoma may occur as solitary noninherited tumors in adults, referred to as steatocystoma simplex, or as multiple lesions inherited as an autosomal dominant disease. In the heritable form, numerous small white or yellowish lesions distributed in the axillae, groin, or chest are noted, although other areas of the body may also be affected.27 The lesions usually occur at puberty, suggesting some androgenic control. Some authors regard steatocystomas as retention cysts, but others consider them to represent a variant of dermoid cysts. The histogenesis of these cysts is now thought to represent a nevoid or hamartomatous condition of the pilar–sebaceous junction. This theory is supported by the description of randomly arranged smooth muscle fibers of the hair erector muscle in close proximity to the steatocystoma.28 Similarly, a report of steatocystoma multiplex in which a layer of smooth muscle is observed

underneath the wall of the cyst also supports the theory that this cyst arises from a hamartoma of the pilosebaceous duct zone.29 HISTOPATHOLOGIC FEATURES Steatocystoma simplex and multiplex share histologic features consisting of a thin-walled cyst lined by stratified squamous epithelium that tends to be very rugated and contains a crenulated eosinophilic cuticle on its surface (Figs. 25-5 and 25-6). Characteristic features of this cyst include the presence of sebaceous glands arising from or adjacent to the cyst wall, as well as occasional hairs. DIFFERENTIAL DIAGNOSIS Steatocystomas may be distinguished from ECs by the thinner cyst wall lining of steatocystoma, as well as the presence of sebaceous glands within the wall and the pink cuticle. Similarly, milia and vellus hair cysts, which are similar in size to steatocystoma, lack the cuticle, as well as the sebaceous glands in the wall.

Dermoid Cysts The typical dermoid cyst is a welldefined, hard, rubbery, raised, yellow to pink lesion with fine hairs on its surface, varying from 1 to 4 cm in size. Dermoid tumors, the solid counterparts of dermoid cysts, also called choristomas, are benign, congenital overgrowths of tissue located in an ectopic location.30 Dermoid cysts are located in the dermis or subcutis, are usually present at birth, and are

DIFFERENTIAL DIAGNOSIS Follicular hybrid cysts can be distinguished from the more common ECs and pilar cysts by the presence of two types of keratinization.

Pigmented Follicular Cyst First described by Mehregan and Medenica,26 pigmented follicular cysts are rare, solitary lesions located predominantly on the head and neck, ranging in size from 0.4 to 1.5 cm. Patients range in age from 20 to 60 years, and there is a strong male predominance. In five of seven cases reported, the lesions were deeply pigmented. HISTOPATHOLOGIC FEATURES The cysts open to the epidermis and are lined by a stratified squamous epithelium in which the keratinocytes closest to the cyst cavity contain keratohyalin granules. The cyst lining shows rete ridge–like areas, and the lumen is filled with numerous thick pigmented hair shafts cut on cross-section.

 FIGURE 25-5 Steatocystoma. The cyst has a serpiginous configuration, and sebaceous elements are present in the wall.

or anterior mediastinum.31 Thymic cysts are usually asymptomatic; however, a small proportion of patients may experience hoarseness, dysphagia, and stridor as a result of compression of pharyngeal tissue by the cyst. Although rare, malignant transformation of thymic cysts has been reported.32 Some thymic cysts may arise from persistent embryonal thymic remnants; however, a larger proportion probably arise as acquired lesions caused by inflammation, ulceration, or reactive lymphoid hyperplasia.33

predominantly located around the eyes and in the midline area of the face. HISTOPATHOLOGIC FEATURES Dermoid cysts are generally rather large, are lined by a stratified squamous epithelium, and contain mature epidermal appendages within their wall (Fig. 25-7). The presence of hairs projecting into the cyst wall is common. In the dermis surrounding the cyst wall, eccrine glands, sebaceous glands, and occasionally apocrine glands may be observed.

DIFFERENTIAL DIAGNOSIS Dermoid cysts differ from ECs because of the presence of adnexal structures in their walls and from steatocystoma because of their thicker lining, lack of a cuticle, and greater number and types of adnexal structures in the cyst wall.

Thymic Cysts Thymic cysts are unusual lesions that may be either developmental or acquired and almost invariably occur in the neck

DIFFERENTIAL DIAGNOSIS Because thymic cysts often contain a dense infiltrate of lymphocytes, a cutaneous lymph node is in the differential diagnosis. However, the presence of scattered Hassle corpuscles and the presence of a cyst wall help distinguish thymic cysts from lymph nodes. The presence of Hassle corpuscles distinguishes thymic cysts from other cysts that contain ciliated epithelium in their lining, such as bronchogenic cysts and branchial cleft cysts.

CHAPTER 25 ■ CUTANEOUS CYSTS AND RELATED LESIONS

 FIGURE 25-6 Steatocystoma. The cyst is lined by an irregular eosinophilic cuticle, and sebaceous elements are present in the wall.

HISTOPATHOLOGIC FEATURES Thymic cysts may be unilocular or multilocular (Fig. 25-8).34 The lining is composed of a thin layer of flattened or cuboidal epithelium or a stratified squamous epithelium with occasional ciliated cells. Some thymic cysts lack a lining completely. Ulceration and inflammation of the cyst wall may be observed, and a connection with Hassle corpuscles may be identified. Although uncommon, pseudoepitheliomatous hyperplasia of the lining of the cyst may be observed.33 The cyst wall is composed of fibrovascular tissue with scattered islands of thymic epithelium around it. Thymic tissue consists of abundant lymphoid cells with Hassle corpuscles and associated cholesterol granulomas.

CYSTS LINED BY MIXED SQUAMOUS AND NONSQUAMOUS AND CILIATED EPITHELIUM

Bronchogenic Cysts

 FIGURE 25-7 Dermoid cyst. The cyst resembles an epidermoid cyst but contains hair fragments within the lumen. In addition, hair follicles and sebaceous glands are associated with the epithelial lining.

Bronchogenic cysts are most commonly located on the neck and within the thoracic cage in the vicinity of the bronchial trees but may also be present on the back, shoulder, abdomen, or face. These cysts are usually located in the subcutis and may occasionally drain through fistulas to the surface of the skin. Bronchogenic cysts are four times more common in males than in females.35 The most common location of cutaneous

549

DIFFERENTIAL DIAGNOSIS Similar to thymic cysts, the abundant lymphoid tissue may suggest a cutaneous lymph node. However, careful inspection reveals a cystic space lined by squamous or pseudostratified ciliated epithelium in branchial cleft cysts.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Thyroglossal Duct Cysts Thyroglossal duct cysts are usually observed in the midline areas of the neck and are detected in childhood or young adulthood. They represent remnants of the thyroglossal duct that have failed to migrate. A characteristic clinical feature is the movement of the cyst with deglutition.

 FIGURE 25-8 Thymic cyst. A large unilocular cyst is lined by cuboidal epithelium and associated thymic tissue. The latter contains lymphoid infiltrates with Hassle corpuscles.

bronchogenic cysts is the suprasternal notch followed by the presternal area, neck, and scapula.36 The pathophysiology of bronchogenic cysts is a result of sequestration of respiratory epithelium from the tracheal bronchial tree during embryonic development. Localization outside the areas of development of the tracheobronchial tree is caused by migration of the tissue to ectopic sites.

development. Alternatively, branchial cleft cysts may represent inclusion of branchialtype epithelium within lymph nodes. HISTOPATHOLOGIC FEATURES The cysts are lined by a stratified squamous or pseudostratified ciliated columnar epithelium (Fig. 25-11). The most characteristic feature, however, is the presence of abundant lymphoid tissue within and surrounding the cyst wall.

HISTOPATHOLOGIC FEATURES Thyroglossal duct cysts are lined by a simple cuboidal or columnar epithelium or stratified squamous epithelium that might contain some ciliated columnar cells (Fig. 25-12). In addition, a pseudostratified columnar ciliated lining may be observed. A tract connecting it to the hyoid bone is frequently present. The most characteristic feature of thyroglossal duct cysts, however, is the presence of thyroid follicles within the wall of the cyst. These are characterized by low cuboidal cells that surround homogeneous pink material. DIFFERENTIAL DIAGNOSIS Although thyroglossal duct cysts share features with other cysts, such as the presence of a stratified squamous or columnar lining,

HISTOPATHOLOGIC FEATURES Bronchogenic cysts are characterized by a lining that is respiratory, consisting of goblet cells filled with mucin, as well as ciliated pseudostratified columnar epithelium (Figs. 25-9 and 25-10). Squamous metaplasia of the cyst wall may occur, resulting in both stratified squamous as well as ciliated columnar cells and goblet cells.35 The wall of the cyst may contain strands of smooth muscle and rarely cartilage. DIFFERENTIAL DIAGNOSIS Bronchogenic cysts may be distinguished from branchial cleft cysts and cutaneous ciliated cysts by the absence of lymphoid follicles in the former and the clinical presentation in the latter.

Branchial Cleft Cysts

550

Branchial cleft cysts are most commonly located in the jaw and preauricular area of the face nestled among lymph node groups in the head and neck. They arise from branchial cleft remnants whose migration was arrested during embryologic

 FIGURE 25-9 Bronchogenic cyst. The cyst is lined by respiratory epithelium and ciliated pseudostratified columnar epithelium.

the presence of thyroid epithelium distinguishes this cyst from all others.

Cutaneous Ciliated Cysts

 FIGURE 25-10 Bronchogenic cyst. High magnification shows ciliated epithelium lining the cyst.

HISTOPATHOLOGIC FEATURES Cutaneous ciliated cysts may be located in either the subcutis or deep dermis and are both unilocular or multilocular. A common feature is the presence of papillary projections into the lumen of the cyst. The lining of the cyst is a simple cuboidal to columnar ciliated epithelium, with some areas of pseudostratified ciliated epithelium. Foci of squamous metaplasia may be seen. The tissues surrounding the cyst are free of skin appendages, glandular elements, and muscle fibers.40

 FIGURE 25-11 Branchial cleft cyst. Note the lymphoid tissue surrounding the cyst wall.

DIFFERENTIAL DIAGNOSIS Other cysts that contain a ciliated lining epithelium may be confused with cutaneous ciliated cysts; however, the absence of associated lymphoid tissue (which would be present in bronchogenic cysts) or associated structures such as thymic tissue or thyroid glands helps to establish the diagnosis. Apocrine hidrocystoma is in the histologic differential diagnosis; however, cutaneous ciliated cysts lack decapitation secretion seen in apocrine hidrocystoma.

CHAPTER 25 ■ CUTANEOUS CYSTS AND RELATED LESIONS

Cutaneous ciliated cysts are uncommon lesions. They usually occur as solitary lesions on the buttocks and lower extremities in women in their teen years to young adulthood, with only two reported cases occurring in men.37,38 Other sites include one case on the shoulder, which may represent a bronchogenic cyst, and one case on the scalp.39 Kurban and Bhawan1 suggest that these cysts should be renamed cutaneous Müllerian cysts to reflect their presumed Müllerian duct origin. Others, however, citing the occasional occurrence of these lesions in men, too, suggest that these lesions arise from eccrine glands that have undergone ciliated metaplasia.37,38

Ciliated Cysts of the Vulva

 FIGURE 25-12 Thyroglossal duct cyst. Thyroid follicles are present near the wall of the cyst.

Synonyms: Paramesonephric mucinous cyst of the vulva Ciliated cysts of the vulva are uncommon developmental anomalies that represent heterotopic rests of Müllerian epithelium,41,42 share many histologic features with cutaneous ciliated cysts, and are considered the same entity by some authors.1 The cysts arise in multiparous young women and may be related to pregnancy or the use of exogenous progesterone. The cysts are usually located

551

connection to the overlying epidermis characterize these lesions (Fig. 25-14). Median raphe cysts are lined by a pseudostratified columnar epithelium, which varies in thickness, although it usually does not exceed five cell layers. In some areas, a single layer may be observed consisting of fusiform cells. Occasional mucin-containing cells may also be seen.43

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

DIFFERENTIAL DIAGNOSIS The characteristic location of these cysts, along with the nature of the lining, usually makes the diagnosis obvious.

CYSTS WITHOUT AN EPITHELIAL LINING

Digital Mucous Cysts  FIGURE 25-13 Ciliated cyst of the vulva. A single row of ciliated cuboidal cells lines the cyst.

on the superior (anterior) portion of the labium minus, range in size from 1.0 to 3.0 cm, and may be painful and discharge fluid. Malignant transformation has not been reported, and excision is curative. HISTOPATHOLOGIC FEATURES The cyst wall is lined by tall columnar or cuboidal clear cells that exhibit cilia on the luminal aspect. In some cases, small papillary projections are present (Fig. 25-13). Squamous metaplasia of the lining may be observed. Nuclei are basally located, and cells rest on a fibrous connective tissue lining. The cells contain neutral mucins, as demonstrated by mucicarmine and period acid-Schiff stains.

occur in young men; and are usually solitary and small, measuring only a few millimeters in diameter.43 Previous reports of apocrine cystadenoma arising on the penis most likely represent median raphe cysts. Median raphe cysts arise as a result of defects in embryologic development of the male genitalia, either from incomplete closure of the urethral or genital folds or from outgrowths of embryologic epithelium after primary closure of the folds. Median raphe cysts do not communicate with the urethra. HISTOPATHOLOGIC FEATURES Irregularly shaped unilocular cystic spaces without

Synonyms: Ganglion Digital mucous cysts are usually located on the dorsum of the finger next to the distal interphalangeal joint. They communicate with the adjacent joint space, to which they are attached by a pedicle. HISTOPATHOLOGIC FEATURES A digital mucous cyst consists of a compressed collagenous fibrous wall, which contains acid mucopolysaccharides that stain positively with Alcian blue and colloidal iron stains. Occasionally, a thin, attenuated, single epithelial lining may be observed, reflecting the origin from the synovial lining of the adjacent joint space. DIFFERENTIAL DIAGNOSIS Other lesions in which mucin is a prominent feature, such as focal papular mucinosis and myxedema, may be confused with

DIFFERENTIAL DIAGNOSIS The close similarity between the lining of the ciliated cyst of the vulva with that of the endocervix may suggest a diagnosis of metastatic endocervical adenocarcinoma; however, the lack of atypia in vulvar ciliated cyst differentiates the two lesions. Mesonephric cysts are more common and can be differentiated from ciliated cysts of the vulva by the nature of the epithelial lining, which is low-columnar and flattened in mesonephric cysts and does not contain mucin.

CYSTS LINED BY PSEUDOSTRATIFIED COLUMNAR EPITHELIUM

Median Raphe Cysts 552

Median raphe cysts are located exclusively on the ventral aspect of the penis;

 FIGURE 25-14 Median raphe cyst. The cyst is lined by pseudostratified columnar epithelium.

digital mucous cyst. However, the characteristic location of digital mucous cysts and the sharply localized distribution of the mucin help to distinguish digital mucous cysts from these other lesions.

Pilonidal Sinus

HISTOPATHOLOGIC FEATURES The sinus tract or cyst wall is located in the deep dermis or subcutis and is associated with a dense neutrophilic and lymphohistiocytic infiltrate. The cyst wall is lined by a stratified squamous epithelium, but the associated inflammatory infiltrate may obliterate or obscure the lining, and, in some cases, only a fibrous wall remains. A diagnostic feature of pilonidal cyst is the presence of hair shafts within the cyst or embedded in the inflammatory infiltrate. A connection with the epidermis is frequently but not invariably identified.

HISTOPATHOLOGIC FEATURES A cyst is present within the cartilage and lacks an epithelial lining. Inflammation is absent, and the overlying epidermis is normal. The cyst contains a straw-colored sterile fluid that is rich in albumin.49 The cavity may be filled with fibrous tissue and granulation tissue,50 and degenerative changes in the cartilage may be observed. DIFFERENTIAL DIAGNOSIS Entities to be considered in the differential diagnosis of PCA include subperichondrial hematoma and relapsing polychondritis. Subperichondrial hematoma displays large collections of blood within the cartilage, and the patient usually has a history of trauma. Relapsing polychondritis may present with a similar clinical appearance, but PCA and relapsing polychondritis can be distinguished by the presence of perichondral inflammation in relapsing polychondritis and the presence of a cyst in PCA.

Metaplastic Synovial Cysts Metaplastic synovial cysts (MSCs) may arise in any site that has undergone

trauma or disruption, including after injection of air into tissue,51 within scars after surgery,52,53 or after a puncture wound.54 Although usually located in the dermis, MSC frequently communicates with the overlying epidermis through fistulous tracts. The clinical impression most frequently includes suture granuloma, but other lesions, including leiomyoma and basal cell carcinoma, have also been included in the clinical differential diagnosis.54 HISTOPATHOLOGIC FEATURES MSCs are located in the dermis and contain broad villi that project into the cyst cavity (Fig. 25-15). The villous projections are lined by inflammatory cells, reactive cuboidal or epithelioid cells, and a fibrinous exudate. Mitotic figures and binucleated lining cells may be observed. The lining is strikingly reminiscent of inflamed synovium, simulating the appearance of villous synovitis. The core of the villous structure consists of loose connective tissue which contains spindled fibroblast-like cells aligned perpendicularly to the surface of the villi, and a scar can usually be identified at the base of the villous structure. Immunocytochemistry is strongly positive for vimentin in the spindled cells of the villi and in the epithelioid-like lining cells53,54 and is negative for epithelial markers. In some cases, the lining cells are weakly positive for α1-antichymotrypsin and lysozyme.53 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis includes other cysts

CHAPTER 25 ■ CUTANEOUS CYSTS AND RELATED LESIONS

Pilonidal cysts (or sinus) most commonly, but not exclusively, arise in the sacrococcygeal region and are more common in men. They may be congenital or acquired, and two theories of origin have been proposed. One school of thought is that pilonidal cysts are developmental abnormalities,8 but others believe the cysts are acquired and result from penetration of hairs into the skin, which induces the formation of a sinus or cyst.44 Inflammation and infection are commonly associated with pilonidal cysts, and, although rare, development of SCC has been reported.45-47 SCC arising in pilonidal sinus is usually well differentiated, but its clinical course is aggressive.

involved,48 with the majority of patients presenting during middle age. PCAs are usually unilateral but may be bilateral.49 They are asymptomatic and arise over the course of several weeks and present with cystic swelling of the anterior auricle. The etiology is unclear but may be a result of embryologic malformation of the pinna in association with ischemic necrosis and trauma.

DIFFERENTIAL DIAGNOSIS The characteristic clinical presentation, in association with the histologic features, usually makes the diagnosis of pilonidal cyst straightforward. However, entities such as Crohn disease, which may display inflamed fistulas extending from the large bowel to the skin in that region, and deep-seated infection should be considered in the histologic differential diagnosis. Crohn disease lacks the epithelial lining and embedded hair shafts of pilonidal sinus and displays noncaseating granulomas. In the absence of a clear cyst or cyst lining, a deep-seated abscess should be excluded with appropriate stains for organisms.

Pseudocyst of the Auricle Synonyms: Endochondral pseudocyst, cystic chondromalacia, intracartilaginous cyst Pseudocyst of the auricle (PCA) is an uncommon lesion arising in the upper anterior portion of the auricle. The majority of cases arise in males, and all ages are

 FIGURE 25-15 Metaplastic synovial cyst. Bulbous projections are lined by cuboidal cells reminiscent of inflamed synovium.

553

that lack a true epithelial lining, including digital mucous cyst and pilonidal sinus. However, digital mucous cyst lack villous structures and display mucin within the cyst cavity. Pilonidal sinus contain an intense inflammatory cell infiltrate, and fragments of hair can usually be identified.

RECENTLY DESCRIBED ENTITIES

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Proliferating Epithelial Cysts

554

PECs were first described by Sau and colleagues7 in 1995; they presented 33 examples. The male-to-female ratio is approximately 1:2, and PECs occur in patients from 21 to 88 years of age. PECs show epidermal-type keratinization and arise in ECs. Unlike proliferating pilar cysts, PECs are widely distributed, with more than 79% arising in areas other than the scalp. Simple excision of PECs may be followed by recurrence of the lesions, with 20% of the 33 patients showing recurrence from 5 months to 3 years after initial excision and three patients having multiple local recurrences. One patient died 2 years after surgery because of intractable local spread. No metastatic cases were observed. HISTOPATHOLOGIC FEATURES PECs are subepidermal cystic tumors; however, a significant proportion (45%) show a connection to the overlying epidermis. The cyst wall lining is similar to a more typical EC; however, in some areas, there is abundant proliferation of cells in which the cells acquire pale eosinophilic cytoplasm and sharp cytoplasmic borders. Other areas show a prominent granular layer adjacent to areas of loose laminated keratin. The epithelium shows various degrees of acanthosis, papillomatosis, hypergranuloses, parakeratosis, and hyperkeratosis. Cellularity and atypia are quite variable, and approximately 6% of the tumors show marked epithelial proliferation. Cytologic atypia may be observed, particularly in the more cellular lesions. Mitotic figures may be observed and may be frequent in some cases. DIFFERENTIAL DIAGNOSIS SCC is the most difficult lesion to distinguish from PEC because focal areas of PEC show marked cytologic atypia, making the distinction from SCC extremely difficult. Features in favor of PEC include a tendency to keratinize centrally, sharp circumscription, and evidence of a preexisting EC. Absence of overlying in situ carcinoma also helps to differentiate between SCC and PEC. Pilomatricoma may be

distinguished from PEC by the absence of sheets of basaloid cells, which are seen in pilomatricoma, and by the presence of trichilemmal keratinization in PEC.

Hybrid Epidermoid and Apocrine Cyst In 1996, Williams and colleagues described a previously unrecognized cyst, which they termed a hybrid epidermoid and apocrine cyst.55 This classification was based on the presence of a cyst lining composed of apocrine cells immediately adjacent to a stratified squamous epithelium with an intact granular layer. Of the four cases they described, two were on the nipple of the breast, and two were on the face. The patients were two men and two women ranging in age from 33 to 47 years. The clinical impression for three of the patients was cyst. Although the pathogenesis of the hybrid epidermoid and apocrine cyst is unknown, the authors speculated that they may arise at the junction of glandular and keratinizing squamous epithelium. They also noted, however, that because apocrine hydrocystomas are common on the face, it is possible that the squamous lining arose from squamous metaplasia of an apocrine hydrocystoma. It is also possible that the lesion represents a collision in which an apocrine hydrocystoma fused with an epidermoid inclusion cyst. HISTOPATHOLOGIC FEATURES The hybrid epidermoid and apocrine cyst is characterized by either a simple cyst without internal convolutions or a more complex cystic structure with papillary infoldings. All of the cysts had a distinctive apocrine lining consisting of cuboidal eosinophilic cells with prominent decapitation secretion. Immediately adjacent to these areas were stratified squamous epithelium typical of an epidermoid inclusion cyst. Abundant loosely packed orthokeratin was present within the cyst cavity. The authors also used immunoperoxidase stains to examine the nature of these cysts. There was strong positive staining of the apocrine portion of the cysts in two of the cases for carcinoembryonic antigen. DIFFERENTIAL DIAGNOSIS The hybrid epidermoid and apocrine cyst is a distinctive lesion and is unlikely to be confused with other cysts. The diagnosis may be overlooked if the cyst has a small component of apocrine cells, in which case epidermoid inclusion cysts would be mistakenly diagnosed. However, the characteristic apposition of the two cell types is a distinctive feature of the lesion.

REFERENCES 1. Kurban RS, Bhawan J: Cutaneous cysts lined by nonsquamous epithelium. Am J Dermatopathol. 1991;13:509-517. 2. Wang BY, Eisler J, Springfield D, et al: Intraosseous epidermoid inclusion cyst in a great toe. Arch Pathol Lab Med. 2003;127(7):e298-e300. 3. Shah V, Shet T: Scrotal calcinosis results from calcification of cysts derived from hair follicles: a series of 20 cases evaluating the spectrum of changes resulting in scrotal calcinosis. Am J Dermatopathol. 2007;29(2):172-175. 4. Egawa K, Honda Y, Ono T: Epidermoid cyst with sweat ducts on the torso. Am J Dermatopathol. 1995;17:71-74. 5. Mehregan DA, Al-Sabah HY, Mehregan AH: Basal cell epithelioma arising from epidermoid cyst. J Dermapathol Surg Oncol. 1994;20:405-406. 6. Kato N, Ueno H: Two cases of plantar epidermal cyst associated with human papillomavirus. Clin Exp Dermatol. 1992; 17:252-256. 7. Sau P, Graham JH, Helwig EB: Proliferating epithelial cysts: clinicopathological analysis of 96 cases. J Cutan Pathol. 1995;22: 394-406. 8. Pinkus H: Sebaceous cysts are trichilemmal cysts. Arch Dermatol. 1969;99:544-555. 9. Wong T-Y, Suster S: Tricholemmal carcinoma: a clinicopathologic study of 13 cases. Am J Dermatopathol. 1994;16:463-473. 10. Eiberg H, Hansen L, Hansen C, et al: Mapping of hereditary trichilemmal cyst (TRICY1) to chromosome 3p24-p21.2 and exclusion of -CATENIN and MLH1. Am J Med Genet A. 2005;133(suppl A):44-47. 11. Brownstein MH, Arluk DJ: Proliferating trichilemmal cyst: a simulant of squamous cell carcinoma. Cancer. 1981;48: 1207-1214. 12. Satyaprakash A, Sheehan, DJ, Sangueza O: Proliferating trichilemmal tumors: a review of the literature. Dermatol Surg. 2007;33(9):1102-1108. 13. Nyquist GG, Mumm C, Grau R, et al: Malignant proliferating pilar tumors arising in KID syndrome: a report of two patients: Am J Med Genet A. 2007; 143(suppl A):734-741. 14. Esterly NB, Fretzin DF, Pinkus H: Eruptive vellus hair cysts. Arch Dermatol. 1977;113: 500-503. 15. Stiefler RE, Bergfeld WF: Eruptive vellus hair cysts: an inherited disorder. J Am Acad Dermatol. 1980;3:425-429. 16. Binhlam JQ, Gross AS, Onadeko OO, et al: Acneiform eruption due to eruptive vellus hair cysts. South Med J. 1992;85: 322-325. 17. Grimalt R, Gelmetti C: Eruptive vellus hair cysts: case report and review of the literature. Pediatr Dermatol. 1992;9:98-102. 18. Ohtake N, Kubota Y, Takayama O, et al: Relationship between steatocystoma multiplex and eruptive vellus hair cysts. J Am Acad Dermatol. 1992;26:876-878. 19. Moon SE, Lee YS, Youn JI: Eruptive vellus hair cyst and steatocystoma multiplex in a patient with pachyonychia congenita. J Am Acad Dermatol. 1994;30:275-276. 20. Nogita T, Chi H-I, Nakagawa H, et al: Eruptive vellus hair cysts with sebaceous glands. Br J Dermatol. 1991;125:475-476. 21. Amichai B, Cagnano M, Halevy S: Coexistence of trichostasis spinulosa and

22.

23. 24. 25. 26. 27.

29.

30.

31. 32.

33. Suster S, Barbuto D, Carlson G, et al: Multilocular thymic cysts with pseudoepitheliomatous hyperplasia. Hum Pathol. 1991;22:455-460. 34. Mishalani SH, Lones MA, Said JW: Multilocular thymic cyst. Arch Pathol Lab Med. 1995;119:467-470. 35. Zvulunov A, Anichai D, Grunwald NH, et al: Cutaneous bronchogenic cysts: delineation of a poorly recognized lesion. Pediatr Dermatol. 1998;16(4):277-281. 36. Van der Putte SCJ, Toonstra J: Cutaneous “bronchogenic” cyst. J Cutan Pathol. 1985; 12:404-409. 37. Leunforte JF: Cutaneous ciliated cystadenoma in a man. Arch Dermatol. 1982; 118: 1010-1012. 38. Ashton MA: Cutaneous ciliated cyst of the lower limb in a male. Histopathology. 1995;26:467-469. 39. Sickel JZ: Cutaneous ciliated cyst of the scalp: a case report with immunocytochemical evidence for estrogen and progesterone receptors. Am J Dermatopathol. 1994;16:76-79. 40. Farmer ER, Helwig EB: Cutaneous ciliated cysts. Arch Dermatol. 1978;114:70-73. 41. True L, Golitz LE: Ciliated plantar cyst. Arch Dermatol. 1980;116:1066-1067. 42. Hart W: Paramesonephric mucinous cysts of the vulva. Am J Obstet Gynecol. 1970;107:1079-1083. 43. Asarch RG, Golitz LE, Sausker WF: Median raphe cysts of the penis. Arch Dermatol. 1979;115:1084-1086. 44. Yabe T, Furukawa M: The origin of pilonidal sinus: a case report. J Dermatol. 1995;22:696-699. 45. Davis KA, Mock CN, Versaci A, Lentrichia P: Malignant degeneration of pilonidal cysts. Am Surg. 1994;60:200-204.

46. Kim YA, Thomas I: Metastatic squamous cell carcinoma arising in a pilonidal sinus. J Am Acad Dermatol. 1993;29:272-274. 47. Jeddy TA, Vowles RH, Southam JA: Squamous cell carcinoma in a chronic pilonidal sinus. Br J Clin Pract. 1994; 48: 160-161. 48. Santos AD, Kelley PE: Bilateral pseudocyst of the auricle in an infant girl. Pediatr Dermatol. 1995;12:152-155. 49. Fukamizu H, Imaizumi S: Bilateral pseudocysts of the auricles. Arch Dermatol. 1984;120:1238-1239. 50. Engel D: Pseudocysts of the auricle in Chinese. Arch Otolaryngol. 1966;83:197-202. 51. Selye H: On the mechanism through which hydrocortisone affects the resistance of tissues to injury: an experimental study of the granuloma pouch technique. J Am Acad Dermatol. 1953;152: 1207-1213. 52. Gonzalez JG, Ghiselli RW, Santa Cruz DJ: Synovial metaplasia of the skin. Am J Surg Pathol. 1987;11:343-350. 53. Stern DR, Sexton FM: Metaplastic synovial cyst after partial excision of nevus sebaceus. Am J Dermatol. 1988;10:531-535. 54. Bhawan J, Dayal Y, Gonzalez-Serva A, Eisen R: Cutaneous metaplastic synovial cyst. J Cutan Pathol. 1990;17:22-26. 55. Williams K, Anderson ND, Babar K, et al: The hybrid epidermoid and apocrine cyst. The combination of apocrine hydrocystoma and epidermoid inclusion cyst. Am J Dermatopathol. 1996; 518(4):364-366.

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28.

eruptive vellus hair cysts. Int J Dermatol. 1994;33:858-859. Morgan MB, Kouseff BG, Silver A, et al: Eruptive vellus hair cysts and neurologic abnormalities: two related conditions? Cutis. 1991;47:413-415. Kumakiri M, Takashima T, Iju M, et al: Eruptive vellus hair cysts—a facial variant. J Am Acad Dermatol. 1982;7:461-467. Brownstein MH: Hybrid cyst: a combined epidermoid and trichilemmal cyst. J Am Acad Dermatol. 1983;9:872-875. Requena L, Yus ES: Follicular hybrid cysts: an expanded spectrum. Am J Dermatopathol. 1991;13:228-233. Mehregan AH, Medenica M: Pigmented follicular cysts. J Cutan Pathol. 1982;9: 423-427. Requena L, Martin L, Renedo G, et al: A facial variant of steatocystoma multiplex. Cutis. 1993;51:449-452. Steffen CH, Ackerman AB: Steatocystoma, in Neoplasms with Sebaceous Differentiation. Philadelphia: Lea and Febiger; 1994:147-181. Sabater-Marco V, Perez-Ferriols A: Steatocystoma multiplex with smooth muscle: a hamartoma of the pilosebaceous apparatus. Am J Dermatopathol. 1996;18(5):548-550. Oakman JH, Lambert SR, Grossniklaus HE: Corneal dermoid: case report and review of classification. J Pediatr Ophthamol Strabismus. 1993;30:388-391. Miller MB, DeVito MA: Cervical thymic cyst. Otolaryngol Head Neck Surg. 1995; 112:586-588. Babu MK, Nirmala Y: Thymic carcinoma with glandular differentiation arising in a congenital thymic cyst. J Surg Oncol. 1994; 57:277-279.

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CHAPTER 26 Tumors of the Epidermis

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Alan S. Boyd

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Many cutaneous biopsies are performed to evaluate a lesion’s malignant potential. Fortunately, most of these tumors are benign. The distinction is important, however, because significant surgical procedures may be needed for some tumors but are inappropriate for others. Further, some of these lesions may indicate underlying conditions that require additional evaluation and treatment. For these, as well as other reasons, it is imperative that dermatopathologists seek to accurately classify the epidermal tumors they are called upon to evaluate.

EPIDERMAL NEVI AND RELATED PROCESSES

Epidermal Nevus Epidermal nevi are proliferations of the epithelium that may be associated with different syndromes. Most tumors are isolated lesions that are present at birth or arise within the first few years of life. Others are associated with what is termed the epidermal nevus syndrome. These patients demonstrate defects of the central nervous system (CNS) (epilepsy, mental retardation), skeletal system (bone anomalies, cysts and deformities), eyes (colobomas, cataracts, choristomas), and oral cavity (absent or malformed teeth).1 The most impressive variant is termed nevus unius lateris; in this subtype, the epidermal nevi are arranged in a whorled fashion on the trunk, extremities, or both in the pattern of Blaschko lines. Greater and more systematized involvement is termed ichthyosis hystrix. The term epidermal nevus syndrome has been applied solely to five conditions—Schimmelpenning syndrome, nevus comedonicus syndrome, pigmented hair epidermal nevus syndrome (Becker nevus syndrome), Proteus syndrome, and the CHILD (congenital hemidysplasia with ichtyhosiform erythroderma and limb defects) syndrome.2 A sixth syndrome, phacomatosis pigmentokeratotica, has been recently described.3 Chromosomal breakpoints, indicating

genetic mosaicism, have been found on some cell lines in affected patients.4 Chou et al.5 described a patient with the epidermal nevus syndrome and hypophosphatemic rickets. CLINICAL FEATURES Epidermal nevi present as papules, nodules, and patches of verrucous epidermal hyperkeratosis. They may be isolated, linear, zosteriform, or whorled.6 Most lesions are different shades of brown but may also be gray, black, or flesh colored. Comedo-like plugs and filliform hyperkeratosis have also been described.7 Inflammation or irritation is usually confined to traumatized epidermal nevi. Most lesions are asymptomatic, but mild pruritus may occur. A form of epidermal nevus with clinical and pathologic features of acanthosis nigricans has been recently reported.8 HISTOPATHOLOGIC FEATURES There are several different variants of epidermal nevi.9 The most common demonstrates sharply demarcated hyperkeratosis with papillomatosis. The epidermis is acanthotic with a focally thickened granular layer and columns of parakeratosis.1 The basal layer is frequently hyperpigmented.10 A second type shows features reminiscent of acrokeratosis verruciformis with a “church spire” type of papillomatosis. There is significant hyperkeratosis, acanthosis, and an exaggerated granular layer. Epidermolytic hyperkeratosis is seen in some specimens and has been linked to mutations in keratin genes 1 and 10.1,11 These lesions demonstrate irregularly shaped keratohyaline granules, perinuclear vacuolization, and moderate to marked hyperkeratosis. Finally, the verruca vulgaris variant demonstrates vacuolated cells with orthohyperkeratosis, parakeratosis, papillomatosis, and an increased number of keratohyaline granules. Other variants resemble a seborrheic keratosis or porokeratosis.6 Psoriasiform changes may also be seen but are more common in an inflamed linear verrucous epidermal nevus (ILVEN). Acantholysis is present in some lesions and may represent a mosaic form of Darier disease.12,13 Although the dermis is typically not involved, a lichenoid or perivascular inflammatory infiltrate may be present. Pigment incontinence may also be found. Squamous cell carcinoma, basal cell carcinoma, trichilemmal cysts, and keratoacanthoma have been described in epidermal nevi.7,14 DIFFERENTIAL DIAGNOSIS Epidermal nevi must be differentiated from seborrheic

keratoses, warts, and acrokeratosis verruciformis. Seborrheic keratoses have horn pseudocysts and a “flat bottom” epidermal acanthosis. Papillomatous variants are more regularly arrayed than are epidermal nevi. Verrucae have more koilocytic changes and hypergranulosis. Additionally, prominent vascular structures and occasional ectasia may be seen in the papillary dermis. These changes are not present in epidermal nevi. Epidermolytic hyperkeratosis is present in numerous lesions and is typically unexplained. Bullous ichthyosiform erythroderma shows the typical changes of epidermolytic hyperkeratosis but is more symmetrical and involves the entire epidermis. In epidermal nevi with epidermolytic hyperkeratosis, the process is usually focal or intermittent. Acrokeratosis verruciformis is papillomatous and hyperkeratotic but regular and symmetrical. Clinical information may be required to differentiate among these entities (Table 26-1).

Dowling-Degos Disease Dowling-Degos disease (DDD) is also known as reticulate pigmented anomaly of the flexures or dark dot disease. It is believed to be in a disease spectrum that includes Haber syndrome, reticulate acropigmentation of Kitamura (RAPK), pigmentation reticularis faciei et colli with epithelial cystomatosis, and familial multiple follicular hamartoma.15-19 It is inherited in an autosomal dominant fashion with variable penetrance and is more common in women.15,19 Mild mental retardation,

Table 26-1 Epidermal Nevus

Clinical Features Verrucous brown papules and patches in an isolated or linear array Some mild scaling and hyperkeratosis Few symptoms Histopathologic Features Irregular epidermal hyperkeratosis, papillomatosis, hypergranulosis Occasional parakeratosis and epidermolytic hyperkeratosis Basal layer hyperpigmentation Scant perivascular lymphohistiocytic inflammatory infiltrate Differential Diagnosis Seborrheic keratosis Wart Epidermolytic hyperkeratosis Acrokeratosis verruciformis

non-scarring alopecia, and an association with human leukocyte antigen (HLA) B6 have been described.16,20 Two loci on chromosomes 12q and 17p13.3 are believed to be linked to this condition.21 The onset is typically in early adulthood. Two patients with Haber syndrome and malignancies arising from cutaneous keratoses have been reported.22

HISTOPATHOLOGIC FEATURES The epidermis is slightly thinned or atrophic.25 The stratum corneum may be slightly hyperkeratotic but is largely unremarkable. Delicately branching club-shaped rete ridges project into the dermis. These rete ridges are hyperpigmented, occasionally in a patchy manner, and are two to four cells in width. Their branching has been likened to an “antler.”16,20 This epidermal proliferation is also present along the infundibulum of hair follicles.17 Increased numbers of melanocytes are present. Melanin is appreciated in basal keratinocytes as finely dispersed granules scattered uniformly within the cytoplasm.26 Small intraepidermal keratin cysts may be seen, and plugging of the follicular infundibulum is present.20 The dermis displays a nonspecific perivascular lymphohistiocytic infiltrate and pigmentladen macrophages. A variant of DDD demonstrating suprabasilar acantholysis (Galli-Galli disease) has also been reported.27 Desmogleins 1 and 2 are present normally in affected tissue, but desmocollin 3 has shown a shift from extracellular to intracellular expression along the basal layer in epidermal downgrowths.28 DIFFERENTIAL DIAGNOSIS DDD (Table 26-2) should be differentiated from adenoid seborrheic keratosis, senile lentigo, and

Clinical Features Reticulate pigmentation of the flexures Pitted perioral scars Comedo-like lesions Histopathologic Features Mild hyperkeratosis Slightly thinned epidermis Downward projection of the epidermal rete ridges Basal layer hyperpigmentation Occasional small horn pseudocysts Differential Diagnosis Adenoid seborrheic keratosis Solar lentigo Acanthosis nigricans

acanthosis nigricans. Adenoid seborrheic keratoses are usually much more proliferative lesions extending in a gland-like array well into and usually through the papillary dermis. The epidermal rete ridges in DDD are unlikely to be that extensive, and horn pseudocyst production is limited. Solar lentigos rarely demonstrate horn pseudocysts and are usually more pigmented than DDD. Acanthosis nigricans shows a more regular papillomatosis without downward projections of rete ridges, greater hyperkeratosis, and minimal basal layer hyperpigmentation.

Acanthosis Nigricans This condition was initially reported by Pollitzer in 1890.29 It is divided into four clinical categories—benign, malignant, syndromic, and obesity associated.30 Associated syndromes include the type A (HAIR-AN) and type B syndrome, both of which are characterized by insulinresistant diabetes mellitus.31,32 Other syndromes include the Hirschowitz syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), the Lawrence-Seip syndrome, and leprechaunism.32-35 Certain drugs induce acanthosis nigricans, including nicotinic acid, estrogens, systemic corticosteroids, heroin, insulin, pituitary extract, oral contraceptives, hydantoinlike derivatives, somatotrophin, fusidic acid, highly active antiretroviral therapy, and methyltestosterone.31,36-38 The cutaneous changes of acanthosis nigricans are believed to result from prolonged growth factor stimulation of keratinocytes and dermal fibroblasts.31 An association with a fibroblast growth factor receptor 3 gene

mutation in a child with familial disease has been described.39 Mucosal involvement is present in about one-third of patients and may be more prevalent in those affected by underlying malignancies. Tumors associated with malignant acanthosis nigricans in adults are typically abdominal adenocarcinomas.40 In pediatric cases, gastric adenocarcinoma is well represented as is Wilm tumor and osteogenic sarcoma.37 CLINICAL FEATURES Acanthosis nigricans is seen in all races but is more common in blacks and Hispanics.31 Obesity is a predisposing factor. It is found in persons of all ages, including at birth, but is most common in young patients.31,41 The earliest changes include a vague darkening or hyperpigmentation of the skin. Dryness and a rough texture are present. As the disease progresses, the affected skin becomes darker and thicker, eventually assuming a velvety texture. Patches may become yellow, brown, gray, or black.31 Skin lines are accentuated as furrowing occurs. Small papillomatous projections are seen in early disease and grow as the process proceeds.32,42 The axillae and sides of the neck are most commonly involved, but almost any cutaneous surface may be affected. The mucosal surfaces are hyperpigmented or slightly stippled but not velvety. Patients with disease beginning in childhood and oriented along Blaschko lines have been reported and may represent a mosaic form of acanthosis nigricans.43

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

CLINICAL FEATURES Affected patients have reticulate flexural pigmentation, infundibular cysts, breaks in dermatoglyphics, and pitted scars around the mouth.18,23 This scarring may extend onto the face. Comedo-like lesions have been described, and this condition has been confused with chloracne.16,18,19,24 Hypopigmented macules and papules have also been reported.23 RAPK shows symmetrical atrophic freckle-like lesions and pitting on the dorsal hands, feet, and sides of the neck.19 Slow, progressive hyperpigmentation of atrophic macules begins in adolescence and may be accentuated by sunlight. These lesions may eventually become gray-blue to black. Pigmented scars are found at the angles of the mouth with comedone-like lesions on the neck.18

Table 26-2 Dowling-Degos Disease

HISTOPATHOLOGIC FEATURES Fully developed lesions show regular papillomatosis, mild acanthosis, and hyperkeratosis.31,32 Parakeratosis is uncommon. Intermittent areas of epidermal atrophy may be present and may be accentuated depending on the patient’s underlying health. Horn pseudocysts are rare. There is mild hyperpigmentation along and above the basal layer. The papillomatosis is believed to derive from an upward projection of the dermal papillae into an already thinned epidermis.42,44 There is usually a scant perivascular lymphohistiocytic infiltrate and mild pigment incontinence. Mucin deposition has been described.31 Mucosal disease demonstrates epithelial hyperplasia with parakeratosis. Papillomatosis may also be seen, but hyperpigmentation is absent, and there is little, if any, pigment incontinence.44 An infiltrate of lymphocytes, plasma cells, and occasional neutrophils is present. DIFFERENTIAL DIAGNOSIS The differential diagnosis for acanthosis nigricans includes

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 558

seborrheic keratoses, epidermal nevi, and confluent and reticulate papillomatosis (Table 26-3). Seborrheic keratoses usually have a greater number of horn pseudocysts, occasional parakeratosis, and “flattening out” along the base of the epidermal proliferation. Stucco keratoses, a variant of seborrheic keratoses, however, may be particularly difficult to differentiate from acanthosis nigricans. Epidermal nevi have a more broad and “rough” papillomatosis with greater amounts of hyperkeratosis. Epidermal atrophy is unusual in these lesions. Confluent and reticulate papillomatosis shows intermittent parakeratosis, a greater degree of basal layer hyperpigmentation, and elastic fiber fragmentation.

have been reported.50 Summertime aggravation has been reported.47 The chest, upper arms, back, and neck are most commonly affected. Papules 1 to 2 mm in size emerge and enlarge to 4 to 5 mm. The eruption becomes confluent around the midline and more reticulated as it expands peripherally. Axillary lesions are slightly verrucous.49 Lesions are initially red to brown and become darker and grayer as they age. A true scale is not present, but scraping the lesions may yield a small amount of keratogenous debris. Patients experience no symptoms, and mucosal involvement does not occur. After the eruption has reached its full expansion, it tends to remain unchanged.47

Confluent and Reticulate Papillomatosis of Gougerot and Carteaud

HISTOPATHOLOGIC FEATURES The epidermis is hyperkeratotic with papillomatosis and parakeratosis. Some follicular plugging with laminated keratin may be seen.49 Downgrowths of the epidermis may be present from between the papillomatous rete ridges. Acanthosis as well as atrophy of the stratum malpighii have been described.47,49 The granular layer is normal or slightly decreased. There is a mild increase or decrease of basal layer pigmentation. Blood vessels in the dermis are slightly dilated and demonstrate a minimal perivascular lymphohistiocytic infiltrate.47 Fragmentation of the elastic fibers in the upper and lower dermis has been described.47,49 Mild papillary dermal edema may be present.47

Confluent and reticulate papillomatosis was initially described in 1927 by Gougerot and Carteaud.45 This disorder may represent an imbalance of the endocrine system, a variant of amyloidosis, an abnormal host response to colonization by Pityosporum organisms, or an inherited condition.46,47 It is currently believed to be a disorder of keratinization. CLINICAL FEATURES This eruption occurs around adolescence.46,47 It affects women more often than men and blacks more often than whites.46,48,49 Although it is considered nonhereditary, familial cases

DIFFERENTIAL DIAGNOSIS Confluent and reticulate papillomatosis must be differentiated from acanthosis nigricans, DDD, and seborrheic keratoses (Table 26-4).

Table 26-3 Acanthosis Nigricans

Clinical Features Velvety plaques involving the axillae and neck Mucosal lesions are seen Associated with obesity, underlying malignancy, various syndromes, and drug intake All ages are affected Histopathologic Features Papillomatosis, moderate hyperkeratosis, and a mildly thinned epidermis Minimal basal layer hyperpigmentation and rare horn pseudocyst formation Mild perivascular inflammation Differential Diagnosis Seborrheic keratoses (including stucco keratoses) Epidermal nevi Confluent and reticulate papillomatosis

Table 26-4 Confluent and Reticulate Papillomatosis

Clinical Features Begins around adolescence Women > men; blacks > whites Small 45-mm patches of hyperpigmentation arising on the chest and back Confluence of the lesions toward the midline Histopathologic Features Papillomatosis, hyperkeratosis, parakeratosis, and acanthosis Increased basal layer pigmentation Epidermal downgrowths from between the rete ridges Differential Diagnosis Acanthosis nigricans Dowling-Degos disease Seborrheic keratoses

Acanthosis nigricans shows less basal layer hyperpigmentation, few dermal changes, and no parakeratosis. Additionally, endophytic epidermal proliferations are not seen with this disease. DDD demonstrates greater pigment deposition along the basal layer and the occasional presence of a horn pseudocyst. Seborrheic keratoses are usually more hyperkeratotic, possess horn pseudocysts, and are more likely to show epidermal acanthosis. Inflammation is also much more likely with these lesions.

Inflammatory Linear Verrucous Epidermal Nevus The inflammatory linear verrucous epidermal nevus (ILVEN) is believed to be a variant of an epidermal nevus and was first reported by Unna in 1896.51 An initial series of 25 cases was presented in 1971.52 CLINICAL FEATURES These lesions arise early in life (half by 6 months of age), although onset during adulthood has also been reported.9,52-55 The legs and thighs are most commonly involved, but the lesions may also be seen on the arms, buttocks, groin, and genitalia. Some authors have postulated that the left side of the body is involved more frequently than the right,52 but others have disagreed.53 Females are more often affected than males.56 A generalized variant and familial occurrence have been described.57 Intense pruritus is common. Associated arthritis, similar to that of juvenile psoriatic arthritis, has been reported.58 Inflammatory linear verrucous epidermal nevi begin as flesh colored to red papules that arise in a linear fashion. The papules become dark red to brown with scaling and crusting. A tendency to follow Blaschko lines may be present. They may clinically resemble eczematous dermatitis or psoriasis and may develop a lichenoid appearance.9,52,59 Controversy exists as to whether ILVEN represents a mosaic form of psoriasis vulgaris.60,61 HISTOPATHOLOGIC FEATURES The epidermis shows exaggerated rete ridges with hyperkeratosis and parakeratosis (Fig. 26-1). There may be a sharp demarcation between the areas of parakeratosis with a decreased to absent granular layer and orthohyperkeratosis with an intact or accentuated granular layer.54,62 This alternating type of pattern is characteristic of that seen in ILVEN. There is acanthosis with psoriasiform changes, mild to moderate papillomatosis, and an even elongation of the rete ridges. Mitotic activity may be brisk, but atypical mitotic

present at birth, but some develop during adolescence or adulthood. Although it is usually an isolated lesion, it may be associated with skeletal defects, CNS abnormalities, ocular pathology, and other cutaneous diseases (eg, ichthyosis, epidermal nevus, furunculosis, cataracts, Becker nevus, basal cell carcinoma, eccrine nevus, follicular tumors, trichilemmal cysts).65-69 Nevus comedonicus has arisen after blunt trauma, herpes zoster, lichen planus, smallpox vaccination, and pyoderma.64,65,68 Lesions are believed to represent rudimentary hair follicles with some type of developmental anomaly.66,67

figures are not seen.52 Exocytosis is present in some specimens, and microabscesses may form.53,54,62 There may be slightly increased dermal vascularity.52 The dermis contains a perivascular and interface inflammatory infiltrate that may be quite brisk at times.52,53 The lymphocytes are primarily T cells.56 An evaluation of the immunohistochemical properties of ILVEN compared with psoriasis vulgaris demonstrated increased keratin-10–positive keratinocytes and greater HLA-DR expression in the former but a markedly reduced number of T lymphocytes relevant to the pathogenesis of the latter.61 DIFFERENTIAL DIAGNOSIS It is important to be able to differentiate an ILVEN from psoriasis, contact dermatitis, eczematous dermatitis, and resolving warts (Table 26-5). Psoriasis vulgaris does not show the typical alternating parakeratosis and orthohyperkeratosis seen in ILVEN. Additionally, the dilated papillary dermal vessels, infiltrating neutrophils, neutrophil-rich Munro microabscesses, and thinned suprapapillary plates favor a diagnosis of psoriasis. Chronic eczematous and contact dermatitis are psoriasiform with mild spongiosis and exocytosis but do not show the parakeratosis seen with ILVENs and have infiltrating eosinophils.52 Senescent warts often demonstrate papillomatosis but usually do not have psoriasiform changes and show parakeratosis emanating from the tips of the papillomatous projections.

Nevus Comedonicus Nevus comedonicus is a linear lesion characterized by a proliferation of keratinfilled comedones and was initially described by Kofmann in 1895.63 It is a rare condition with no suggestion of a heritable pattern or gender preference.64,65 It has been primarily described in whites but may be seen in all races. Most lesions are

Table 26-5 Inflammatory Linear Verrucous Epidermal Nevus

Clinical Features Begins at an early age, often in the first year of life Red to brown hyperkeratotic papules that coalesce into a linear lesion Usually on the extremities, buttocks, and genitalia Pruritus is common and may be intense Histopathologic Features Alternating hyperkeratosis and parakeratosis overlying an increased and decreased granular layer Papillomatosis and psoriasiform hyperplasia Exocytosis with microabscess formation Perivascular and interface lymphocytic infiltrate Differential Diagnosis Psoriasis vulgaris Chronic eczematous or contact dermatitis Senescent wart

HISTOPATHOLOGIC FEATURES Epitheliumlined invaginations are present and may be normal or decreased in thickness (Figs. 26-2). Irregular papillomatous projections proliferate into the surrounding dermis. Epidermolytic hyperkeratosis has been described.65,70,72 Atrophic or abortive hair follicles and rudimentary sebaceous glands may be seen.64,65,67 The epithelial lining forms a compact, lamellated keratin plug. Parakeratosis is absent.67 The interfollicular epidermis appears normal.64 The surrounding dermis is largely unremarkable unless one of the comedos has ruptured. Cytokeratin expression in these neoplasms has been reported as normal, but filaggrin was found in closed comedones, suggesting that a disorder of terminal differentiation related to this protein may play a role in its pathogenesis.73 A similar lesion, the dilated pore nevus, has been described as a hamartoma of the dilate pore of Winer and clinically and histologically resembles a nevus comedonicus.74 The former lesion shows a more prominent granular layer and a greater degree of epithelial proliferation. It appears likely that nevus

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

 FIGURE 26-1 Inflammatory linear verrucous epidermal nevus. The epidermis is hyperkeratotic and papillomatous with interface inflammation.

CLINICAL FEATURES Nevus comedonicus is usually unilateral and linear or zosteriform. There is some suggestion that these tumors follow the lines of Blaschko.65 Bilateral and symmetric involvement has been described.66 They involve the face, neck, thorax, and abdomen.64,65 Lesions consist of slightly raised papules containing a firm, dark hyperkeratotic plug that resembles a comedo.64,67,70 The skin has a rough texture and is hypo- or hyperpigmented between comedos.65 The keratin plugs are adherent and not easily removed. There may be a slight burning sensation to the lesion, but most are without symptoms. Some lesions become chronically inflamed and suppurative. Fistulas, scarring, and abscesses may result.64,65,69,71

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A

 FIGURE 26-2 Nevus comedonicus. (A) The epithelium-lined comedonal invaginations extend into the dermis. (B) Large cystic invaginations predominate.

comedonicus may represent a spectrum of pilosebaceous malformations with the dilated pore nevus representing one end of that spectrum.

have been reported.76 The condition is believed to be inherited as an autosomal dominant trait.77-80 The patient’s health is otherwise normal.

DIFFERENTIAL DIAGNOSIS Nevus comedonicus must be differentiated from a dilated pore of Winer, a trichofolliculoma, a pilar sheath acanthoma, the upper portion of an infundibular (epidermoid) cyst, and a porokeratotic eccrine ostial and dermal duct nevus (Table 26-6).66,74 A dilated pore of Winer is a solitary lesion and shows a more proliferative and hyperplastic epithelium as is expands into the surrounding dermis. Association with sebaceous glands is rare. A trichofolliculoma is a solitary proliferation of incompletely differentiated hair follicles inserting into a single dilated infundibulum. This infundibulum is filled with keratinous debris and small hair shafts. Pilar sheath acanthomas are proliferations of the sebaceous duct and demonstrate a diminished to absent granular layer and pink staining keratinocytes. Infundibular cysts occasionally demonstrate a connecting infundibulum with features typical for a nevus comedonicus. However, a single structure is usually present, and the epithelial lining is not proliferative. Finally, the porokeratotic eccrine ostial and dermal duct nevus is usually found on acral skin and demonstrates a coronoid lamella.

CLINICAL FEATURES Lesions appear in childhood or adolescence as open comedones and small hyperkeratotic papules.77,79 These papules may appear as

Familial Dyskeratotic Comedones 560

B

This entity was initially described in 1972.75 To date, fewer than 20 cases

Table 26-6 Nevus Comedonicus

Clinical Features Close set or grouped aggregate of dark papules with keratin-filled plugs Usually unilateral and linear Found mostly on face, neck, and trunk Occasionally arise after a traumatic event May be associated with rupture, inflammation, abscesses, and scarring Histopathologic Features Epidermal invagination filled with compact and lamellated keratin Slight papillomatous proliferation into surrounding dermis Atrophic sebaceous glands and rudimentary hair bulbs present Granulomatous inflammation and scarring with comedo rupture Differential Diagnosis Dilated pore of Winer Trichofolliculoma Pilar sheath acanthoma Infundibular cyst Porokeratotic eccrine ostial and dermal duct nevus

cutaneous horns. The eruption is generalized but spares the palms, soles, and mucous membranes. The nails and hair are normal.79 The papules occasionally have a pruritic or burning sensation. Inflammation may be noted if the comedones rupture. HISTOPATHOLOGIC FEATURES Epitheliumlined invaginations are present and are filled with laminated keratinous material.77-79 Focal areas of acantholysis and dyskeratosis are present, particularly at the base of the invagination. Grains, corps ronds, and suprabaslar clefts are appreciated, but hair shafts and other pilosebaceous structures are generally absent. Proliferation of epidermal “villi” into the surrounding dermis is not seen. Electron microscopy reveals decreased desmosomal attachments.79 Acantholytic cells and grains possess a dense perinuclear tonofilament and keratohyaline aggregation similar to that in other acantholytic diseases. DIFFERENTIAL DIAGNOSIS The differential diagnosis for familial dyskeratotic comedones includes Darier disease, warty dyskeratoma, and comedones or nevus comedonicus (Table 26-7).79 Darier disease does not demonstrate formation of comedones and usually has a much greater degree of acantholysis and corps rond formation. Warty dyskeratomas tend to be larger, “flask” shaped, more acantholytic, and more villous. Comedones as seen in isolated lesions or nevus comedonicus may have pilosebaceous structures associated with the lesions but do not

Table 26-7 Familial Dyskeratotic Comedones

demonstrate acantholysis or dyskeratotic keratinocytes.

PSEUDOEPITHELIOMATOUS HYPERPLASIA

Granuloma Fissuratum Sutton initially described this lesion in 1932 as occurring in the mouth.81 Granuloma fissuratum may arise from poorly fitting dentures and accumulation of food particles with maceration. In 1965, Epstein reported its occurrence behind the superior pole of the ear and proposed a relationship to poorly fitting spectacles.82 It is also believed to arise on the nose from similar factors.83 Glass frames constructed with nitrate and cellulose acetate result in rough matt finishes, and prolonged skin contact may provoke these lesions.84 The weight of the glasses, concomitant skin disease, maceration, and abnormal anatomy also contribute.85,86 Some investigators believe this condition is a variant of prurigo nodularis. Resolution of the disease occurs in 1 to 6 months if the glasses are repaired or replaced. This disease is also known as acanthoma fissuratum and spectacle-frame acanthoma.85,86 A similar clinical presentation has been described as affecting the posterior fourchette in middle-aged women.87 CLINICAL FEATURES Lesions appear as smooth to fissured growths on the nasal bridge and behind the ears, usually at the upper pole of the sulcus.88 A shallow to deep longitudinal fissure is present. Most cases are unilateral, but bilateral cases have also been described.86 Lesions are flesh colored to red and are firm.

HISTOPATHOLOGIC FEATURES The epidermis shows acanthosis and hyperkeratosis with mild to moderate parakeratosis. The granular layer is present and may be accentuated. Spongiosis is variably present.85,88 The epidermis forms a central depression corresponding to the longitudinal fissure seen clinically. This depression may be filled with keratinous debris and inflammatory cells.86 Elongation and broadening of the rete ridges has been described.88 Blood vessels in the papillary dermis may be dilated. The perivascular inflammatory infiltrate consists of lymphocytes, plasma cells, and eosinophils. Mild dermal fibrosis may be present.86 DIFFERENTIAL DIAGNOSIS Granuloma fissuratum should be differentiated from lichen simplex chronicus, prurigo nodules, and chronic eczematous or contact dermatitis (Table 26-8). Lichen simplex chronicus and prurigo nodules generally show little or no spongiosis and a very prominent granular layer. Dermal fibrosis is usually present with “collagen streaking” between the rete ridges and mild pseudoepitheliomatous or psoriasiform epidermal hyperplasia. Additionally, a longitudinal depression is not found in these conditions. Similarly, with chronic eczematous or contact dermatitis the granular layer is well formed, and a psoriasiform hyperplasia is common. Eosinophils may be numerous, but a longitudinal depression is not appreciated.

Table 26-8 Acanthoma Fissuratum

Clinical Features Smooth, flesh-colored to red nodules at the upper pole of the postauricular sulcus and on the nasal bridge Provoked by improperly fitting spectacle frames Histopathologic Features Longitudinal epidermal depression filled with hyperkeratotic and inflammatory debris Acanthosis, hyperkeratosis, and parakeratosis Perivascular inflammatory infiltrate of lymphocytes, plasma cells, eosinophils Mild dermal fibrosis Differential Diagnosis Lichen simplex chronicus Prurigo nodule Chronic eczematous or contact dermatitis

Prurigo Nodularis Prurigo nodularis results when a focal proliferative epidermal response occurs secondary to repeated trauma. Hyde initially described it in 1909 as an eruption with recalcitrant pruritus that typically involved the extremities of women.89 Neural hyperplasia was noted and the disease has been termed Pautrier neuroma. Different etiologies have been proposed for this disease, including a Merkel cell disorder, arthropod assaults, protracted folliculitis, trauma, deposition of eosinophil granules, and underlying eczematous dermatosis.90-92 Prurigo nodularis is found in association with hypertension, HIV infection, obesity, renal dysfunction, anemia, hepatic disease, Helicobacter pylori colonization of the gut, and associated psychiatric disorders such as anxiety or depression.90,93,94 Most patients have an elevated IgE count, and increased interleukin-31 levels in cutaneous lesions have been reported.90,95 Lesions demonstrating atypical mycobacteria within the upper epidermis and on tissue culture have been described, leading to speculation that these organisms may play an etiologic role in this condition.96 Squamous cell carcinoma and keratoacanthoma arising in long-standing nodules have been described.97,98 CLINICAL FEATURES Lesions present as small nodules on the extensor surfaces of the lower extremities.90,99 The arms and trunk may be involved, but areas that cannot be reached are free of disease. No part of the body is exempt from involvement, including the face. Proximal lesions are more common. Prurigo nodules are dark, lichenified, verrucous, and firm and may possess overlying scale crust.100 Excoriation is not uncommon. A halo of postinflammatory pigmentation may be present.90 Pruritus is usually described as profound and is provoked by stress and heat.100 Middle-aged women are most commonly affected. The condition is rare in children. HISTOPATHOLOGIC FEATURES The epidermis shows the typical changes of longstanding and repeated trauma, namely, orthohyperkeratosis, a thickened granular layer, and acanthosis with occasional mild spongiosis.99 The epidermal proliferation may be psoriasiform (see Fig. 4-15). The tumors are symmetrical and usually well circumscribed. The changes are reminiscent of chronic eczematous or contact dermatitis. If particularly proliferative, the epidermis may demonstrate

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

Clinical Features Generalized eruption of open comedones and hyperkeratotic papules Autosomal dominantly inherited Begins in childhood or adolescence Histopathologic Features Dilated follicle-like structures with laminated keratinous material Acantholysis, dyskeratosis, and suprabasalar clefting are present Few corps ronds and grains Pilosebaceous structures absent Differential Diagnosis Darier disease Warty dyskeratoma Idiopathic comedones or nevus comedonicus

Symptoms are uncommon. Perilesional inflammation may be present. The overlying skin is usually intact, and ulceration is rare.86

561

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 562

pseudoepitheliomatous hyperplasia, that is, the proliferation of a mildly eosinophilic and pale epidermis with asymmetric, bulbous epithelial acanthosis. In the dermis, a mild to moderate perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and occasional eosinophils is seen.100 If the lesions are chronic, plasma cells may be present. Mast cells are increased, and Merkel cells are increased in number.92,100-102 Occasional neutrophils are present.91 The papillary dermis shows mild fibrosis between the downgrowing rete ridges.99 Fibroblasts may be abundant. Blood vessels are increased, and subepidermal fibrin is deposited.90 Increased amounts of melanocyte-stimulating hormone have been found in capillary endothelial cells, suggesting an immunomodulatory effect by this protein.103 Nerve counts in affected tissues are greater than in controls; however, the previously reported phenomenon of neural hyperplasia has been disproven.90,100 Ultrastructural findings include abnormalities in neural axons and surrounding Schwann cells.99 Schwann cells demonstrate absent endoplasmic reticulum; diminished numbers of mitochondria; and a few asymmetric, membrane-bound vacuoles. DIFFERENTIAL DIAGNOSIS The differential diagnosis for prurigo nodularis includes lichen simplex chronicus, keratoacanthoma, and pseudoepitheliomatous hyperplasia associated with other disorders (Table 26-9). Lichen simplex chronicus is not a nodule but rather a patch

or plaque. As such, the symmetry and circumscription seen with prurigo nodularis are lacking. Additionally, the epidermal hyperplasia is not as pronounced and tends to be more regular or psoriasiform. Keratoacanthomas commonly demonstrate the proliferative epidermal characteristics seen in prurigo nodularis. However, the keratogenous plug, epidermal atypia, and intraepidermal neutrophilic microabscesses are not present in prurigo nodularis. Pseudoepitheliomatous hyperplasia is a pathologic reaction pattern that arises after trauma or irritation from a variety of causes. Deep fungal infections, Spitz nevi, granular cell tumors, and halogenodermas may demonstrate this reaction pattern. Special stains for microorganisms and different cell types may help differentiate these diseases from prurigo nodularis.

ACANTHOMAS/KERATOSES

Epidermolytic Acanthoma Shapiro and Baraf initially described epidermolytic acanthomas in 1970.104 These tumors present as isolated or disseminated lesions.105 The epidermolysis may represent an increased metabolic activity of the corneocytes or a neoplastic recapitulation of a developmental anomaly.106 Human papillomavirus (HPV) infection has not been found using polymerase chain reaction (PCR) testing.107 An abnormality in the genes responsible for the production of keratins K1 and K10 has been proposed. Lesions may be

induced by ultraviolet (UV) light or trauma.108 CLINICAL FEATURES Most patients are middle aged. Lesions are found on almost all body sites and are more common in men than women.109 Multiple lesions in the genital and perigenital skin have been reported.110,111 Epidermolytic acanthomas are 2 to 5 mm, slightly raised papules with verrucoid features. Some are smooth surfaced, and others are mildly scaly. Tumors are flesh colored to slightly gray. HISTOPATHOLOGIC FEATURES The stratum corneum is compact or loosely laminated and is moderately to markedly hyperkeratotic.106,109,112 Some parakeratosis may be present.105,109,112 Eosinophilic anuclear bodies may be present and represent individually keratinized cells that have been retained in the stratum corneum. The basal layer is typically not involved, but the remainder of the stratum malpighii is abnormal.109,112 The granular layer is most affected and demonstrates thickening with coarse, enlarged keratohyaline granules (Fig. 26-3).105,106 Vacuolar changes are prominent. The spinous layer demonstrates similar changes and eosinophilic granules.105,106 Eosinophilic material arranged in strands is present in the spinous and granular layers. The cell layer immediately above the stratum basale demonstrates clear cell changes and prematurely cornified keratinocytes.109 A nonspecific perivascular lymphohistiocytic infiltrate is seen in the dermis.106

Table 26-9 Prurigo Nodularis

Clinical Features Nodules with lichenification and excoriation Very pruritic Occurs preferentially on the proximal extremities in middle-aged women Histopathologic Features Extensive hyperkeratosis with hypergranulosis in a psoriasiform or pseudoepitheliomatous pattern Occasional mild spongiosis and parakeratosis Perivascular inflammation with occasional eosinophils and plasma cells Mild papillary dermal fibrosis Differential Diagnosis Lichen simplex chronicus Keratoacanthomas Pseudoepitheliomatous hyperplasia (eg, deep fungal infections, Spitz nevi, granular cell tumors)

 FIGURE 26-3 Epidermolytic acanthoma. The spinous and granular layers are vacuolated with enlarged keratohyaline granules. Hyperkeratosis is also present.

On electron microscopy, the basal cells appear normal aside from some increased numbers of mitochondria and endoplasmic ribosomes.105,106 Suprabasal cells demonstrate abnormal tonofilament aggregation around the nucleus. This pattern is accentuated in the upper levels of the epidermis. Desmosomes are normal.106 The eosinophilic strands in the stratum spinosum are also abnormal tonofilaments set in a whorling pattern. Intracellular edema begins in the upper spinous layer and is seen throughout the granular layer. Cells of the stratum corneum do not appear to cornify uniformly.

Table 26-10 Epidermolytic Acanthoma

Clinical Features Small, flat or verrucous papules Most common on the extremities Occurs in middle-aged persons and more often in men than in women Histopathologic Features Hyperkeratosis with dense, loosely packed keratinocytes Large, coarse basophilic granules in the granular layer with vacuolated keratinocytes Fine eosinophilic granules and strands in the spinous and granular layers Normal basal layer Differential Diagnosis Epidermolytic hyperkeratosis seen in different cutaneous tumors and diseases Warts, particularly the palmoplantar type

Warty dyskeratoma was originally described by Helwig113 and Allen,114 but the term was coined by Syzmanski in 1957.115 These lesions are believed to arise from pilosebaceous structures; however, this view has been disputed116 because serial sections through some lesions have failed to show evidence of follicular derivation. Additionally, oral warty dyskeratomas have not been found in a distribution similar to that of ectopic sebaceous glands. Some investigators believe that warty dyskeratomas are isolated variants of Darier disease.117 Oral lesions may arise secondary to irritation and trauma. The use of tobacco and other chemical carcinogens has been implicated in their etiology.117-119 Glaborous lesions arise on sun-exposed areas perhaps due to prolonged UV light exposure.117 Infectious etiologies have been ruled out.120 Circulating antibodyinduced acantholysis, as seen in pemphigus, has been suspected; a patient with circulating anti-intercellular substance antibodies at a titer of 1:10 has been reported.118 CLINICAL FEATURES Glaborous lesions are generally single and slow growing and are found predominantly on the head, neck, and extremities.117,118 Tumors appear primarily on patients in the fourth to sixth decades of life and more often in men than women.115,117,120,121 Multiple warty dyskeratomas have been described.112,116,120 Tumors are flesh colored to brown papules with a rolled, smooth edge and a central, hyperkeratotic plug. Foul-smelling, cheesy material may drain from these lesions.118,120 Pruritus and bleeding may occur, but most papules are without symptoms. The diagnosis is rarely made clinically.120 Malignant degeneration has not been described. Oral lesions are rare but are similar to glaborous tumors. They are usually nonpainful and are found on keratinizing surfaces exposed to trauma.117,118 Similar to their glaborous counterparts, they are small papules or nodules with a central crater. They may assume a papillomatous appearance and are flesh colored to white. HISTOPATHOLOGIC FEATURES Glaborous lesions are usually associated with pilosebaceous structures, and early changes are limited to the upper portion of the follicular infundibulum.121 Single follicles are usually involved, but involvement of multiple follicles has also been described.121

Adjacent sebaceous glands are present in some specimens. The epithelium surrounding the follicular ostia may form a collarette with hypergranulosis and acanthosis.122 The follicles become cystic, enlarged, and flask shaped (Fig. 26-4).115,120 They extend deep into the reticular dermis and are filled with parakeratotic and hyperkeratotic debris.112,115,120 The papillomatous epithelial wall lining extends into the surrounding dermis. Acantholysis and dyskeratosis of the involved keratinocytes are seen. Corps ronds and grains are formed. These features are similar to those seen in Darier disease. Suprabasal lacunae are present, and keratin pearl-like structures may be seen in long-standing lesions. Villi are covered by a single layer of epithelial cells and extend into the cystic cavity. The basement membrane zone demonstrates a loss of fine elastic twigs.122 The cystic structure is surrounded by a sheath of fibrovascular connective tissue.121 There is a moderate perivascular inflammatory infiltrate in the dermis consisting of lymphocytes, histiocytes, rare eosinophils, and occasional plasma cells. Postinflammatory pigment incontinence has been described.115,121 Oral lesions are similar to those from glaborous skin.115,117,119 Corps ronds and grains are not as well developed in mucosal lesions. Ongoing mechanical trauma in these areas may dislodge the keratotic plug.118 Ultrastructurally, the dyskeratotic and acantholytic cells are similar to those in Darier disease.117 The cytoplasm contains dense, perinuclear bands of tonofilaments. Numerous ribosomes and polyribosomes are present.119 Acantholysis may result from poor desmosome–tonofilament complexes between cells. DIFFERENTIAL DIAGNOSIS Warty dyskeratomas should be differentiated from other acantholytic diseases such as Darier disease (the hypertrophic variant), benign familial pemphigus, and pemphigus vegetans (Table 26-11).121 None of these diseases forms the typical flask-shaped invagination seen in warty dyskeratoma. Additionally, the acantholysis is probably less than with benign familial pemphigus and pemphigus vegetans. Pemphigus vegetans demonstrates numerous infiltrating eosinophils and may be ruled out using direct immunofluorescence testing. Darier disease usually shows more dyskeratosis and corps rond or grain formation than warty dyskeratoma. Syringocystadenoma papilliferum may show villi formation similar to that seen in warty dyskeratomas and should be

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

DIFFERENTIAL DIAGNOSIS Epidermolytic hyperkeratosis may be seen in numerous skin diseases, including bullous ichthyosiform erythroderma, ichthyosis hystrix, keratoderma palmaris et plantaris, nevus unis lateris, epidermolytic leukoplakia, and acrosyringeal epidermolytic papulosis neviformis (Table 26-10).70 Small biopsies of these entities may not be discernible from an epidermolytic acanthoma without clinical information. Epidermolytic hyperkeratosis is also present in a number of isolated skin lesions such as infundibular cysts, seborrheic keratoses, and actinic keratoses.106 It is important to differentiate epidermolytic acanthomas from warts. Endophytic palmoplantar warts (myrmecia) typically show perinuclear vacuolization and numerous keratohyaline granules. However, these granules are usually more eosinophilic than those appearing in epidermolytic hyperkeratosis. Additionally, vascular dilatation in the dermal papillae and prominent papillomatosis are seen.

Warty Dyskeratoma

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A

B

 FIGURE 26-4 Warty dyskeratoma. (A) Single hair follicles enlarge into a “flask” shape. (B) The lining epidermis shows dyskeratosis and acantholysis.

differentiated from these tumors. However, the epidermis is often eroded, plasma cells are generally abundant, and no keratinous plug is present.112,115

Table 26-11 Warty Dyskeratoma

Clinical Features Isolated lesions on the sun-damaged skin of middle-aged persons Also seen on the oral mucosa Papulonodule with central pore or umbilication May discharge foul-smelling material Histopathologic Features Flask-shaped cystic invagination involving a pilosebaceous structure Parakeratotic and hyperkeratotic material in infundibulum Suprabasal acantholysis with villi and acantholysis Dyskeratosis, corps ronds, and grains are present Differential Diagnosis Darier disease Benign familial pemphigus Pemphigus vegetans Syringocystadenoma papilliferum

Acantholytic Acanthoma Acantholytic acanthoma was originally described by Brownstein in 1988.123 These are isolated lesions without a relationship to other disorders.124 It is termed an acanthoma because the growths are composed of proliferating benign keratinocytes. They are known to proliferate in the face of diminished immune surveillance and immunosuppression may be causative.123 CLINICAL FEATURES The lesions are usually isolated and present on the trunk or extremities.123,124 The mucous membranes, face, soles, and palms are spared.125 They are 5 to 15 mm in diameter and are erythematous to dark. Most patients are men, and most are older.124,125 The lesions are usually asymptomatic, but itching has been noted.123,125 HISTOPATHOLOGIC FEATURES The epidermis demonstrates hyperkeratosis, parakeratosis, and irregular hyperplasia.102,103,105 The lesions are symmetrical and well circumscribed. Some papillomatosis is occasionally present, and focal crusting and spongiosis may be appreciated. Acantholysis is present throughout most of the epidermis and is accentuated in the granular or suprabasilar layers.125

Dyskeratotic cells and grains are occasionally present.125,126 Epidermodysplasia verruciformis–like change has been reported.127 Atypia is absent. There is a nonspecific perivascular lymphohistiocytic infiltrate in the underlying dermis. Occasional eosinophils are seen.123,125 DIFFERENTIAL DIAGNOSIS Focal and limited biopsies of acantholytic disorders such as pemphigus vulgaris, pemphigus vegetans, benign familial pemphigus, and Grover disease may mimic an acantholytic acanthoma (Table 26-12).124 These disorders, however, are eruptions with variably widespread involvement. Eosinophils are prominent in pemphigus, and differentiation using immunofluorescent techniques is helpful. The acantholysis of benign familial pemphigus is commonly very extensive, and Grover disease may demonstrate numerous dyskeratotic cells with grains and, very often, more than one pattern of acantholytic change. Seborrheic keratoses may have sporadic acantholysis but usually contain hyperpigmentation along the basal layer, horn pseudocysts, and a “flat bottom.” Acantholytic actinic keratoses show keratinocyte atypia, and warty dyskeratomas are flask shaped with a parakeratotic plug.

Table 26-12 Acantholytic Acanthoma

Seborrheic Keratosis Seborrheic keratoses are the most common human neoplasm, involving more than 23 million persons in the United States.128 About 20% of the elderly have these lesions. The histologic features of seborrheic keratoses were described in 1926 by Freudenthal.129 These neoplasms arise in most persons as incidental tumors. One subset of patients may develop seborrheic keratoses when they have underlying malignancies. The sign of Leser-Trelat is a sudden eruption of seborrheic keratoses in persons with concomitant cancers, most commonly an adenocarcinoma of the gastrointestinal tract.112 Malignancies from the breast and lung have also been reported.130 Three patients with leukemia were noted to have multiple inflamed lesions after receiving cytarabine chemotherapy.131 This sign was originally described separately by Edmund Leser and Ulysse Trelat in the late 19th century.132 It is a rare phenomenon and may be associated with the development of acanthosis nigricans, acquired ichthyosis, and hypertrichosis lanuginosa.133 The seborrheic keratoses are indistinguishable clinically and histologically from those occurring in healthy patients but arise rapidly on the chest and back. They may demonstrate a “Christmas tree” or “splash” pattern.133 Pruritus is common and portends a poor prognosis. This phenomenon is believed to arise from tumorsecreted growth factors.132 Seborrheic keratoses in persons with colon cancer have been described as demonstrating a “halo” effect. Seborrheic keratoses have been reported to arise with pregnancy, acromegaly,

CLINICAL FEATURES Seborrheic keratoses have a “stuck-on” appearance. They are flesh colored to dark black and range in size from 1 to 2 mm to several centimeters in diameter (Fig. 26-5A). They may be found anywhere except the palms and soles. The head, neck, and trunk are the most common sites. With exceptional hyperkeratosis, these lesions may present as a cutaneous horn.144 A variant of seborrheic keratoses termed stucco keratoses arise as warty 1- to 3-mm verrucous papules with a propensity for involvement of the distal extremities. HISTOPATHOLOGIC FEATURES There are several different histologic variants of seborrheic keratoses. These have been designated as acanthotic, hyperkeratotic or papillomatous, adenoidal (reticulated), clonal, macular or incipient, pedunculated, and irritated or inflamed. These variants demonstrate a characteristic pattern of growth—basal and squamous proliferation with hyperkeratosis, papillomatosis, and horn pseudocyst production.145 Spongiosis is present in some lesions, particularly those that have been irritated, but atypia is unusual.146 Mitotic figures may be seen and are normal in configuration.146 Squamous eddies may be observed as well and are not necessarily restricted to irritated or inflamed lesions.146,147 Additional features include sebaceous and trichilemmal differentiation.112,148 The presence of clear cells along the base of the lesion has been noted with the potential for confusion with an associated melanoma in situ.149 These cells are S-100 and MART-1 negative but have an unusual pattern of peripheral staining when evaluated with keratin stains. Regression and atrophy of seborrheic keratoses has been described,150 and peritumoral amyloid deposition is present in up to 18% of lesions.112,151,152

Acanthotic This is one of the most common variants of seborrheic keratosis. On low power the lesions appears to have a smooth dome shape.151 The epidermis is broad and composed of basaloid cells (Fig. 26-5B and 26-5C). Horn pseudocysts are present and may be very large.

Hyperkeratosis is minimal, and papillomatosis is essentially absent.112 The base of the lesion demonstrates a “flat bottom.” Hyperpigmentation is usually visible along the basal layer but may involve the upper cell layers as well. Verruciform xanthoma–like changes have been reported in the papillary dermis underlying an acanthotic seborrheic keratosis.153

Hyperkeratotic (Papillomatous) The epidermis shows a papillomatous, “church spire” proliferation. There is orthokeratotic and parakeratotic hyperkeratosis. The rest of the stratum malpighii is acanthotic with basaloid and squamous cell proliferation. The stratum corneum is loosely laminated and interdigitated.112 The base of the lesion is flat. There is usually some hyperpigmentation along the basal layer. Stucco keratoses are probably variants of hyperkeratotic seborrheic keratoses. These lesions demonstrate a regular, sharp, pointed papillomatosis. Pigment deposition is minimal. They may be indistinguishable from acrokeratosis verruciformis of Hopf. Adenoidal (Reticulated) In this variant, the epithelium is elongated and reticulated with moderate to prominent pigment deposition. Small horn pseudocysts are present. Epithelial anastomosis is common and surrounds some horn pseudocysts. The pattern is reminiscent of a proliferative solar lentigo, and some investigators believe that these tumors are identical.151,154

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

Clinical Features Solitary, asymptomatic papule or nodule on the trunk 5-15 mm in diameter and hyperkeratotic Most common in middle-aged men Histopathologic Features Acantholysis throughout most of the epidermis Hyperkeratosis, parakeratosis, and acanthosis Symmetric and circumscribed Differential Diagnosis Pemphigus vulgaris, pemphigus vegetans, benign familial pemphigus, and Grover disease Acantholytic changes of seborrheic keratoses or actinic keratoses Warty dyskeratoma

exfoliative dermatitis, acanthosis nigricans, Gougerot-Carteaud syndrome, and WearyKindler syndrome. Increased epidermal growth factor and epidermal growth factor receptors are present in these lesions.134-141 Evidence of fibroblast growth factor 3 mutations have also been noted in seborrheic keratoses, particularly in the acanthotic variant.142,143

Clonal Clonal seborrheic keratoses demonstrate a nesting pattern.151 The epidermis is mildly hyperkeratotic with acanthosis. Within the acanthotic epidermis are “clones” of basaloid epidermal cells surrounded by otherwise unremarkable keratinocytes. This pattern is termed the Borst-Jadassohn phenomenon and may be seen in other cutaneous tumors. Macular Also known as an “incipient” seborrheic keratosis, the macular variant demonstrates subtle changes.112 The epidermis is minimally acanthotic and hyperkeratotic. Epidermal proliferation is flat and even across the bottom. There may be increased basal layer pigmentation, but it is generally minimal and difficult to discern. Pedunculated (Sessile) These typically arise on the eyelids and neck and in the axillae. 112,151 There is attenuated collagen in the dermis with dilated

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blood vessels that often contain inspissated erythrocytes. The epidermis is generally acanthotic, hyperpigmented, and similar to that seen with an acanthotic seborrheic keratosis.

A

B

C  FIGURE 26-5 Seborrheic keratosis. (A) The lesion shows well-defined, waxy, “stuck-on” appearance with raised keratotic excresences. (B) The epithelium is acanthotic with coalescent horn pseudocysts. (C) Note the anastomosing cords of squamous epithelium and pseudohorn cyst.

566

Irritated (Inflamed) This is a common designation and is often applied to one of the above-mentioned variants that displays exocytosis, apoptosis, acantholysis, scale-crust formation, spongiosis, and trichilemmal keratinization.112,146,155 Basaloid cells undergo conversion into squamoid cells by acceleration of cellular maturation.151 The formation of these “squamous eddies” has been shown to be associated with an increased progression toward cellular apoptosis and are anatomically related to hair follicle epithelium.156,157 The papillary dermis contains a perivascular and interface inflammatory infiltrate composed of lymphocytes and mononuclear cells. A purely lichenoid infiltrate is not believed to be associated with externally irritated lesions.158 Neutrophilic microabscesses may be present, but eosinophils are rare and raise the possibility of a secondary contact dermatitis from topically applied medicaments.155 Plasma cells are not common but are seen with long-standing lesions. Some extravasation and exocytosis of erythrocytes may be observed.146 Dermal papillae may be hyalinized with necrotic adjacent epithelium.130 Seborrheic keratoses that have been traumatized by rubbing have demonstrated hair germ buds.117 The presence of an inflammatory component may be associated with spontaneous involution of these tumors.138 Bcl-2 expression is downregulated compared with non-inflamed seborrheic keratoses, suggesting that it may exert an anti-apoptotic role in the latter.159 Miscellaneous Seborrheic keratoses with fibrotic stroma and nests and cords of squamous epithelium have been reported as “desmoplastic seborrheic keratoses.”160 Most arise on the head and neck. The histologic features of the proliferative epithelium are typical for those of other seborrheic keratoses. Psoriasiform keratosis is a term used for isolated lesions with histologic features of both seborrheic keratosis and psoriasis vulgaris.161 The presence of intracorneal neutrophils is a notable finding. Single examples of a lesion with intercellular mucin deposition resembling an adamantinoma and with basaloid keratinocytes radially arranged around small central spaces have been termed adamantinoid seborrheic keratosis and

DIFFERENTIAL DIAGNOSIS The differential diagnosis for seborrheic keratosis varies

depending on the histologic type (Table 26-13). Hidroacanthoma simplex or eccrine poroma, basal cell carcinoma, fibroepithelioma of Pinkus, epidermal nevi (particularly the inflammatory linear verrucous variant), and epidermal acantholysis should be differentiated from seborrheic keratoses.112,146 Hidroacanthoma simplex and eccrine poromas have very bland proliferating cells with a “clonal” pattern of growth. Ductal differentiation may be seen, and the lesions are endophytic rather than exophytic or papillomatous. Basal cell carcinomas have the epidermal acanthosis and hyperpigmentation seen in acanthotic seborrheic keratoses. However, atypia, apoptosis, stromal retraction, peripheral palisading, and mucin production are much more common in basal cell carcinomas. Similarly, the fibroepithelioma of Pinkus is a reticulated variant of basal cell carcinoma but does not demonstrate horn pseudocyst production and shows a surrounding fibromucinous stroma. Epidermal nevi may be very difficult to differentiate from inflamed seborrheic keratoses. Both lesions are papillomatous, hyperkeratotic and acanthotic. However, the regular acanthosis that results in the “flat bottom” of seborrheic keratoses is generally absent from epidermal nevi. Additionally, horn pseudocysts are not present in these latter lesions. Acantholysis may be found in various

Table 26-13 Seborrheic Keratosis

Clinical Features Present on middle-aged and older patients on the head, neck, and trunk Flesh-colored to black papules with a “stuckon” appearance From 1 mm to several centimeters in diameter and sharply demarcated Smooth to warty with a crumbly texture Histopathologic Features Benign squamoid and basaloid proliferation with acanthosis, hyperkeratosis, papillomatosis, reticulation, and horn pseudocysts Basal layer hyperpigmentation Infiltrating lymphocytes in the dermis and epidermis Differential Diagnosis Hidroacanthoma simplex or eccrine poroma Basal cell carcinoma Fibroepithelioma of Pinkus Epidermal nevus (particularly the inflammatory linear verrucous variant) Acantholytic changes of isolated lesions

inflamed and benign processes, including acantholytic acanthoma, acantholytic actinic keratosis, and Darier disease. Epidermal hyperpigmentation and horn pseudocyst production favor the diagnosis of seborrheic keratosis.

Dermatosis Papulosa Nigra This disorder was first described in 1925 by Castellani.184 It occurs almost exclusively in blacks, Filipinos, Mexicans, Vietnamese, and American Indians.184,185 Whites have been described with dermatosis papulosa nigra, but it is uncommon.184 Women are more commonly affected than men, and there seems to be a genetic component to this disease.184 An eruption of lesions associated with an adenocarcinoma of the colon, similar to the sign of Leser-Trelat, has been reported.186 CLINICAL FEATURES These lesions are found almost exclusively on the face.112,184 They are well demarcated, are 1 to 5 mm in diameter, and have a pedunculated appearance. Most are hyperpigmented, but some are flesh colored. They are rarely pruritic. HISTOPATHOLOGIC FEATURES The histopathologic features are essentially identical to those of seborrheic keratoses. 184 Mild hyperkeratosis with parakeratosis, acanthosis, and basal layer hyperpigmentation are present. Some specimens demonstrate reticulated epidermal proliferation and horn pseudocysts. The dermis shows mildly attenuated collagen, giving the lesions a fibroepithelial polyp–like appearance. Immature pilosebaceous structures may be appreciated.184 Inflamed lesions are similar to inflamed seborrheic keratoses and show spongiosis, perivascular lymphocytes, scale-crust formation, and exocytosis. DIFFERENTIAL DIAGNOSIS These lesions should be differentiated from fibroepithelial polyps and seborrheic keratoses, particularly the pedunculated variant (Table 26-14). Fibroepithelial polyps typically have very attenuated collagen and dilated vascular spaces with inspissated erythrocytes. These features are generally lacking in dermatosis papulosa nigra. Dermatosis papulosa nigra are usually smaller than seborrheic keratoses and may show a completely circumscribed and symmetrical lesion despite a small biopsy specimen. The pedunculated variant of a seborrheic keratosis may be identical to dermatosis papulosa nigra.

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

seborrheic keratosis with pseudorosettes, respectively.162 Seborrheic keratoses have been found in association with benign and malignant lesions. Keratotic compound nevi have features of an adenoidal seborrheic keratosis and compound nevus.163,164 These are typically found on the trunks of young women. Trichostasis spinulosa has been noticed in some lesions, and seborrheic keratosis–like changes have been reported in the lining of infundibular (epidermoid) cysts.165 Basal cell carcinoma, squamous cell carcinoma, eccrine porocarcinoma, melanoma, keratoacanthoma, adenocarcinoma, nevus sebaceus, Bowen disease, primary cutaneous ganglioneuroma, and bowenoid transformation128,145,154,166-175 have been described in association with seborrheic keratoses. A nonmelanoma skin carcinoma was found associated with 4.6% of seborrheic keratoses.154 In persons with widespread cutaneous diseases such as psoriasis or cutaneous T-cell lymphoma, seborrheic keratoses taken from involved skin may demonstrate histopathologic changes of these dermatoses.112 HPVs have been detected in some seborrheic keratoses but are not believed to be causative.176,177 Type 5 HPV is found in cutaneous seborrheic keratoses from persons with epidermodysplasia verruciformis,178 and 42% of lesions from the groin were found to contain types 6, 11, and 16 HPV.177 Seborrheic keratoses from nongenital skin have also demonstrated evidence of types 6 and 18 HPV using PCR testing.179 Involved keratinocytes show pale staining and clumping of keratohyaline granules in the upper stratum malpighii. HPV particles were found on electron microscopy in all four cases studied.176 Increased melanin production in infected cells has also been described.176 Herpesvirus infections of isolated seborrheic keratoses were noted in two patients without other evidence of herpetic lesions.180 The presence of proliferation-associated proteins and genetic abnormalities has also been studied. Increased expression of p16 has been found in these lesions, suggesting that the proliferating keratinocytes reside in a senescent state with G1 arrest.181 The p63 gene, a member of the p53 gene family, is upregulated in the basaloid cells of seborrheic keratoses.182 Clonal keratinocytes have been reported in these neoplasms; however, evaluation for chromosomal imbalances has been negative.183

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Table 26-14 Dermatosis Papulosa Nigra

568

Clinical Features Small, dark, pedunculated papules on the face Restricted to blacks, Hispanics, Vietnamese, American Indians, and Filipinos Histopathologic Features Epidermal acanthosis or reticulation with basal layer hyperpigmentation Polypoid appearance Inflamed lesions with spongiosis, exocytosis, and perivascular lymphocytes Differential Diagnosis Fibroepithelial polyp Seborrheic keratosis, particularly the pedunculated variant

Melanoacanthoma Melanoacanthoma was initially described by Bloch in 1927187 and named in 1960 by Mishima and Pinkus.188 Whereas cutaneous lesions are almost exclusively restricted to whites,189 oral melanoacanthomas are present mostly in black women.189,190 Glaborous lesions are present in persons older than age 55 years with no gender preferences, and they develop slowly.189-191 Oral lesions are more common in young adults.190 They are usually solitary and develop over weeks to months.191 The pathophysiology of melanoacanthomas is unclear but may involve a block in the transfer of melanin from melanocytes to epithelial cells.190 Pigment retention by secondarily stimulated melanocytes may result from trauma. These lesions are probably reactive rather than neoplastic. CLINICAL FEATURES Melanoacanthomas are well-demarcated, slightly raised, and usually solitary and arise on the head, neck, abdomen, and extremities.189,190 They are up to several centimeters in diameter and are very dark. These lesions are similar to a heavily pigmented seborrheic keratosis.112 Oral melanoacanthomas are also dark and solitary. They are most common on the buccal or labial mucosa. HISTOPATHOLOGIC FEATURES Histopathologic features are essentially identical for glaborous and mucosal lesions. The epidermis is acanthotic and mildly hyperkeratotic.189,190 Some elongation and fusion of rete ridges is seen. Spongiosis is greater in oral melanoacanthomas.191

Large dendritic melanocytes contain considerable pigment. Pigment incontinence is prominent with uptake by dermal melanophages.190 Mitotic activity and epidermal atypia are not appreciated. S-100 stains reveal intraepidermal melanocytes with large dendrites. Oral lesions may have mildly increased vascularity and occasional eosinophils.189,190 Ultrastructurally, large dendritic melanocytes are seen in the basal and spinous layers of the epidermis.190 Visible melanin is restricted to melanocytes. Staining of melanocytes with HMB-45 has been reported.192 DIFFERENTIAL DIAGNOSIS Melanoacanthomas may be difficult to differentiate from heavily pigmented seborrheic keratoses, particularly the acanthotic variant (Table 26-15). Most pigmented seborrheic keratoses demonstrate horn pseudocysts, pigmented keratinocytes, and mild to moderate hyperkeratosis.

Clear Cell Acanthoma These lesions, also known as pale cell acanthomas,112 were first described in 1962 by Degos et al.193 They were previously thought to be a variant of a seborrheic keratosis,194 and a lesion with keratoacanthoma-like features has been reported.195 The profile of composite keratins is different from that of the acrosyringium but similar to those found in normal skin.194 Clear cell acanthomas have been described in psoriatic plaques, suggesting that they represent modified psoriasis.196 Recent research has suggested that these lesions may be inflammatory rather than neoplastic in

Table 26-15 Melanoacanthoma

Clinical Features Glabrous lesions arise on the head, neck, and abdomen of middle-aged or older patients Oral lesions are seen in younger patients, particularly black girls and women Tumors are slightly raised, very dark, and several centimeters in diameter Histopathologic Features The epidermis is acanthotic, well demarcated, and usually symmetric Pigmentation is prominent and restricted to the melanocytes and dermal melanophages Differential Diagnosis Seborrheic keratosis, particularly the acanthotic and hyperpigmented variant

nature. Upregulation of keratinocyte growth factor, a growth factor prominent in psoriasis, has been described in clear cell acanthomas.197 Additionally, the reporting of these lesions in association with inflammatory, neoplastic, and fibrotic cutaneous conditions suggests they may represent a psoriasiform reaction pattern.198 CLINICAL FEATURES Patients are usually middle aged or older, and most are white. Men and women are affected equally. Lesions are single and are present on the lower legs and feet.199,200 Tumors are moist and smooth with well-circumscribed borders. A “stuck-on” appearance is present in some lesions. They are brown to erythematous in color and may have a vascular appearance. Clear cell acanthomas may blanch when pressure is applied.112 Some lesions are scaly or crusted and appear eczematous in nature.112 Tumors are about 10 mm in diameter and are asymptomatic. Polypoid and giant variants have been described.201,202 A squamous cell carcinoma in situ developing in a clear cell acanthoma has been reported.203 HISTOPATHOLOGIC FEATURES The epidermis is acanthotic with clear cell changes, which are readily demarcated from adjacent normal epidermis (Figs. 26-6).112,199,200,204 Pale cells are polyhedral and larger than normal keratinocytes. They are also periodic acid-Schiff (PAS) positive and diastase sensitive, indicating the presence of glycogen.86,145 Mitoses are few, and significant atypia is uncommon.200 Spongiosis is present. Rete ridges are elongated, occasionally in a psoriasiform manner, and may show fusion. A collarette is seen at the margins of the lesion. The granular layer is absent, and infiltrating neutrophils are seen.202 Neutrophilic microabscesses have been reported.200 The stratum corneum may be parakeratotic with serous exudate.200 Melanin is present in dermal melanophages but is often absent in the epidermis and along the basal layer.112 A pigmented variant has been described and demonstrates impressive numbers of melanocytes with elongated dendrites containing melanin granules.205 A cystic variant has also been reported.204 Follicular and acrosyringeal structures are present.200,204 Blood vessels may be present in increased numbers and are slightly dilated. A perivascular lymphohistiocytic infiltrate is appreciated.112,199 Occasional neutrophils may be present. Sweat glands may be dilated and hyperplastic, indicating sweat retention.199

the cells are aneuploid or tetraploid and that abnormal clones are present.209,210 Most cases are single, but patients with multiple lesions have also been described.207 Large cell acanthomas have a benign and indolent clinical course.210 Some investigators believe that women are more commonly affected,207,210 but others have found an equal incidence between the genders.208

B  FIGURE 26-6 Clear cell acanthoma. (A) The epidermis is psoriasiform with areas of clear cell proliferation. (B) Clear cell changes are well demarcated from the adjacent epidermis.

Ultrastructurally, the affected keratinocytes show increased glycogen.199 The nuclei and cytoplasmic organelles are otherwise normal. Melanocytes lack melanin granules. The pigmented variant of clear cell acanthoma shows increased melanosomes within dendritic cells.205 DIFFERENTIAL DIAGNOSIS The differential diagnosis for clear cell acanthoma includes seborrheic keratosis, eccrine poroma, and psoriasis (Table 26-16). Seborrheic keratoses may have an increase in intracellular glycogen but lack the sharply demarcated, pale cell changes in adjacent epidermis. Additionally, horn pseudocysts and the “flat bottom” appearance of seborrheic keratoses are usually lacking. Eccrine poromas do not have clear cell changes and demonstrate ductal differentiation. Psoriasis vulgaris demonstrates regular psoriasiform hyperplasia, prominent parakeratosis, and neutrophilic microabscesses. Clear cells are absent.

Large Cell Acanthoma Large cell acanthoma was initially described in 1967 by Pinkus.206 It is likely induced by prolonged sun exposure

because it arises in areas of solar damage on elderly patients.207 These tumors may be a variant of actinic keratosis207 or solar lentigo.208 DNA analysis has shown that

Table 26-16 Clear-Cell Acanthoma

Clinical Features Found on the lower extremity or foot in middle-aged or older patients Lesions are well demarcated and erythematous and have a moist surface A peripheral collarette of scale may be appreciated Histopathologic Features Acanthosis with clear cell changes is present and is well demarcated from normal epithelium Psoriasiform-like hyperplasia with some fusion of rete ridges Infiltrating neutrophils in the epidermis Clear cells are PAS positive and diastase resistant Epidermal melanin absent Differential Diagnosis Seborrheic keratosis with clear cell changes Eccrine poroma Psoriasis vulgaris

HISTOPATHOLOGIC FEATURES The pathologic features are believed to be pathognomonic.211 The lesions are well circumscribed with a clear demarcation between affected and uninvolved epidermis.207,211 Keratinocytes are enlarged with proportionally larger nuclei (Fig. 26-7). These nuclei are pleomorphic but not hyperchromatic.208,211 Mitotic activity is not prominent, and the acrosyringia are spared.207 Rete ridges are bulbous.212 Orthohyperkeratosis is appreciated and the granular layer may be enhanced or reduced. The basal layer shows modest hyperpigmentation. The number of melanocytes has been reported as normal in number211,212 and increased.213 Solar elastosis and telangiectasias are present in the dermis.207,208,210,211 Perivascular inflammation may be present but is usually mild. Three types of large cell acanthoma have been described: the classic lesion, one with verrucous hyperkeratosis (similar to an acrokeratosis verruciformis of Hopf), and a flat hyperkeratotic variant.212 These lesions have been proposed to represent a reactive pattern with a possible relationship to senile lentigos.213 DIFFERENTIAL DIAGNOSIS Large cell acanthomas must be differentiated from actinic keratoses, seborrheic keratoses, and solar lentigos (Table 26-17).211 Actinic keratoses usually demonstrate a loss of the granular layer, parakeratosis, and cytologic atypia with mitotic activity. Seborrheic keratoses have horn pseudocysts but are not well demarcated at the lateral aspects of the lesion and do not show enlarged nuclei and keratinocytes. Solar lentigos have a more lentiginous proliferation of rete ridges with prominent hyperpigmentation. Additionally, cellular and nuclear enlargement are not present.

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

CLINICAL FEATURES Large cell acanthomas are usually less than 1 cm in diameter.119,211 They arise on sun-damaged skin and are dry and smooth. Lesions are slightly hyperpigmented and occasionally hyperkeratotic.207,209,211

A

569

hypermethylation has been described in actinic keratoses compared with normal skin.223 p16INK41 is a tumor-suppressor protein minimally expressed in actinic keratoses compared with squamous cell carcinoma in situ.224,225 p63 and p53 protein expression is enhanced in actinic keratoses.226,227 Increased proliferation cell nuclear antigen staining has been found in the basal and suprabasal layers of these tumors.228

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

A

570

B  FIGURE 26-7 Large cell acanthoma. (A) The stratum corneum shows hyperorthokeratosis, and the epidermis is slightly hyperplastic. (B) The keratinocyte nuclei are distinctly enlarged and slightly pleomorphic in the basal, and the suprabasal layers of the epidermis as are clearly demonstrated.

KERATINOCYTIC DYSPLASIA

Actinic Keratosis In 1926, Freudenthal described what are now known as actinic keratoses.214 These precancerous changes of the skin are found in 11% to 25% of the population

Table 26-17 Large Cell Acanthoma

Clinical Features Arise on the sun-damaged skin of elderly patients Lesions are slightly hyperpigmented, flat, and mildly hyperkeratotic <1 cm in diameter Histopathologic Features Well-demarcated, enlarged keratinocytes and nuclei Rare mitotic figures Slight hyperkeratosis without parakeratosis Bulbous rete ridges with mild hyperpigmentation along the basal layer Solar elastosis and telangiectasias Differential Diagnosis Actinic keratosis Seborrheic keratosis Solar lentigo

and are most common on the sunexposed skin of elderly patients.215 Some clinicians consider them to be equivalent to squamous cell carcinoma in situ.216-218 The surrounding clinically “normal” skin shows atypia, suggesting that a stepwise progression of keratinocyte atypia exists from the subclinical to overt squamous cell carcinoma.219 Proposals have been made for classifying these lesions similar to that of evolving carcinoma of the uterine cervix.220 There is concern that these lesions will eventually convert to a frank cutaneous malignancy. Among untreated lesions, this risk is approximately one per 1000 per year.221 Thick, hyperkeratotic, and ulcerative lesions are most at risk. About 20% to 25% of patients with actinic keratoses eventually develop a squamous cell carcinoma.219 The estimated time of progression to squamous cell carcinoma is approximately 2 years.222 Genetic and immunologic studies of actinic keratoses have been undertaken with increasing frequency. E-cadherin, an intracellular adhesion molecule expressed in epithelial tissues, is known to be inactivated by gene hypermethylation, resulting in an enhanced ability for human cancers to invade or metastasize. Increased E-cadherin gene

CLINICAL FEATURES Typical actinic keratoses are small, hyperkeratotic growths on sun-exposed surfaces in middle-aged and older patients.221 They are well demarcated from the surrounding skin and are slightly red. The overlying scale is white to gray or yellow.229 Most lesions are stable and less than 1 cm in size.230 Affected patients usually have a history of prolonged sun exposure or are those who tan poorly and freckle easily.221 Lesions are usually asymptomatic, but mild pruritus or tenderness may be present. Organ transplant recipients and other immunosuppressed patients may have many more and thicker lesions.231 In addition, a significant percentage of actinic keratoses from this patient population have demonstrated evidence of HPV DNA, a proposed cofactor in cutaneous carcinogenesis.232 The surrounding areas typically demonstrate overt evidence of long-standing actinic damage. Differentiation from a squamous cell carcinoma, particularly in thick lesions, may be impossible. The spreading pigmented actinic keratosis is a variant of actinic keratosis that is larger and more deeply pigmented.233 Lesions are 1 cm or larger in diameter and spread in a centrifugal manner. The base is erythematous with adherent scales. The face is most often involved.234 The transfer of pigment from melanocytes to keratinocytes may be impaired.229 The hyperpigmentation may be a protective mechanism to prevent further solar damage. Other variants of actinic keratosis have also been described. Lichenoid actinic keratoses are likely to be slightly larger than most lesions and to arise on the chest.235 Hypertrophic actinic keratoses are more commonly seen on the distal upper extremity.236 A proliferative variant of actinic keratosis has also been described.230 These are red, scaly macules or patches without well-defined borders or symptoms. They are poorly circumscribed and may reach 3 to 4 cm in diameter.237 Scarring from previous therapy is common because these lesions respond poorly to routine

methods of eradication. More recent evaluations of proliferative actinic keratoses have concluded that they likely represent low-grade squamous cell carcinomas.238

 FIGURE 26-8 Hypertrophic actinic keratosis. The epidermis is acanthotic and variably atypical. Hyperkeratosis may be minimal or significant.

actinic keratoses.240 Bowenoid actinic keratoses display prominent bowenoid features (Fig. 26-9).230 Full-thickness atypia, dyskeratotic cells, and mild parakeratosis are prominent. The infundibulum of hair follicles may be involved by this atypia, but the outer root sheath is spared. A biopsy should demonstrate complete excision of the lesion to differentiate it from squamous cell carcinoma in situ. Pigmented actinic keratoses display moderate pigment incontinence and hyperpigmentation along the basal layer.240 Distinct nests of melanocytes are not present. The use of immunohistochemical stains for melanocytes has shown a varying ability to differentiate these lesions from more ominous melanocytic neoplasms such as lentigo maligna.247,248 Using an azure-B counterstain may help alleviate some of these difficulties. Actinic keratoses with an interface inflammatory infiltrate are known as lichenoid actinic keratoses (Fig. 26-10).235 Recognizing the atypical keratinocytes may be difficult. Proliferative actinic keratoses demonstrate keratinocyte atypia extending to the level of the sebaceous glands230 and a proclivity to involved adnexal structures.238 The spreading pigmented variant of actinic keratosis is hyperkeratotic and parakeratotic with occasional dyskeratosis.229,234 The epidermis is atypical and buds slightly into the underlying dermis. Acantholysis with basal layer clefting may be present.234 The epidermal pigmentation begins abruptly with the onset of keratinocyte atypia. Melanin is seen in all layers of the epidermis, including the parakeratotic stratum corneum. Pigment incontinence and solar elastosis are prominent in the dermis.229,234 Ultrastructurally, spreading pigmented actinic keratoses have a normal number of melanocytes with types II to IV melanosomes. These melanosomes are typically single and may be present in both keratinocytes and Langerhans cells. DIFFERENTIAL DIAGNOSIS The differential diagnosis for actinic keratoses depends largely on which variant is being evaluated. For routine actinic keratoses, considerations include squamous cell carcinoma in situ, superficial basal cell carcinoma, spongiotic dermatoses, and bowenoid papu losis (Table 26-18). Whereas squamous cell carcinoma in situ and bowenoid papulosis demonstrate fullthickness atypia with dyskeratotic cells, actinic keratoses have atypia restricted to the basal layer or the lower cell layers of

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

HISTOPATHOLOGIC FEATURES Actinic keratoses demonstrate an atypical epidermal proliferation. There is hyperkeratosis with parakeratosis and usually a loss of the underlying granular layer. The parakeratotic nuclei may be large with oval or circular features. A decreased expression of stratum corneum chymotryptic enzyme, a serine protease involved in skin desquamation, has been reported in these lesions.239 The basal layer becomes proliferative with slight budding into the dermis.240 Mild spongiosis above the atypical basal cells is common. The keratinocytes demonstrate increased mitotic activity221,240 and may possess more or less basophilia than the surrounding epidermal cells.241 Enlarged nuclei with prominent nucleoli are also present. Some liquifactive degeneration of the basal layer may be present.240 Acantholysis is seen as a focal occurrence or as a dominant process. Adnexal structures are usually spared, and the acrotrichia or acrosyringia shows a normal orthokeratotic stratum corneum above it. The dermis demonstrates a mild superficial perivascular inflammatory infiltrate with some evidence of neoangiogensis.221,242 Increased expression of cyclooxygenase-2, a proangiogenesis protein, has been reported

in actinic keratoses.227,243 Solar elastosis is variably present, and some evidence suggests that lesions with greater amounts of this material demonstrate enhanced expression of pro-apoptotic and cellular proliferation markers such as bcl-2 and Ki67.244 The presence of dermal tenascin, an extracellular matrix protein expressed around neoplastic cutaneous lesions, has reportedly been associated with the degree of keratinocyte atypia in actinic keratoses but does not correlate with different pathologic subtypes.245 There are different histopathologic variants of actinic keratoses. Hypertrophic actinic keratoses have a thickened, acanthotic epidermis (Fig. 26-8). Atypia is common along the basal layer but may be minimal. An overall irregular, psoriasiform hyperplasia may be seen. Papillomatous proliferation is more common in acral lesions.236 The papillary dermis may show mild fibrosis with elongation of dermal capillaries. An increased expression of p53 protooncogene in these neoplasms has been reported and may represent an early and critical event in their development.246 Atrophic actinic keratoses show a thinned and atrophic stratum malpighii, typically with substantive overlying hyperkeratosis.236 Atypical cells are found predominantly along the basal layer. Acantholytic actinic keratoses demonstrate widespread keratinocyte acantholysis.240 Dyskeratotic cells may be seen. Actinic keratoses with prominent epidermolysis are known as epidermolytic

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Table 26-18 Actinic Keratosis

572

 FIGURE 26-9 Bowenoid actinic keratosis. Epidermal atypia is full thickness and resembles Bowen’s disease.

the spinous layer. Additionally, few dyskeratotic cells are present in actinic keratoses. Whereas squamous cell carcinoma in situ reportedly stains positively for cytokeratin 10, bowenoid actinic keratoses do not.249 Both actinic keratoses and superficial basal cell carcinomas may demonstrate small buds of atypical cell protruding downward from the epidermis. Typically, basal cell carcinomas demonstrate prominent peripheral palisading, stromal retraction, and dermal mucin deposition. With difficult cases, Ber-EP4 staining (positive in basal cell carcinomas but negative in actinic keratoses and normal epidermis) may aid in differentiating between the two.250 Spongiotic dermatoses must also be ruled out because some actinic keratoses demonstrate minimal keratinocyte atypia and mild spongiosis, particularly if they have been irritated. The presence of different

types of inflammatory cells in the dermis may aid in differentiation. Hypertrophic actinic keratoses must be differentiated from inflamed seborrheic keratoses because both lesions show acanthosis and may have minimal atypia. The presence of horn pseudocysts, papillomatosis, and exocytosis by inflammatory cells supports a diagnosis of a seborrheic keratosis. Pigmented actinic keratoses and the spreading pigmented actinic keratosis must be differentiated from solar lentigos and minimally acanthotic seborrheic keratoses. Keratinocyte atypia and the lack of lentiginous proliferation support a diagnosis of actinic keratosis. Acantholysis and epidermolysis may be seen in various dermatoses and in lesions such as acantholytic and epidermolytic acanthomas. These neoplasms, however, do not demonstrate keratinocyte atypia and normally fail to show proliferation of

Clinical Features Small, erythematous keratotic lesions on the sun-damaged skin of elderly patients Scale may be white to yellow-brown Borders are sharply demarcated Typically asymptomatic, but itching or tenderness may occur Histopathologic Features Hyperkeratosis with intermittent large parakeratotic nuclei Keratinocyte atypia is prominent along the basal layer Spongiosis in the immediate suprabasalar layer Budding of basal layer keratinocytes into the dermis Perivascular inflammation and solar elastosis Differential Diagnosis Squamous cell carcinoma in situ Superficial basal cell carcinoma Bowenoid papulosis Spongiotic dermatoses

the basal layer. Finally, lichenoid actinic keratoses should be distinguished from benign lichenoid keratoses and inflamed seborrheic keratoses.235 Given the nature of the inflammatory infiltrate, this may be difficult because the interface may be obscured. Keratinocyte atypia is a key feature. Benign lichenoid keratoses demonstrate more keratinocyte dyskeratosis and the presence of colloid bodies in the papillary dermis. They are also more expansive than lichenoid actinic keratoses.

Actinic Cheilitis

 FIGURE 26-10 Lichenoid actinic keratosis. The epidermis shows keratinocyte atypia with a lichenoid inflammatory infiltrate in the papillary dermis.

Actinic cheilitis is also known as cheilitis exfoliativa, solar cheilosis, or actinic keratosis of the lip.251 Initial studies suggested an association between this condition and prolonged sun exposure.252 Other potential etiologies include tobacco use, poor dentition, herpes simplex virus (HSV) infection, and syphilis.251,253,254 This condition is largely restricted to persons with considerable UV light exposure.253,255 Persons with fair skin are at higher risk, and although it has been described in blacks, it is rare.251,253 Lesions typically arise on the lower lip either because this site is unprotected from solar rays or the angle at which these rays strike the vermilion surface.255 Evolving squamous cell carcinoma has a greater potential for lymphatic spread than does squamous cell carcinoma of the glaborous skin.

HISTOPATHOLOGIC FEATURES The epithelium is thickened, acanthotic, and hyperkeratotic.251 Parakeratosis is present, and ulceration is noted in a minority of cases. The keratinocytes display mild to moderate atypia.253 These dysplastic changes are associated with increasing epidermal acanthosis and thickening of the keratin layer.254 Mitotic activity is present. The dermis shows moderate to severe solar elastosis and a nonspecific perivascular inflammatory infiltrate. Lesions adjacent to invasive squamous cell carcinoma reportedly have a more intense pattern of inflammation.256 Scattered plasma cells are seen,251 and dilated blood vessels are common. The pattern of cytokeratin expression in individuals with actinic cheilitis differs from that of normal oral mucosa and is unrelated to the degree of cytologic atypia.257 With actinic keratoses, p53 is upregulated in tumoral tissue, but bcl-2 protein is diminished.256,258 Expression is also increased. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes contact cheilitis and plasma cell cheilitis (Table 26-19). Contact cheilitis is similar to contact dermatitis elsewhere in that spongiosis, lymphocytes, and eosinophils are prominent. Keratinocyte atypia is not appreciated, and parakeratosis is not as prominent as in actinic cheilitis. Plasma cell cheilitis demonstrates large masses of plasma cells without keratinocyte atypia.

Arsenical Keratosis Precancerous keratoses have been described in patients exposed to arsenic-containing

Table 26-19 Actinic Cheilitis

Table 26-20 Arsenical Keratosis

Clinical Features Lower lip involved in patients with extensive sun exposure Scaling, crusting, and erosions are seen Loss of elasticity, dryness, and atrophy Histopathologic Features Epidermis with acanthosis, hyperkeratosis, and parakeratosis Keratinocyte atypia is mild to moderate Solar elastosis and telangiectasias in the dermis Differential Diagnosis Contact cheilitis Plasma cell cheilitis

Clinical Features Hyperkeratotic papules on the palms and soles in persons exposed to arsenic Lesions are compact with a yellow to brown color Histopathologic Features Compact hyperkeratotic stratum corneum Mild to moderate keratinocyte atypia Transformation to basal cell carcinoma or squamous cell carcinoma occurs Perivascular dermal inflammation is present, but solar elastosis is not Differential Diagnosis Actinic keratosis Verruca vulgaris Bowen disease

substances such as medications (Fowler solution), mining or smelting products, well water, industrial compounds, and pesticides or fungicides.259 An association between arsenic exposure and Bowen disease is also well known.260-263 This metal continues to be used in Chinese proprietary medicines and Indian ethnic remedies. HPV types 41 and 23 have been found in these lesions.264 CLINICAL FEATURES Lesions begin as small papules with dense hyperkeratosis.259,262 They are yellow but may be slightly brown or dark. The palms and soles are primarily affected, and a mild keratoderma is sometimes present. The thenar and lateral borders of the palms and roots of the fingers are most commonly affected.261 Keratoses may coalesce to form plaques. Similar lesions are found elsewhere on the body. Keratoses begin as soon as 4 years after exposure but usually take 20 to 30 years to manifest.260 HISTOPATHOLOGIC FEATURES The stratum corneum is hyperkeratotic and compact. Mild papillomatosis may also be present. The granular layer is usually accentuated but may be thinned or absent.260 Keratinocyte atypia is present particularly along the basal layer.259 Cytologic atypia may be so mild as to be almost nonexistent or as profound as in Bowen disease.261 Budding into the dermis may be seen. These lesions are divided into type A (benign) and type B (bowenoid or malignant).261 The dermis shows some perivascular inflammatory cells, but the typical solar elastosis seen in actinic keratoses is absent. The adjacent epithelium is slightly thinned with absent or atrophic adnexal structures.261 Transformation into a basal

cell carcinoma or squamous cell carcinoma has been described.259 Some areas demonstrate seborrheic keratosis–like changes. Beta1 integrins, a group of basal keratinocyte proteins associated with epidermal differentiation and proliferation, have been shown to be downregulated in arsenical keratoses and adjacent unaffected skin.265 DIFFERENTIAL DIAGNOSIS Arsenical keratoses must be distinguished from actinic keratoses, warts, and Bowen disease (Table 26-20).260 Actinic keratoses usually show a less compact hyperkeratosis, mild suprabasal spongiosis, and solar elastosis. Warts are more papillomatous than arsenical keratoses, typically have columns of parakeratosis, may possess large keratohyaline masses, and usually show dilated capillaries in the uppermost papillary dermis. Additionally, warts show no significant keratinocyte atypia. Whereas Bowen disease has “full-thickness” atypia involving all the layers of the epidermis, arsenical keratoses rarely demonstrate such features. Additionally, Bowen disease has dyskeratotic keratinocytes and a less compact stratum corneum.

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

CLINICAL FEATURES Actinic cheilitis is almost universally restricted to older persons with significant actinic damage. Men are affected much more often than women. The lip displays a generalized atrophy with scaling, dryness, and erosions.251,255 There is a mottled appearance with an indistinct vermilion border. The lip is pale white to pink or brown. Linear striations, thickened keratoses, and crusting may be apparent.253 The lip tends to lose its plasticity. A recurrent cycle of crusting and healing may be described. Prolonged ulceration is worrisome for a squamous cell carcinoma. An acute form of actinic cheilitis has been described that is less common in the elderly.251 It occurs predominantly in the summer months after sunlight exposure. The lip becomes red and swollen with severe congestion, fissuring, and ulceration. Blisters may also appear.

INTRAEPIDERMAL CARCINOMAS

Bowen Disease Bowen disease was originally described by Bowen in 1912266 and is believed by most investigators to be a squamous cell carcinoma in situ. These lesions are associated with chronic solar damage, radiation therapy, and arsenic or paraquat exposure.259,267,268 This disease may also

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be more common in uncircumcised males.269 HPV 2, 16, 18, 33, 34, 57b, and 82 have been reported in anogenital Bowen disease.270-272 HPV types 23, 5, 16, 18, 20, 21, 31, 33, 34, 54, 56, 58, 61, 62, 73, and 82 have been described in extragenital disease, usually on the extremities.268,270,273-277 Human herpesvirus 8 (HHV8) in cutaneous malignancies and premalignant lesions has been described in organ transplant recipients.278 An evaluation of Bowen disease in otherwise healthy patients noted no association,279 although these findings have been disputed.280 HPV-associated extragenital disease is linked to black race, an acral location, young age, and a hyperkeratotic or verrucous appearance.281 It was originally believed that Bowen disease was a marker for internal malignancy and that cancers were more common in this population.268,282 However, recent data cast doubt on this assertion.268,283-286 A case of vulvar Bowen disease with abnormalities of chromosome 11 has been described.287 CLINICAL FEATURES There are two clinical variants of Bowen’ disease—that involving the anogenital area and that of glaborous skin. Anogenital disease involves the mucous membranes, but mucosal sites such as the oral cavity and conjunctiva are also involved.268 Glaborous lesions appear as slowly enlarging, well-demarcated patches or plaques.267,268,281 Some are large and poorly defined.267 Tumors display mild scaling or crusting. Verrucous and hyperkeratotic variants are seen. Presentation as a cutaneous horn and within a lesion of porokeratosis has also been described.288,289 Most are flesh colored to erythematous. A pigmented variant has also been reported and may simulate melanocytic neoplasms.290,291 Normal-appearing skin may be present within some plaques.292 Most patches of Bowen disease are a few millimeters to a few centimeters in diameter.293 Lesions are most common on sun-exposed sites, particularly the lower extremities, in women.267,294 Lesions on the face are also more common in female patients. Terminal hair follicles may protect against this disease, but vellus follicles are more often involved. Patients are usually in the sixth to eighth decades of life.268 Bowen disease pursues a relatively benign course.281 HISTOPATHOLOGIC FEATURES The stratum corneum is hyperkeratotic and usually parakeratotic.268,295,296 The parakeratosis may be extensive and platelike. The rest of the epidermis is acanthotic with occasional psoriasiform hyperplasia

(Fig 26-11A). The cells display “fullthickness” atypia with a “windblown” appearance.268,297 There is a loss of epidermal polarity in that normal and progressive keratinocyte maturation has ceased.295 Keratinocytes are enlarged and have atypical nuclei with frequent mitoses (Fig. 26-11B). Dykeratosis is variable but is usually prominent. Keratinocytes may be multinucleated and are slightly eosinophilic in some sections.296 Importantly, involvement of the adnexae, particularly pilosebaceous structures, may be present.268 The infundibulum, sebaceous glands, and external root sheath may be replaced by tumor cells.267 Hyperpigmentation along the basal layer and dermal melanophage proliferation is accentuated in pigmented variants. Clear cell and pagetoid variants have also been reported.298 Dermal invasion occurs in 3% to 5% of cases, most often in head and neck lesions in middle-aged to older men.297,298 A perivascular inflammatory infiltrate is typically present, and eosinophils are seen, particularly when topical medicaments have been applied.268,292 Invasive tumors may demonstrate adnexal differentiation. Some increased vascularity may be seen.292 Regression with fibrosis

and scarring of the papillary dermis has been described.292 Numerous dyskeratotic cells with associated Fas antigen (an apoptosis-related tumor necrosis factor receptor protein) have been described with this phenomenon.299 Amyloid deposition is present in both lesional and interlesional skin. This may result from cytokeratin degradation from dyskeratotic keratinocytes.292 Differentiation toward a sebaceous carcinoma300 and eccrine sweat gland carcinoma have been described.297 An association with invasive eccrine porocarcinoma and trichilemmal carcinoma have also been reported.301,302 The presence of the tumor-suppressor protein p16INK4a has been suggested as a possible surrogate marker for identifying Bowen disease associated with high-risk HPV infection.303 However, unlike in tumors of the cervical mucosa, the expression of p16 does not appear to be associated with expression of the retinoblastoma protein.304 DIFFERENTIAL DIAGNOSIS Bowenoid actinic keratoses, bowenoid papulosis, extramammary Paget disease, epidermotropic carcinoma metastatic to the skin, erythroplasia of Queyrat, actinic keratosis,

A

B  FIGURE 26-11 Bowen’s disease. (A) The epidermis is psoriasiform and slightly hyperkeratotic. (B) Keratinocytes demonstrate “full-thickness” atypia with increased mitotic activity and dyskeratosis.

Table 26-21 Bowen Disease

and podophyllin-treated condylomata acuminata must be differentiated from Bowen disease (Table 26-21).268,269,295,297,305 Bowenoid actinic keratoses and bowenoid papulosis are identical to Bowen disease. However, these tumors are smaller and have usually been completely removed by the biopsy. The presence of cytokeratin 10 in Bowen disease but not bowenoid actinic keratoses has been reported.306 Extramammary Paget disease usually shows pale cells that stain for PAS, carcinoembryonic antigen (CEA), cytokeratin 5/8, cytokeratin 7, and cytokeratin 19.306 Murine monoclonal antibodies have been used to distinguish between these two diseases,307 although cytokeratin 7, previously believed to be present only in Paget disease, has also been described in pagetoid Bowen disease.308 Epidermotropic carcinoma metastatic to the skin, such as eccrine porocarcinoma, demonstrates atypical cells within the epidermis but usually in a pagetoid pattern. Dyskeratotic cells are also more prevalent in Bowen disease. Erythroplasia of Queyrat may be Bowen disease of the glans penis and as such cannot be consistently distinguished from the latter. Immunoperoxidase staining for p27 and Ki-67 have shown usefulness in separating Bowen disease from actinic keratoses.305 Finally, podophyllintreated condylomata acuminata demonstrate dyskeratotic cells with large, atypical

Erythroplasia of Queyrat This disorder was initially described by Tarnovsky in 1891293 but named after Queyrat in 1911.309 Many investigators consider it to be identical to Bowen disease293,310; however, some differences do exist between the two conditions. Erythroplasia of Queyrat is not associated with internal malignancies or arsenic exposure, and dermal invasion with metastatic spread is more likely.310 Trauma, friction, poor hygiene, smegma irritation, concomitant syphilis, and other sources of inflammation (including plasma cell balanitis) are believed to incite this disease.310-312 Lesions have been present an average of 2 years before diagnosis.269 Twenty percent of invasive tumors demonstrate nodal spread, but only about 5% of such lesions result in the patient’s death.311 Infection with HPV types 8, 16, 39, and 51 has been reported.313,314 CLINICAL FEATURES Lesions are typically present in uncircumcised men in the third to sixth decades of life.311 The lesions are most common on the glans but may also be present on the urethral meatus, corona, sulcus, and prepuce.269 The vulva, oral mucosa, conjunctiva, and urethra may also be involved.310,311 Erythroplasia of Queyrat is usually a single lesion, but multiple tumors have also been described. They are smooth, red, velvety plaques with minimal induration.269,293,310,315 The surface may be moist and glistening or hyperkeratotic and scaling.293,311 The margins are well demarcated. Symptoms are few, but some mild itching or bleeding may be present.311 HISTOPATHOLOGIC FEATURES The histologic changes are similar to those of Bowen disease. The epidermis is irregularly acanthotic with occasional psoriasiform changes and shows a loss of polarity.311,315 Dyskeratotic cells are present.310,311,315 The nuclei are atypical, and hyperchromatic and multinucleated cells may be present. Ten percent of cases demonstrate dermal invasion (squamous cell carcinoma).311 The dermis contains a perivascular inflammatory infiltrate with a variable number of plasma cells.

DIFFERENTIAL DIAGNOSIS Erythroplasia of Queyrat should be distinguished from Bowen disease and bowenoid papulosis (Table 26-22).269 Bowen disease is very similar to erythroplasia of Queyrat, but the latter has fewer multinucleated and dyskeratotic cells, more infiltrating plasma cells, and less hyperkeratosis. Bowenoid papulosis may also be indistinguishable from erythroplasia of Queyrat. The epidermis may show an overall “papule” type of appearance on low power. Frank koilocytosis is uncommon,316 but small basophilic bodies with a surrounding halo may be present in the stratum granulosum and stratum corneum.

Intraepithelial Epithelioma The intraepithelial or intraepidermal epithelioma (IEE) is a controversial lesion. The presence of an intraepithelial spread of atypical keratinocytes was initially described by Borst in 1904 and Jadassohn 22 years later.317 Borst likely described the intraepidermal spread of a squamous cell carcinoma, but Jadassohn was probably reporting the same phenomenon occurring in basal cell carcinoma. Montgomery first coined the term intraepithelial epithelioma of BorstJadassohn in 1929.318 The IEE constitutes the intraepidermal spread of keratinocytes with varying degrees of atypia. Some authors believe that most cases constitute inflamed seborrheic keratoses, squamous cell carcinomas, hidroacanthoma simplex, Bowen disease, epidermal nevi, or clear cell acanthomas.317,319 The names Borst and

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

Clinical Features Glabrous and anogenital patches a few centimeters in diameter Well-demarcated and scaling with mild erythema Patients are usually older, and lesions arise in sun-damaged areas Women more often affected than men Histopathologic Features Epidermis demonstrates acanthosis and hyperkeratosis Mild to moderate psoriasiform hyperplasia Full-thickness epidermal atypia with dyskeratotic cells and atypical mitoses Loss of epidermal polarity Frequent involvement of adnexal structures Differential Diagnosis Bowenoid actinic keratoses and bowenoid papulosis Extramammary Paget disease Epidermotropic carcinoma metastatic to the skin Erythroplasia of Queyrat Podophyllin-treated condylomata acuminata

mitotic figures and may be mistaken for Bowen disease. However, the atypia is usually not full thickness; epidermal changes consisting of a “knuckling” rather than a psoriasiform pattern and koilocytic cells may be present.

Table 26-22 Erythroplasia of Queyrat

Clinical Features Well-demarcated, red, velvety plaques on the glans penis in uncircumcised men Usually asymptomatic but may demonstrate mild itching or bleeding May involve other areas of the penis, vulva, or other mucosal surfaces Histopathologic Features Full-thickness epidermal atypia with abnormal mitoses and dyskeratotic keratinocytes Loss of epidermal polarity Plasma cells in the dermis Differential Diagnosis Bowen disease Bowenoid papulosis

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Jadassohn should probably be abandoned when discussing IEE because their descriptions likely are more referable to a histologic phenomenon (reaction pattern) than a distinct clinical lesion.320 Acrosyringeal derivation has been proposed for this tumor.321

576

CLINICAL FEATURES Intraepithelial epitheliomas are small, flat, verrucous plaques with a tan or gray appearance. They are usually single and resemble a seborrheic keratosis or epidermal nevus. They are most common on the lower extremity but may also be present on the head and neck.317,320 They average about 2 cm in diameter and have an irregular outline.321 Ulceration and nodal metastases have been described.321 HISTOPATHOLOGIC FEATURES The epidermis is hyperkeratotic, acanthotic, and somewhat papillomatous.320,321 Dermal invaginations may be present.321 Within the epidermis are demarcated nests of cells arising in a disorderly and centrifugal manner (Fig. 26-12). These nests proliferate in a microscopic pattern known as acervate (ie, growing in clusters or heaps).321 A rim of normal epithelium is present between these nests and the basement membrane. The nesting cells may have slightly basaloid or eosinophilic cytoplasms.320,321 Varying degrees of immaturity and atypia are present.

Sebaceous differentiation has also been reported.322 Clefting is present around some nests of cells.321 Overlying parakeratosis, dyskeratosis, and squamous eddies are seen.320,321 Melanin deposition within the cellular nests has been described. The papillary dermis may demonstrate mild thinning and a superficial perivascular lymphocytic infiltrate.321 DIFFERENTIAL DIAGNOSIS Intraepithelial epitheliomas must be distinguished from clonal or inflamed seborrheic keratoses, Bowen disease, Paget disease, melanoma in situ, and intraepidermal poroma (Table 26-23).321 Clonal and inflamed seborrheic keratoses typically have horn pseudocysts, regular papillomatosis, and a “flat bottom.” Bowen disease proliferates not in a clonal pattern but rather with full-thickness atypia. Dyskeratosis is also much more prominent. Paget disease and melanoma in situ represent a proliferation of single cells or small nests rather than the larger ones found in intraepithelial epithelioma. Atypia, mucin deposition, and melanin production may also be found. Distinction may be assisted by the use of immunoperoxidase staining. Intraepidermal poroma is likely to be the most difficult tumor to differentiate from IEE. In these tumors, clefting is not seen, and the nests of cells are much larger. Additionally, atypia and dyskeratosis are not present.

 FIGURE 26-12 Intraepidermal epithelioma. In the epidermis are nests of keratinocytes with slight atypia proliferating in an “acervate” pattern.

Table 26-23 Intraepithelial Epithelioma

Clinical Features Flat, verrucous papules or plaques resembling a seborrheic keratosis or epidermal nevus Gray to tan, slightly elevated, < 2 cm in diameter Present on the leg, head, and neck Histopathologic Features Hyperkeratotic, acanthotic, and slightly papillomatous Intraepidermal proliferation of nests of cells with mild to moderate atypia Dyskeratosis clefting and some dermal invasion may be present Differential Diagnosis Clonal or inflamed seborrheic keratosis Bowen disease Mammary and extramammary Paget disease Malignant melanoma Intraepidermal poroma

INTERMEDIATE LESIONS

Keratoacanthoma Keratoacanthomas are rapidly growing cutaneous tumors with atypical histologic features that resolve leaving an atrophic scar. They were initially described in 1889 by Sir Jonathan Hutchinson as a “crateriform ulcer of the face” and today are believed to represent a low-grade squamous cell carcinoma.323 They are also known as molluscum sebaceum. Most keratoacanthomas arise as solitary lesions in sun-exposed sites; however, different clinical syndromes are associated with these tumors.324 Multiple keratoacanthomas of Ferguson Smith is an autosomal dominant disorder that begins in childhood to early adulthood. Numerous lesions arise and disperse over the years. This disorder must be differentiated from the generalized eruptive keratoacanthomas of Grzybowski. In this disease, the erupting keratoacanthomas are smaller (2 to 3 mm in diameter) and may number in the hundreds or thousands. Familial inheritance is not present, and pruritus is common. Facial involvement may be severe, resulting in ectropion and masked facies.325 Mucosal lesions have been described. Another condition, multiple persistent keratoacanthomas, occurs sporadically and consists of slowly healing tumors. Two syndromes, the Muir-Torre syndrome and xeroderma pigmentosum, demonstrate an increased incidence of tumor formation.

CLINICAL FEATURES Keratoacanthomas typically arise on the sun-exposed skin of older persons although they have also been reported in children.324,335,336 The

A

peak incidence begins in the sixth decade of life, and lesions are commonly found on the face, hands, and forearms in men and on the face and legs in women.324 Men are more commonly affected than women. Lesions pass through several stages of development.324 The initial or proliferative phase consists of a smooth, hemispheric nodule that enlarges rapidly over a 2- to 4-week period. These are flesh colored to slightly erythematous and asymptomatic. The next stage, the mature form, demonstrates a dome- or berry-shaped nodule with a central crater containing a plug of compact keratin. This stage lasts several weeks or months. The final phase is that of a resolving lesion. These keratoacanthomas resorb and expel the keratogenous core. Over weeks to months, they become progressively more depressed and eventuate into a scar with variable atrophy. Several clinical scenarios are seen with keratoacanthomas.324 In the agglomerate type, several nodules coalesce to form a large keratotic plaque. The giant keratoacanthoma is a particularly large lesion, up to 9 cm in diameter. Keratoacanthoma centifugum (coral reef keratoacanthoma, nodulovegetating keratoacanthoma, aggregated keratoacanthoma) shows expansive growth, occasionally to 20 cm in diameter. As the lesion is expanding, the central area heals with scarring and atrophy. Subungual keratoacanthomas are painful, persistent lesions that arise under the nails, usually on the fingers.

The thumb and fifth finger are most commonly involved, and bony destruction may take place. Mucosal keratoacanthomas may develop in the mouth and on other mucous membranes, including the bulbar conjunctiva, nasal mucosa, and genitalia. HISTOPATHOLOGIC FEATURES Early lesions demonstrate an invaginating epidermis with a keratin-filled crater (Fig. 26-13A). Adjacent epithelium shows acanthosis, hypergranulosis, and premature cornification.324 Parakeratosis may be present, but orthohyperkeratosis is the rule. Invaginating strands of epithelium may be carcinoma-like (pseudoepitheliomatous) and typically possess an eosinophilic or “glassy” appearance (Fig. 26-13B).324,337 Some acantholysis may be present. Fully developed keratoacanthomas have similar features that are more exaggerated. The overlying epidermis develops “lips” or buttresses surrounding the crateriform plug, which has expanded and consists of parakeratotic material. Epidermal proliferations become more exaggerated as they invade the dermis. Mitotic activity and atypical mitotic figures are more common, particularly at the edges of the epithelial proliferation. Intraepidermal neutrophilic and eosinophilic microabscesses are present. Horn pearls are seen.324 Within the epidermis, occasional fragments of entrapped collagen and elastin fibers are present.324 An inflammatory infiltrate is composed largely of lymphocytes, but eosinophils are also

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

Keratoacanthomas have been found in association with numerous benign and malignant lesions, including nevus sebaceus of Jadassohn, scar, vaccination site, melanoma, basal cell carcinoma, arterial puncture site, linear epidermal nevus, nevomelanocytic nevus, fibroepitheial polyp, and miliaria.14,324,326-330 They have also arisen in HSV infections, radiodermatitis, pustular psoriasis, seborrheic dermatitis, discoid lupus erythematosus, lichen planus, lichen simplex chronicus, folliculitis, weather beaten skin, erythema multiforme, PUVA-treated skin, eczematous dermatitis, and drug eruptions.324,327,331 Keratoacanthomas are also known to occur after cutaneous trauma, including that incited by tattoos.324,332 These tumors are believed to arise secondary to long-standing solar damage because they originate in sun-exposed areas and their occurrence parallels increased UV exposure.324 However, chemical tumorigenesis has been demonstrated in animals, and human tumors have developed after exposure to tar, pitch, and podophyllin.324,327 Viral causes have also been postulated, and HPV types 25 and 6 has been found in some lesions.324,333,334 There appears to be a genetic predisposition to develop keratoacanthomas.324 Tumors are thought to begin in hair follicles.324

B

 FIGURE 26-13 Keratoacanthoma. (A) The typical keratoacanthoma shows a crateriform configuration with hyperkeratotic plug and surrounding buttresses of squamous epithelium. (B) Proliferating cells of keratoacanthomas are eosinophilic and variably atypical.

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prominent.338 Neutrophils and plasma cells are present. The stroma may be granulomatous if epithelium has ruptured into the dermis and is being resorbed. Atypical eccrine sweat duct hyperplasia may also be present. Melanocyte proliferation with increased dendricity has been described in proliferative epithelium.339 Involuting or resolving lesions begin to take on a flattened, less crateriform appearance.325 The epidermis becomes variably acanthotic and hypergranulotic with sharp, jagged rete ridges. Dyskeratotic keratinocytes are seen. Atypia and the eosinophilic quality of the invading epithelium are diminished. Small keratin-filled cystic structures may be seen in the papillary dermis.340 Dermal vascularity is increased, and fibrosis is variably prominent in the papillary dermis. Granulation tissue in the deep aspects of the tumor has been reported.324 The inflammatory infiltrate becomes largely lichenoid with giant cells, plasma cells, and neutrophils. This involutional phase is believed to be immunologically mediated.340 Infiltrating inflammatory cells, largely cytotoxic T cells, invade the tumor and ameliorate the proliferative state of the tumor.341 Increased expression of bak and decreased expression of Bcl-2 in resolving keratoacanthomas compared with squamous cell carcinomas suggest a potential role of these apoptosis-regulating proteins in lesion regression.342 Similar to most neoplastic processes, perineural and vascular invasion have been described.343-345 Perineural invasion is more common with head and neck lesions. These tumors tend to be large and deeply infiltrating. However, the prognosis does not seem to be adversely affected by this process.343 Vascular invasion has not been associated with metastatic disease. It appears likely that involvement of vessel walls by tumor cells is more of a passive phenomenon dictated by the proximity of large vessels than one of malignant invasion.344 Atypical and tripolar mitotic figures have also been described but are not associated with an increased incidence of recurrence.346,347 Aneuploidy is present in some keratoacanthomas, but to a lesser extent than in well-differentiated squamous cell carcinoma.324 Ultrastructurally, keratoacanthomas demonstrate an increased number of desmosomes compared with normal skin.324 Intranuclear inclusions have been described. There has been considerable discussion regarding the malignant potential of

keratoacanthomas.337,348-351 Metastatic spread of lesions, considered by some the sine qua none of malignancy, has been described in some keratoacanthomas.337,348,351 It is unclear how these lesions will ultimately be categorized, but currently they may be considered to be low-grade squamous cell carcinomas with a rare tendency to metastasize. DIFFERENTIAL DIAGNOSIS Keratoacanthomas must be distinguished from conventional squamous cell carcinomas,324 dilated pores, infundibular cysts, and resolving inflamed warts (Table 26-24).340 Conventional squamous cell carcinomas do not produce an involuting epithelial proliferation with compact keratogenous material. Atypical eccrine ductal hyperplasia, intraepidermal microabscesses, tissue eosinophilia, and intraepithelial elastic fibers are more commonly found in keratoacanthomas than squamous cell carcinomas.324,352 Whereas keratoacanthomas take up peanut agglutinin stain, squamous cell carcinomas do not.353 Immunohistochemical analysis of keratoacanthomas and squamous cell carcinomas for desmosomal proteins desmoglein 1 and 2 have demonstrated the downregulation of these proteins in the latter but not in the former.354 Similar findings have been reported for

Table 26-24 Keratoacanthoma

Clinical Features Flesh-colored to erythematous nodules with a central keratin plug Typically present on middle-aged or older patients in sun-exposed sites Resolving lesions are scarred and atrophic Lesions may exist at previous sites of trauma or with various dermatoses Histopathologic Features Overlying epithelium forms “lips” with adjacent hypergranulosis and hyperkeratosis Cutaneous plug is eosinophilic and parakeratotic Infiltrating epithelium is eosinophilic and may be atypical with increased mitotic activity Entrapped collagen and elastic fibers are seen Horn pearls and neutrophilic or eosinophilic microabscesses are present Differential Diagnosis Squamous cell carcinoma Dilated pore or infundibular cyst Resolving inflamed wart

the adherens junction protein E-cadherin.355 The adhesion molecule CD44 appears to be upregulated in keratoacanthomas compared with squamous cell carcinomas; the reverse is true for βcatenin.356 Evaluation of angiotensin type 1 receptors in keratoacanthomas revealed a negative peripheral pattern of stain uptake, but squamous cell carcinomas showed diffuse staining throughout tumor aggregates.357 The cell surface carbohydrate sialyl-Tn is expressed to a greater degree in keratoacanthomas than in squamous cell carcinomas.358 Diminished p53, Ki-67 antigen, and cyclooxygenase-2 expression in keratoacanthomas compared with squamous cell carcinomas has been reported; p16 expression appears to be similar between these tumors.359-361 The increased presence of oncostatin M, a glycoprotein belonging to the interleukin-6 family, in keratoacanthomas has led to the suggestion that these tumors represent evolving squamous cell carcinomas.362 The expression of matrix metalloproteinases (MMPs) in these two tumors has also been investigated, with the loss of MMP-19 being more consistent with an evolving squamous cell carcinoma.363 Gross chromosomal aberrations, including chromosomal instability, are significantly more prevalent in squamous cell carcinomas than keratoacanthomas.364 Use of a panel of immunoperoxidase stains for apoptosis-associated proteins, telomerase-associated protein (TP1), and the cell adhesion protein E-cadherin reportedly provides different patterns of uptake sufficient to differentiate between keratoacanthomas and squamous cell carcinomas.365 Dilated pores and infundibular cysts demonstrate aggregations of keratin but usually without inflammation or parakeratosis. The epithelial lining is also benign without the typical eosinophilic changes seen in keratoacanthomas. Resolving inflamed warts may be endophytic but typically are exophytic as well. The “lips” or buttressing commonly present in keratoacanthomas are absent from these lesions as are the eosinophilic features of the proliferating epithelium, the neutrophilic microabscesses, and the infiltrating eosinophils.

MALIGNANT TUMORS

Basal Cell Carcinoma Basal cell carcinoma is the most common malignant disease in humans and accounts for 50% of all cancers in the

keratoses, nevomelanocytic nevi, condyloma acuminata, primary melanomas, metastatic melanoma deposits, port wine stains, infundibular cysts, hemangiomas, and pilomatricomas have all been associated with basal cell carcinomas.372,377,380,382,384-390 Basal cell proliferation with peripheral cell palisading and stromal retraction is occasionally seen in the epidermis overlying a dermatofibroma. These changes may represent proliferating epidermal basal cells or follicle induction by underlying stroma.390-392 Basal cell carcinomas may also be associated with malignant tumors such as melanomas, squamous cell carcinomas, lentigo malignas, Merkel cell carcinomas, and keratoacanthomas.380,384,393-399 Basal cell carcinomas are believed to derive from the epidermis, specifically the basal cell layer and the outer root sheath of the hair follicle.377,394 The cells of origin are likely pleuripotential and may be progenitor epithelial cells in the case of adults or primary epithelial germ cells in the case of linear unilateral basal cell nevi. The expression of CD10 in basal cell carcinomas supports the contention that these tumors are of follicular derivation.400 Anti-keratin antibodies have shown that basal cell carcinomas possess a keratin component that is not normally found in the basal layer and stain similarly to the lower part of the hair follicle epithelium.401 The presence of cytokeratin 15 in trichoepitheliomas and its relative absence in basal cell carcinomas suggest that these malignancies arise infrequently from the so-called “bulge region” of the hair follicle.402 More recent evidence suggests that basal cell carcinomas differentiate toward follicular matrix cells.403 The oncogene BMI-1 is upregulated by the sonic hedgehog pathway and is strongly expressed in basal cell carcinomas, implying an association in pathogenesis between the former and latter.367,404 The patient’s immune system affects the pathogenesis and eventual outcome of these tumors. Environmental carcinogens, such as oncogenic viruses, may be potentiated by concomitant immunosuppression.381 Basal cell carcinomas are 10 times more common in persons who have undergone a solid organ transplant,405 and herpesvirus-like DNA sequences have been found in these lesions.406 The presence of oncogenic subtypes of HVP have also been reported in basal cell carcinomas.376 Tumors may be more aggressive, with an increased tendency to recur or metastasize.407 Certain histologic types may

also be more prevalent among immunosuppressed patients. Infiltrative basal cell carcinomas are more common than nodular tumors in immunocompromised patients, with the superficial subtype more prevalent in solid organ transplant recipients.381,399,408 Superficial basal cell carcinomas predominate in persons with diabetes mellitus or chronic renal failure and are the predominant pattern among persons with HIV.381 HIV infection also increases the risk of developing these tumors.376 Basal cell carcinoma arises on the sunexposed cutaneous surfaces, primarily in persons beginning in middle age. Just over half of all patients are men, and about 85% of these tumors appear on the head and neck.366,409 Only about 10% to 15% of these tumors develop on sun-protected skin.380 A truncal location is believed to be associated with genetic polymorphisms in glutathione S-transferase and cytochrome P-450.410 Lesions have been described on the genital and perianal skin but, interestingly, in patients without a history of significant UV light exposure.411 About 20% to 30% of the lesions occur on the nose alone, making it the most commonly involved site.366 Basal cell carcinomas are most prevalent among whites. Blacks and Hispanics are also affected but to a lesser extent.412 Among blacks, women are more likely to be affected. As with whites, most lesions in blacks arise on the head and neck; however, the nose is less often involved. The high melanin content in black skin may protect against tumor development.413 The histologic subtypes are similar between the races.413 CLINICAL FEATURES Typical lesions are flesh colored or translucent to slightly erythematous papules and nodules with raised, rolled borders (see Fig. 26-14A). Bleeding and crusting are occasionally seen. Telangiectasias may be present, particularly at the borders. Some lesions ulcerate, but significant scaling is unusual. Large tumors destroy structures such as the ears, eyes, and nasal passages. Different variants may have different clinical presentations. Pigmented basal cell carcinomas are more common in blacks and Hispanics.414 They present as variably pigmented nodular lesions and may simulate melanocyte tumors. The hyperpigmentation may be light brown to dark black and involve all or only parts of the lesion. The cicatricial or scarring basal cell carcinoma has an actively spreading, indurated border with an atrophic or scarlike border.380

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

United States.366,367 Australia has the highest incidence of basal cell carcinoma worldwide. This tumor is also termed basal cell epithelioma, basalioma, or rodent ulcer and was originally described by Jacob in 1824.368 Between 1971 and 1977, the incidence of basal cell carcinoma increased 18%.369 More than one million new cases are diagnosed annually.367,370 Basal cell carcinomas typically begin after age 30 years and peak at age 70 years.371 Childhood disease is rare in immunocompetent patients but has been described in otherwise healthy children with excessive UV exposure.372-374 In children, tumors are typically on the head, disproportionately display more aggressive histologic features, and they have a relatively high rate of recurrence. Persons with blue or green eyes, easy freckling, blond or red hair, and significant outdoor exposure are at increased risk for these tumors.371 In young women, there is an association with tanning bed use and cigarette smoking.375 Intense intermittent sun exposure has been correlated with a greater risk of tumor development compared with continuous sun exposure.367,376 Anatomic areas with increased sebaceous gland concentration are more likely to be involved.369 Risk factors for basal cell carcinoma include exposure to arsenic, psoralens, x-irradiation, coal tar derivatives, and UV light.259,369,371,376-380 Tumors may arise in scars, thermal burns, and chronic inflammation (eg, draining sinuses, leg ulcers, hidradenitis).377,378,380 Immunocompromised patients are at increased risk for basal cell carcinoma perhaps due to impaired cell-mediated immunity and an increased susceptibility to oncogenic viruses.381 People with certain genodermatoses, including albinism, xeroderma pigmentosum, Rasmussen syndrome, Rombo syndrome, Rothmund-Thomsen syndrome, Bazex syndrome, and Darier disease have an increased incidence of basal cell carcinoma.369,376,380,382 There is some evidence that nodular basal cell carcinomas are more strongly associated with occupational sunlight than the superficial variant.383 Different tumors have been associated with basal cell carcinoma. These may be little more than coincidence, but in some instances, the cutaneous malignancy may have arisen from prolonged irritation and inflammation. Warts, porokeratomas, varicella scars, neurofibromas, lesions of lupus vulgaris, tattoos, leishmania scars, nevi sebaceus, linear epidermal nevi, seborrheic

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A

580

B

 FIGURE 26-14 Nodular basal cell carcinoma. (A) Nodular pinkish translucent tumor with telangiectasias. (B) These tumors are composed of nodular aggregates of atypical basaloid cells with peripheral palisading and stromal retraction.

Halo basal cell carcinomas are 1- to 2-mm erythematous papules on sunexposed sites with surrounding hypopigmentation.380 Multicentric (multifocal, “field-fire”) basal cell carcinoma shows grouped tumors arising close to each other.380 A polypoid variant has also been described.415,416 Finally, the linear variant demonstrates a longitudinal arrangement of tumoral deposits with a predilection for the periocular region, perhaps propagated by the Koebner phenomenon.417-419 Nodular basal cell carcinoma is the most common histologic subtype. Basal cell carcinoma rarely invokes significant symptoms. Burning, stinging, or shooting pain is uncommon but may indicate perineural invasion.420 This complication is present in 0.1% to 1.0% of cases and may be seen with recurrent lesions or those previously treated with radiotherapy. Motor symptoms from neural involvement have also been described. Lesions of the preauricular and cheek area are most commonly involved.420 The tumor spreads proximally along perineural tissue planes and may be the only symptoms before clinical evidence of recurrence. The vertical depth of invasion has been positively correlated with male gender, increased horizontal diameter, and more aggressive tumor subtypes such as micronodular or infiltrative basal cell carcinoma.421 Metastatic basal cell carcinomas are a rare occurrence, with fewer than 300 cases reported in the literature.366,422 Primary tumors from the face and ears most commonly give rise to these metastases, and the median interval between tumor appearance and metastasis is 9 years.367 Metastatic spread is most closely linked to the size of the original lesion, its duration, and the

depth of tumor invasion but less so to the histologic subtype.409,422-424 Some believe that more aggressive histologic subtypes (morpheaform, infiltrative, metatypical, and basosquamous) possess a greater capacity for metastatic spread, although this is a matter of contention. The lymph nodes, lungs, bone, and skin are common sites of metastasis.422 Mean survival after metastatic spread ranges from 8 months to 3.6 years.425 A history of previous radiotherapy to the neoplasm may be associated with metastatic spread.424 Tumors larger than 3 cm in diameter have a 2% incidence of metastases or death. At 5 cm in diameter, this rate is 25%, and with lesions 10 cm in diameter, the metastatic or death rate is 50%.426 Tumors that are larger than 100 cm2 have almost universally resulted in metastatic disease or death.284 “Giant” basal cell carcinomas are greater than 5 cm in diameter, and one case with HPV types 31, 33, and 35 has been reported.379,409,427 Basal cell carcinomas arising in persons younger than age 35 years may demonstrate rapid and aggressive growth patterns.424 HISTOPATHOLOGIC FEATURES Basal cell carcinomas form different histologic patterns. It is inappropriate to simply render the diagnosis of basal cell carcinoma because different variants behave differently with variable outcomes and prognoses.428

Nodular More than half of all basal cell carcinomas are of the nodular type (also known as nodulo-cystic).366 Clinically, these represent the typical slow-growing, pearly nodules with rolled borders and telangiectasias.366 Histologically, the tumors demonstrate aggregates of basophilic staining neoplastic cells with

well-defined contours.428 Palisading of the peripheral row of cells is usually obvious, and retraction from surrounding stroma is seen (see Fig 26-14B). Central palisading of tumor cells has rendered some lesions with a schwannoma-like appearance.429,430 Aggregates of cells that have become particularly large may demonstrate central necrosis with eosinophilic, granular features presumably due to an outstripping of the growing nodule’s blood supply. Mucin may be present within the aggregates of neoplastic cells, and when exaggerated, form large pools, giving the tumor a ”cystic” structure. The surrounding stroma tends to be myxoid in nature and slightly fibrotic. Calcification may be present, particularly in long-standing lesions, although this phenomenon reportedly has a proclivity for more aggressive histologic subtypes.431 Mitotic activity and keratinocyte dyskeratosis are usually mild but may be marked in more aggressive lesions. Some of these same features have been described in specimens obtained by “scraping” the tumors and evaluating the cells cytologically.432 However, differentiation among the various subtypes was not possible. Tumors with a reticulated configuration of basaloid cells extending into the dermis have been termed adenoid basal cell carcinomas but likely represent a variant of nodular tumors. The strands are several cells wide and may show significant peripheral palisading and stromal retraction. Mucin deposition is often quite prominent. Lumina may be present and are often filled with colloidal or amorphous granular material. Connections with the overlying epidermis may not be readily visible but are usually established by cutting additional tissue sections. Pigmented basal cell carcinomas demonstrate melanin

 FIGURE 26-16 Basal cell carcinoma with sebaceous differentiation. Aggregates of nodular basal cell carcinoma show sebaceous differentiation.

of these glycosaminoglycans may result from active fibroblast production rather than degenerative processes. Nodular basal cell carcinomas demonstrating granular features and large cytoplasmic inclusions have been termed

 FIGURE 26-15 Pigmented basal cell carcinoma. The features are similar to those of nodular basal cell carcinoma. Melanin is present within basaloid cells and tissue macrophages.

granular cell basal cell carcinoma.439 Focal areas of typical nodular basal cell carcinoma merge with the granular lobules.380 Nuclei are bland to vesicular with little mitotic activity and are occasionally eccentric. The cytoplasm is eosinophilic and granular. The granules measure up to 15 μm in diameter and may have halos around them. Ultrastructurally, the granules appear like lysosomes.380,439 Smaller granules fuse to form larger ones. Tonofilaments and desmosomes are present. Unlike the cells of granular cell tumors, these neoplasms are clearly of epidermal origin. Clear cell basal cell carcinomas demonstrate variable numbers of transparent tumor cells (Fig. 26-17). Most tumors have the overall configuration of a nodular basal cell carcinoma, and aggregates of typical basaloid cells are usually present. Clear cell changes may be present only at the periphery of a tumor lobule or may involve the whole lobule.440,441 The affected cells are round to polyhedral with pale, eosinophilic, vacuolated, or finely granular cytoplasms.441 Palisading is usually minimal to absent. Nuclei are eccentrically placed and are atypical but not profoundly so.440,441 PAS staining for glycogen is variably positive, but mild deposition of sulfated mucin is seen.440,441 Electron microscopy shows numerous vacuoles occupying almost the entirety of the cytoplasm and indenting the nuclei.323 The vacuoles do not have a limiting membrane and appear empty. They are believed to represent end-stage mitochondria or lysosomal degeneration.380,441

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

within the tumor aggregates or within melanophages in the surrounding stroma (Fig. 26-15).433 An entity termed malignant basomelanocytic tumor has been reported and comprises a neoplasm with biphasic immunohistochemical expression of markers for malignant melanoma and basal cell carcinoma.434,435 Sebaceous differentiation of basaloid cells may also be present.436 These cells arise in a typical nodular basal cell carcinoma and possess a “lipidized” cytoplasm (Fig 26-16). They may be difficult to differentiate from sebaceous neoplasms. Adamantinoid basal cell carcinomas are histologically similar to the dental ameloblastoma or adamantinoma.437 Tumor masses possess a surrounding layer of cells with palisading nuclei.437,438 These cells have stellate cytoplasms with elongated nuclei. The row of cells immediately adjacent to the outer row develop thin connecting bridges across empty spaces, which give these tumors their adamantinoid features.438 Ultrastructurally, these cells demonstrate moth-eaten cytoplasmic features.438 Basaloid cells within the interior of these lobules are unremarkable without abnormally enlarged or multilobulated nuclei or increased mitotic activity. Hyaluronic acid, chondroitin sulfate, and glycogen are prevalent.437,438 The presence

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minimal palisading.448 Tumor nodules are widely dispersed in an asymmetric pattern (Fig. 26-19). Retraction spaces are uncommon. The surrounding stroma is collagenous and slightly myxoid, particularly adjacent to the tumor nodules.428,448 The presence of smooth muscle actin within the malignant cells is thought to facilitate invasion and has been correlated with a more aggressive clinical picture.449 A “mixed” basal cell carcinoma is a hybrid between a nodular and micronodular tumor with approximately equal portions of each type of lesion.428 This pattern is not uncommonly observed, but the designation is infrequently used. The term basal cell carcinoma with mixed histology has also been recently used to refer to tumors demonstrating more than one type of pathologic pattern.450

 FIGURE 26-17 Clear cell basal cell carcinoma. Aggregates of clear tumor cells are seen in association with lobules of nodular basal cell carcinoma.

Some nodular basal cell carcinomas show signet ring or crescent-shaped nuclei. 380 Tumor cells contain large, hyalinized intracytoplasmic aggregations that distort the nuclei. These inclusions stain for high- and low-molecular-weight cytokeratin but not actin or vimentin. 442 The inclusions are believed to represent an aberrant form of keratinization in which intermediate filaments aggregate at the cell periphery. Pleomorphic basal cell carcinomas have also been called basal cell epithelioma with monster cells.443,444 These tumors have features of a typical nodular basal cell carcinoma.445 Growth is usually well circumscribed and solid but occasionally with adenoid or cystic features. Scattered throughout the tumor are enlarged mononuclear or multinucleated tumor cells (or both) (Fig. 26-18).445 The nuclei are hyperchromatic and irregularly outlined with a vesicular appearance. Prominent nucleoli are also occasionally seen. Mitoses are seen but are not necessarily atypical. All cases evaluated have been aneuploid.444,445 Enhanced expression of proliferationassociated antigens (PCNA, Ki-67) has been reported in these enlarged cells.446 Similar giant cells in the surrounding stroma have been reported and are believed to derive from the same tissue lineage as the pleomorphic cells within tumor nodules.447

Micronodular These tumors are plaquelike, indurated, firm, and poorly defined.448 Typically, they are difficult to remove and have an increased incidence of recurrence. Histologically, micronodular basal cell carcinomas demonstrate rounded nodules of tumor similar to the nodular variant but are smaller. They are approximately the size of hair bulbs and display

Superficial This variant has previously been called superficial multicentric. This term has lost popularity because it is believed that the individual nests of tumor cells arise not from multiple sites (multicentric) but rather from a single site and serpiginously wind through the epidermis as they proliferate. Nests of basaloid cells extend from the epidermis and hair follicle epithelium.428 Tumor islands are relatively small and tend to have a broad base of attachment to the epidermis (Fig. 26-20). Neoplastic cells resemble primordial germ cells.428 Peripheral palisading is usually prominent, and the surrounding stroma is

 FIGURE 26-18 Pleomorphic basal cell carcinoma. Enlarged nuclei and giant cells are present within the lobules of nodular basal cell carcinoma.

subcutis and muscle are occasionally appreciated. Inflammation is minimal. This tumor is more aggressive, more difficult to eradicate, and capable of greater destruction than nodular variants. Clinically, infiltrative basal cell carcinomas are yellow-white in color without a sharply defined or rolled border.399 Tumors blend imperceptibly with the surrounding skin.

 FIGURE 26-20 Superficial basal cell carcinoma. Atypical basaloid cells show stromal retraction and a broad attachment to the overlying epidermis.

somewhat blanched due to the presence of mucin. Tumor lobules have a wellrounded and well-defined peripheral contour. Retraction spaces are usually prominent but are not typically filled with mucin. Mitotic activity is present but is rarely significant. Clinically, the lesions appear as erythematous patches or plaques with mild to moderate scaling, superficial ulcerations, and welldefined borders.371 They are typically round or oval but may be irregular in shape. Tumors larger than 1.5 cm in diameter commonly have an infiltrating component.

Infiltrative (Infiltrating) Infiltrative basal cell carcinomas exist on the continuum between the nodular (nodulo-infiltative variants) and morpheaform variants both histologically and clinically. These tumors are composed of atypical basaloid cells in varying sized nodules and islands with irregular, jagged peripheral contours (Fig. 26-21).399,428 Elongated strands four to eight cells wide invade the deeper dermis.399 The surrounding stroma is fibrous but minimally mucinous. Peripheral palisading and stromal retraction are rare.428 The tumor is poorly circumscribed.399 Invasion of the

Metatypical (Basal Cell Carcinoma with Squamous Differentiation) This subtype of basal cell carcinoma has been the source of some confusion regarding its histologic features.453,454 It is probably best to use this designation when evaluating a basal cell carcinoma with features intermittent between nodular basal cell carcinoma and squamous cell carcinoma. These tumors have basaloid cells with variable eosinophilic features, prominent mitotic activity, and numerous apoptotic cells (Fig. 26-23). Peripheral palisading and stromal retraction are rare to absent. Nuclei are enlarged, and some spindling of cells may be seen. Premature cornification is common, and keratin pearls are occasionally seen.453 These tumors tend to be more aggressive, with a greater incidence of perineural and lymphatic spread.453 They may grow with the speed of squamous cell carcinomas and have clinical features of both tumor types.371 Basosquamous The diagnosis of basosquamous basal cell carcinoma is most appropriately used when evaluating a tumor with contiguous areas of basal cell carcinoma and squamous cell carcinoma.371 The typical features of both tumor types are present with a minimal intermediate area of blending between the two.453 The term mixed

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

 FIGURE 26-19 Micronodular basal cell carcinoma. Small nests of atypical basaloid cells proliferate in a myxoid stroma. Many basal cell carcinomas exhibit considerable phenotypic heterogeneity; thus, one or more morphologic pattern is frequently observed in the same tumor.

Sclerosing (Morpheaform) Sclerosing basal cell carcinomas are also known as morpheaform (morpheic), fibrosing, scirrhous, or desmoplastic and comprise up to 5% of all lesions.451 Tumors are white or yellow and are fibrotic. They are usually macular and rarely ulcerate or bleed.371 No particular anatomic site is preferred.452 Tumor islands are small, thin, and elongated (Fig. 26-22). They tend to be less than five cells in width and possess sharp, angulated ends.428 Peripheral palisading is absent, and stromal retraction is rare. Mitotic activity is usually present but is not marked. The surrounding dermis is fibrous and dense to the point of sclerosis. Tumors are usually poorly circumscribed and may invade deeply into the muscle and fat.

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A

 FIGURE 26-21 Infiltrating basal cell carcinoma. (A) Linear strands and islands of basaloid epithelium are present. (B) The basaloid epithelium exhibits some peripheral palisading of nuclei. The tumor stroma is slightly sclerotic.

carcinoma of the skin has been used when no intermediate tumor cells are present.453 These criteria for this tumor are uncommonly fulfilled, and the diagnosis should be appropriately infrequent.

Eccrine Epithelioma This tumor is also known as a syringoid eccrine epithelioma, malignant syringoma, malignant chondroid syringoma, and adenocarcinoma of eccrine glands.455 There is some question as to whether this histologic subtype represents a variant of a basal cell carcinoma or a malignancy of eccrine sweat glands. These lesions typically arise as flesh-colored nodules or large sclerotic plaques on the head and neck of elderly patients. The tumors are asymptomatic and slow growing.456,457 Within the dermis are dilated and branching ductal structures with syringoma-like

A

584

B

features. Alveolar or cystic spaces are consistently found and contain Alcian blue–positive mucinous material.456 The epithelial cells are basaloid in character and are embedded in a fibrovascular stroma. Clear cell changes are appreciated. Ductal lumina are present and contain acidophilic, granular material that is PAS positive. CEA and epithelial membrane antigen staining of neoplastic cells is positive.458 Tumors may invade deeply with perineural invasion and involvement of subcutaneous fat. There is a high rate of recurrence and a significant potential for metastasis.456,458 The presence of eccrine differentiation among otherwise unremarkable basal cell carcinomas has also been reported.459 Within tumor aggregates are found collections of cells similar to the intraepidermal portion of embryonic

eccrine ducts (Fig. 26-24). Staining for CEA is positive within these ductal structures.

Keratotic (Infundibulocystic, Pilar) Basal cell carcinomas may demonstrate differentiation toward hair follicle infundibulum.460 Proliferating basaloid cells show continuity with the overlying epidermis as well as adjacent hair follicles.461 Budlike structures may be appreciated along with follicular bulbs and dermal papillae. There is some solid and reticulated pattern of growth with few mitotic figures (Fig. 26-25). Basaloid cells may appear squamous with amphophilic cytoplasm.451 Tumor nodules contain cysts that lack a granular cell layer and are filled with keratin and parakeratotic material. Granular parakeratotic cornification has also been described in these

B

 FIGURE 26-22 Sclerosing (morpheaform) basal cell carcinoma. (A) and (B) Aggregates of basaloid tumor cells are rounded or elongate and isolated in a sclerotic stroma.

cystic structures.462 These cysts represent attempts at hair shaft formation. Calcification is occasionally present, and palisading may be seen. Stroma is usually not abundant and may be minimally fibrotic or mucinous.461

Follicular Follicular basal cell carcinomas, also termed matrical basal cell carcinomas, demonstrate tumor aggregates with features suggestive of differentiation toward the hair follicle matrix.463,464 Shadow cells

are present adjacent to islands of basaloid cell proliferation. These cells possess a central unstained area compatible with the shadow of a lost nucleus. Calcification may be present.464 Mitotic activity is minimal, and tumor cells are not excessively anaplastic.463 These lesions must be differentiated from a pilomatricoma and pilomatrical carcinoma.463 The expression of β-catenin and osteopontin in these tumors has recently been reported.465,466

 FIGURE 26-24 Basal cell carcinoma with eccrine differentiation. Typical lobules of nodular basal cell carcinoma show ductal differentiation containing sudiforous material.

Basal Cell Carcinoma with Myoepithelial Differentiation This newly described variant has some features of a nodular basal cell carcinoma.473,474 In the papillary dermis, the tumor nodules are unremarkable. Deeper in the dermis, the basaloid cells become oval to spindled and develop eccentric nuclei with homogenous ground-glass eosinophilic cytoplasm.473 Scattered cells with signet ring formation are seen, and the surrounding stroma is chondromyxoid. Tumor cells stain positively for cytokeratins with CAM 5.2 and AE1/AE3 and muscle specific actin. Stains for vimentin, epithelial membrane antigen, glial fibrillary acid protein, and S-100 are variably positive.474 This staining pattern is compatible with myoepithelial cells and their neoplasms and supports the contention that basal cell carcinomas

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

 FIGURE 26-23 Metatypical basal cell carcinoma. Tumor islands are slightly basaloid with absent palisading and stromal retraction. Dyskeratosis and keratin pearl formation are seen.

Fibroepithelioma of Pinkus This tumor was initially described by Pinkus in 1953.467 They typically arise on the lumbosacral regions as pink to flesh-colored nodules with a constricted base.452,468 Elongated, branched, and trabecular strands of basaloid cells extend deep into the dermis and proliferate symmetrically (Fig 26-26A). Horn cysts may be present, and palisading is seen. Stromal retraction is uncommon. The surrounding stroma is fibromucinous, and stromal–stromal separation may be present. Eccrine ducts are appreciated within some strands of basaloid cells (Fig 26-26B).469 This finding suggests that the tumor arises as a replacement of eccrine sweat ducts by infiltrating basaloid cells. Whereas the basal cell carcinoma component of this tumor expresses cytokeratins 14 and 17, the ductal structures express cytokeratins consistent with intraepidermal eccrine ducts.470 A cystic variant of the fibroepithelioma has been described.468 Some controversy exists as to whether this tumor represents a basal cell carcinoma or a benign adnexal neoplasm with follicular differentiation such as a trichoepithelioma or trichoblastoma. Androgen receptors, commonly found on basal cell carcinomas, have been noted with increased frequency in fibroepitheliomas of Pinkus compared with trichoepitheliomas or trichoblastomas but have also demonstrated retention of Merkel cells, a feature of benign follicular tumors.471 Low levels of staining with Ki-67 and p53 and significant numbers of cells expressing cytokeratin 20 have been reported in these tumors, supporting the contention that they more closely resemble trichoblastomas than basal cell carcinomas.472

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 586

 FIGURE 26-25 Infundibulocystic basal cell carcinoma. Connection to the epidermis is seen. Basaloid cells proliferate in a reticulated manner and form small cysts.

derive from uncommitted stem cells that are capable of differentiating along multiple lines.473,475 Basal cell carcinomas have varying degrees of inflammation. Most inflammatory cells are lymphocytes, and most are T cells.377,476 The helper-to-suppressor ratio ranges from 1.0 to 2.2.377,476 Natural killer cells and B cells are present but are rare.377 Plasma cells are prominent around lesions that have ulcerated but otherwise are uncommon. About 30% to 50% of infiltrating T cells express activation antigens on their cell surfaces.377 Monocytes and macrophages comprise 1% to 25% of infiltrating cells, and most express HLA-DR antigens.377,476 A Th2dominant microenvironment has been reported with CD4+/CD25+ T cells and immature dendritic cells present around the tumor aggregates, with malignant cells expressing interferon-associated genes.477 There has previously been concern that a sufficiently dense inflammatory infiltrate may mask residual basal cell carcinoma aggregates when Mohs micrographic surgery is being performed.478 However, sectioning through tissue blocks has been shown to allow for appropriate sampling of the tumor. Langerhans cells make up 4% to 15% of the inflammatory infiltrate.377 Mast cells

may play a significant role in the biology of these tumors.377,479 An increased number of these cells is present around tumor islands. The expression of tumor necrosis factor family proteins by mast cells in basal cell carcinoma has been reported and may contribute to their tumorigenesis.480 Mast cells are prevalent around fibrotic tumors, and this increased fibrosis may result from cell degranulation. These cells are also more common among patients who smoke cigarettes. Patients who are immunosuppressed and have diminished T-cell counts have a corresponding decrease in the number of peritumoral inflammatory cells.351 The increased proclivity for tumors in these patients to invade deeper, recur, and metastasize is likely due to diminished immune surveillance. Amyloid deposition is found in 50% to 75% of basal cell carcinomas and is more common in cystic, adenoid, and nodular subtypes.481,482 Host and tumor location do not influence amyloid deposition. This substance is believed to derive from degenerating epithelial cells via filamentous degeneration or apoptosis.481 Mucin deposition is common among basal cell carcinomas. This contributes to peritumoral blanching. Mucin is composed of hyaluronic acid and dermatan

sulfate366 and is produced by tumor cells. Sclerosing basal cell carcinomas produce a cytokine that stimulates fibroblast production of mucin.366 More aggressive histologic variants, such as infiltrative basal cell carcinomas, demonstrate increased tumoral and stromal hyaluronan production, suggesting interaction between the malignant cells and their microenvironment may play a role in their clinical behavior.483 Basal cell carcinomas have significantly increased levels of cholesterol, phospholipid, triglyceride, and total lipids than surrounding “normal” skin. Hyaline inclusions have also been described in some basal cell carcinomas.479 These inclusions are composed of various types of intermediate filaments and stain for vimentin, keratin, and smooth muscle myosin.475 Collagenous crystalloids have been described in the collagen surrounding some basal cell carcinomas.484 These structures consist of radially arranged clusters of eosinophilic needle-shaped fibers. They stain for types I and I collagen, are slightly birefringent, and measure 20 to 40 μm in diameter. They are believed to derive from degenerative processes of the extracellular matrix. Ossification within tumors has been reported and may reach considerable size.485,486 There is evidence that patients whose tumors contain bone may have significant underlying medical conditions. A variant with osteosarcomatous differentiation has also been reported.487 Some basal cell carcinomas, particularly fibrotic variants, may demonstrate regression.380,488 New collagen is deposited with decreased skin appendages and increased vascularity. Tumor islands lose their peripheral palisading and undergo apoptosis. The presence of increased numbers of apoptotic or dyskeratotic tumor cells has been correlated with more aggressive variants of basal cell carcinoma.489 Infiltrating inflammatory cells are CD3- and CD4positive lymphocytes, and occasional plasma cells. T-helper cells (CD4) may induce this regression by cytokine production.488 Compared with normal skin, a significantly greater number of basal cell carcinomas with regression demonstrate infiltrating T cells in adjacent hair follicles.490 This suggests that activated T cells with cytotoxic capabilities may be specifically effecting the damage on tumor aggregates. Basal cell carcinomas take up cytokeratin stains. These proteins are intermediate filaments that are produced by epithelial cells.366 Tumors express primarily types 5 and 14, which is consistent with tumors of a “basaloid” origin. These tumors also stain for α-2

B  FIGURE 26-26 Fibroepithelioma of Pinkus. (A) The tumor proliferates symmetrically as reticulated strands of basaloid cells surrounding fibromucinous stroma. (B) Ductal differentiation is present in some areas.

and β1 integrins but are negative for intercellular adhesion molecule–1 (ICAM-1), leukocyte function antigen–1 α(LFA-1α), and vascular cell adhesion molecule–1 (VCAM-1).491 There is no association between integrin staining and tumor subtype. HLA-DR antigens are present on some tumor cells, particularly when they are in close proximity to HLA-DR+ infiltrating lymphocytes.476 Basal cell carcinomas do not typically express class I HLA antigens, but in tumors that do, they are more commonly the histologically nonaggressive subtypes.376 p53 protein expression has been found in most basal cell carcinomas, but the mutations giving rise to this expression may be secondary

in nature and not significantly contribute to tumorigenesis.376,492 This protein is preferentially expressed on more aggressive tumors, including infiltrative and morpheaform subtypes.493,494 p63, a p53 homologue, is also expressed in basal cell carcinomas.495 Whereas apoptosisinhibiting proteins, such as Bcl-2 and surviving, are upregulated in these neoplasms, ZAC, a zinc finger transcription factor that induces apoptosis, is lost in basal cell carcinomas.376,496,497 Ultrastructurally, basal cell carcinomas have enlarged nuclei with small nucleoli and numerous chromatin aggregations.376 Nodular islands of tumor demonstrate a continuous band of types IV and V collagen

DIFFERENTIAL DIAGNOSIS The differential diagnosis for basal cell carcinomas depends on the different subtypes that are being evaluated. Nodular basal cell carcinomas must be differentiated from benign adnexal proliferations such as eccrine spiradenoma, nodular hidradenoma, and trichoepithelioma or trichoblastoma. Eccrine

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

A

and laminin, indicating the presence of a basement membrane. These basement membranes are intermittently discontinuous. Morpheaform and basosquamous variants do not possess a basement membrane, perhaps contributing to their aggressive behavior. Tumors that are able to dissolve basement membranes potentiate their invasive behavior by cell movement across physiologic barriers.498 Increased collagenase production by peritumoral fibroblasts decreases anchoring fibrils and collagen content.366 Desmosomes are present, but their numbers are diminished.366 This likely accounts for tumor friability seen clinically. Hemidesmosomes are decreased in number and are responsible for the retraction spaces between tumor nodules and surrounding stroma.366 Microfilaments of the cellular cytoskeleton are uncommon in normal epithelium but are found in basal cell carcinoma cells.499 These are more prevalent in invasive subtypes. X chromosome inactivation has demonstrated clonality in sporadically arising tumors.500 Mutations in the PATCHED gene have also been reported as have tumors with microsatellite instability.501-504 Basal cell carcinomas that reappear after previous treatment are considered recurrent lesions. This occurs in about 9% of conventionally treated lesions and 1% of those removed using Mohs micrographic surgery.366 Lesions of the nose and ears are most prone to recurrence.366,409 Most recurrences occur within 3 years, but about 20% do so between the sixth and tenth postoperative year.409 There is a 40% recurrence rate when treating recurrent lesions. Recurrences may be difficult to discern clinically because the tumor may be intermingled with repair reaction and scarring.371 Hemorrhage, erythema, and ulceration are indications of recurrence. Aggressive variants recur more often than nodular lesions.366,428,505 There is a significant association between tumor recurrence and the measured distance to the closest free tissue margin, an aggressive tumor growth pattern, “spiked” shape of tumor nodules, poor peripheral palisading, nuclear pleomorphism, and an infiltrating invading edge.366

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 588

spiradenomas are well-demarcated intradermal nodules with no connection to the overlying epidermis. Tumor nodules are composed of cells with small, dark nuclei and larger cells with pale-staining nuclei. Mitosis and dyskeratosis are uncommon. Nodular hidradenomas and other tumors of the acrosyringium do not necessarily have a connection with the epidermis and have few mitoses. Differentiation toward eccrine ducts may be present. These tumors invade deeper than most nodular basal cell carcinomas, do not commonly necrose, and demonstrate no peripheral cell palisading or mucin deposition. Trichoepitheliomas and trichoblastomas may be the most difficult tumors to distinguish from nodular basal cell carcinoma and the infundibulocystic or keratotic variants. These former tumors may have connections to overlying epidermis as well as occasional foci of calcification. Small keratin cysts are seen, but the proliferation of basaloid cells does not typically palisade and is rarely associated with mucin production. Mitotic activity and apoptosis are also diminished. Trichoepitheliomas produce papillary mesenchymal bodies.506 These bodies are fibroblastic proliferations representing abortive attempts to construct papillary mesenchyme. Trichoepitheliomas and trichoblastomas typically induce a mild to moderate fibrosis to the surrounding dermis. This stromal change is usually prominently demarcated from otherwise normal dermis. Stromal–stromal separation is seen. The stroma of trichoepitheliomas and trichoblastomas is CD34 positive, but that around basal cell carcinomas is CD34 negative.463,507 These findings have been disputed, however.508 Bcl-2 staining of basal cell carcinomas shows diffuse uptake throughout the tumor aggregate, but trichoepitheliomas stain only along the outermost epithelial layer.509 Focal positivity to staining for cytokeratin 7 and 8 has been noted in nodular basal cell carcinomas but not in trichoblastomas.507 Immunohistochemical staining for CD10 has demonstrated a significantly greater positivity in basal cell carcinomas than trichoepitheliomas.510 Basal cell carcinomas are also more likely to express the nuclear proliferative protein Ki-67 and p53 than are trichoepitheliomas.511 Merkel cell carcinomas may also demonstrate some of the features of nodular basal cell carcinomas, including stromal retraction, mucin deposition, peripheral palisading, and epidermal involvement.512 Use of immunohistochemical stains, such as cytokeratin 20 and neuron specific enolase, is usually helpful in differentiating between these two malignancies. Keratotic and infundibulocystic basal cell carcinomas

must also be distinguished from basaloid follicular hamartomas and reticulated seborrheic keratoses.461,513 Basaloid follicular hamartomas are composed of thin anastomosing cords of cells with squamoid and basaloid features. The surrounding stroma is scant and mildly fibrotic but may occasionally separate from the surrounding dermis (ie, stromal–stromal separation). Differentiation from nodular basal cell carcinoma and fibroepithelioma of Pinkus using immunohistochemical staining for Ki-67 and CD-34 has been described.514 Reticulated seborrheic keratoses typically have prominent pigmentation along the basal layer, a flat bottom, horn pseudocysts, and banal basaloid cells. Infiltrative or morpheaform basal cell carcinoma must be differentiated from microcystic adnexal carcinoma and desmoplastic trichoepithelioma. Microcystic adnexal carcinoma demonstrates rare mitotic activity and ductal differentiation in deeper tissues. Necrosis is uncommon. CEA and S-100 staining results are occasionally positive.515 Desmoplastic trichoepitheliomas show an invagination of the epidermis consistent with the “dell” present in the lesions clinically. Proliferating cells are basaloid, and keratin cysts are seen. Mitoses are very rare, and mucin, calcification, and apoptosis are absent. Stromelysin-3, an MMP, is present in stromal fibroblasts surrounding morphea-like basal cell carcinomas but not those associated with desmoplastic trichoepitheliomas.516 Superficial basal cell carcinomas appear similar to actinic keratoses and seborrheic keratoses. Proliferative actinic keratoses show aggregation and palisading of atypical basal cells. However, mucin deposition in the papillary dermis and stromal retraction are absent. BerEP4, a monoclonal antibody that stains basal cell carcinomas, has been shown to reliably differentiate these malignancies from actinic keratoses.517 Seborrheic keratoses may have basaloid cell proliferation. Mitotic activity and peripheral palisading, however, are not seen, and horn pseudocysts are usually present. Basal cell carcinomas with a glandular appearance (adenoid, fibroepithelioma of Pinkus, eccrine epithelioma) demonstrate ductal structures and must be distinguished from sweat gland carcinomas such as primary cutaneous adenoid cystic carcinoma, malignant mixed tumor of the skin, and aggressive digital papillary adenocarcinoma.518 Primary cutaneous adenoid cystic carcinomas have a cribiform or “punched-out” configuration with rare attachment to the epidermis or

hair follicles. Mitotic activity is rare, and peripheral palisading is uncommon. CEA staining is variably positive. Malignant mixed tumor of the skin (malignant chondroid syringoma) demonstrates a proliferation of ducts and invades deeply. This proliferation is not well demarcated and tends to be in the deeper dermis. Islands of cells and trabeculae are seen. Atypia is subtle. The surrounding matrix is largely mucinous or chondroid. Basaloid cells are CEA positive. Aggressive digital papillary adenocarcinomas show little involvement with the epidermis and extend deep into subcutaneous tissues and bone. These tumors are poorly circumscribed. Papillary projections are seen along with significant mitotic activity and tumor necrosis. Clear cell basal cell carcinomas must be differentiated from other clear cell neoplasms such as sebaceous adenomas, sebaceomas, tricholemmomas, clear cell hidradenomas, and clear cell acanthoma.440,519 Balloon cell nevus (and balloon cell melanoma) and metastases of renal cell carcinoma must also be distinguished from these tumors.441 Sebaceous adenomas have clear cells and basaloid cells but do not demonstrate atypia or mucin production. Whereas sebaceomas are almost universally Ber-EP4 negative, basal cell carcinomas typically stain moderately to strongly for this protein. Evidence of sebaceous differentiation is also usually visible. Tricholemmomas do not have significant mitotic activity and may show areas of hypergranulosis. Clear cell hidradenomas demonstrate ductal differentiation with few mitoses and no mucin production or stromal retraction. Clear cell acanthomas only involve the epidermis and show infiltrating neutrophils but no atypia. Balloon cell melanocytic proliferations have no stromal retraction or mucin deposition. Malignant variants may show a pagetoid spread. These tumors are S-100 positive and cytokeratin negative in distinction to clear cell basal cell carcinomas. Metastatic renal cell carcinoma typically has numerous extravasated erythrocytes and minimal connection to the epidermis. Basaloid cells are also absent. Finally, some basal cell carcinomas lack typical basaloid staining and appear eosinophilic (Table 26-25). Tumors such as metatypical basal cell carcinomas may be confused with squamous cell carcinomas. This distinction may be an academic one because squamous cell carcinomas and metatypical basal cell carcinomas behave similarly; however, with more nodular lesions, a definitive diagnosis may be important. Staining with Ber EP4 has been used to distinguish

Table 26-25 Basal Cell Carcinoma

Nevoid Basal Cell Carcinoma Syndrome This syndrome was initially described by Howell and Caro in 1959.522 It is also known as Gorlin syndrome, basal cell nevus syndrome, and Gherkin-Goltz syndrome.523,524 This complex of symptoms is inherited as an autosomal dominant trait,523 but about 35% to 50% of affected patients represent new mutations.524 The disease usually begins between 17 and 35 years of age but has been described in children as young as 2 years.525 Disease activity is increased at puberty.524,525 The prevalence is approximately one in 56,000.378 Because of the relatively young age of affected patients, there is not a strong association between cumulative sun exposure and tumor development. However, in susceptible persons, sun exposure does exacerbate the development of basal cell carcinomas.378 A malfunctioning tumorsuppressor gene known as PATCHED on chromosome 9q22-q31 is believed to cause this condition.526,527 Neoplasms also reported in patients with nevoid basal cell carcinoma syndrome include rhabdomyosarcoma, ovarian fibrosarcoma, and leiomyosarcoma.528 CLINICAL FEATURES The features of nevoid basal cell carcinoma syndrome are divided into five major categories.524-526 The first is the presence of numerous basal cell carcinomas. These may range from a few to 1000 and are similar to routine basal cell carcinomas.525 They may be very small and flesh colored to brown. Tumors appear as dome-shaped papules to soft nodular or flat plaques on the face and trunk. Lesions vary from 1 to 10 mm525 and may be mistaken for skin tags, nevi, molluscum contagiosum, or hemangiomas.524,529 These tumors may be aggressive, particularly when they involve the embryonic clefts of the face.530 The second feature is the development of numerous cysts, particularly epithelium-lined jaw cysts. These lesions begin to develop after age 7 years and may cause pain, tooth shifting, drainage,

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

Clinical Features Flesh-colored to pearly, raised papules and nodules on sun-exposed sites May bleed or ulcerate and occasionally destroy contiguous structures Indurated plaques are seen Superficial variant with erythema, scaling, and some epidermal breakdown Pigmented variant with hyperpigmentation, at times very black Histopathologic Features Nodular Small to large aggregates of basaloid cells emanating from the epidermis or follicular structures Peripheral palisading, stromal retraction, and mitoses are present Necrosis, apoptosis, calcification, and mucin production are variable Focal accumulation of melanin in the pigmented variant Discrete areas of clear cell changes in clear cell variant Superficial Small, discrete islands of basaloid cells present intermittently along the basal layer Prominent peripheral palisading and stromal retraction Peritumoral mucin production Keratotic infundibulocystic (pilar) Keratin-filled cysts with features suggesting follicle derivation Reticulated basaloid cells with some mitotic activity and mucin production Stromal retraction is unusual Infiltrative, morpheaform Small islands of basaloid cells with an angulated and “spiky” configuration Poor peripheral palisading and minimal stromal retraction Fibrotic and variably mucinous stroma Deep infiltration and poor circumscription Fibroepithelioma of Pinkus Aggregates of basaloid cells in the uppermost dermis Extension into the dermis of elongated strands of palisading basaloid cells Mucin in the dermis and stromal fibromucinous changes “Glandular” appearance to the tumor at low power Metatypical Tumor nests with more eosinophilic characteristics Poor peripheral palisading and stromal retraction Keratin pearls, increased mitotic activity, and premature cornification Differential Diagnosis Nodular, micronodular Eccrine spiradenoma Nodular hidradenoma Trichoepithelioma or trichoblastoma Superficial Actinic keratosis Seborrheic keratosis Keratotic, infundibulocystic Trichoepithelioma or trichoblastoma Basaloid follicular hamartoma Reticulated seborrheic keratosis Infiltrative, morpheaform Microcystic adnexal carcinoma Desmoplastic trichoepithelioma Adenoid, fibroepithelioma of Pinkus Primary cutaneous adenoid cystic carcinoma Malignant mixed tumor of the skin (malignant chondroid syringoma) Aggressive digital papillary adenocarcinoma Clear cell Sebaceous adenoma Tricholemmoma Clear-cell hidradenoma Clear-cell acanthoma Balloon cell nevus and balloon cell melanoma Metatypical Squamous cell carcinoma

between the two types of malignancy.520 Basal cell carcinomas may take up this stain, but squamous cell carcinomas do not. This procedure may also be used to differentiate actinic keratoses from superficial basal cell carcinomas. Similarly, increased mRNA expression of endothelin, a peptide with growthpromoting function, has been reported in basal cell carcinomas but not in squamous cell carcinomas or actinic keratoses.521

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 590

and jaw swelling.524,525 Cutaneous cysts may also be present and arise on the trunk and limbs in about 50% of affected patients.524 These cysts contain thick, discolored liquid with features similar to steatocystomas.531,532 Intermittent milial cysts are present in 35% to 50% of patients.524 Skeletal anomalies are prevalent in this syndrome and include bifid ribs, frontal bossing of the skull, bridging of the sella turcica, and spinal deformities.525 Intracranial calcification, particularly of the falx cerebri, is seen.378,524 Medulloblastomas, meningiomas, and craniopharyngiomas have been reported in patients with this condition.533 Finally, pitting of the palms and soles is seen.534 These pits are 1 to 3 mm in depth and 2 to 3 mm in diameter. They develop during the second decade of life.525 Additional features include neuropsychiatric defects such as schizophrenia, electroencephalographic abnormalities, mental retardation, and cerebellar degeneration.525,530 Tumors and abnormalities of the reproductive system may also occur. Two families from Spain have been recently described with multiple infundibulocystic basal cell carcinomas but without other stigmata of the nevoid basal cell carcinoma syndrome.535 HISTOPATHOLOGIC FEATURES Histologically, the basal cell carcinomas are identical to those found in patients without this syndrome.525 The tumors are most commonly of the nodular and superficial subtype with the morpheaform, adenoid, and fibroepithelial variants less likely. Calcification and pigment deposition may be increased.536 Neuroendocrine tumor differentiation (uptake by chromogranin and neuron-specific enolase stains) has been reported in a patient with metastatic disease.533 A carcinosarcoma with features of a basal cell carcinoma and fibrosarcoma has been reported in a patient with this syndrome.528 The cutaneous cysts are similar to infundibular cysts.531 These tumors have an epithelial lining with a distinct granular layer and produce keratin. Some cysts, however, resemble keratinous jaw cysts. These lesions show a festooned or corrugated epithelium two to five cells thick that lacks a granular layer. These features are similar to those of steatocystomas, but sebaceous glands are absent.531 Cutaneous pits demonstrate a sharply defined absence of keratin. The epidermis is thinned at the base, and the rete ridges proliferate irregularly. The granular layer is diminished.534 These pits are

believed to result from premature desquamation of the keratinocytes.

gram-positive filamentous or coccoidal bacteria are present.

DIFFERENTIAL DIAGNOSIS The differential diagnosis for these tumors is the same as for idiopathic basal cell carcinomas (Table 26-26). The cutaneous cysts in this syndrome are similar to infundibular cysts and steatocystomas. Infundibular cysts may appear similar to dilated pores because both possess a lining containing a granular layer. Steatocystomas usually have sebaceous glands in the lining wall and may contain small hair shaft fragments. These may also be confused with dermoid cysts, which show more pilosebaceous differentiation and the presence of eccrine or apocrine glands. Cutaneous pits may be seen in pitted keratolysis, but in this disease,

Squamous Cell Carcinoma

Table 26-26 Nevoid Basal Cell Carcinoma

Clinical Features Numerous flesh-colored to brown papules 1-10 mm in diameter Develops on the face and trunk beginning around puberty Autosomal dominant inheritance Jaw and cutaneous cysts, skeletal anomalies (particularly bifid ribs), ectopic central nervous system calcification, and palmar or plantar pitting Histopathologic Features Basal cell carcinomas Essentially identical to those found idiopathically Most commonly nodular and superficial variants Calcification and pigment deposition are more common Jaw and cutaneous cysts Epithelial lining with granular layer similar to infundibular cysts Epithelial lining with corrugated, compact lining similar to steatocystomas Cutaneous pits Sharply defined absence of keratin and thinned epidermis at base of pit Diminished or absent granular layer Differential Diagnosis Basal cell carcinomas Eccrine spiradenoma Nodular hidradenoma Trichoepithelioma or trichoblastoma Jaw and cutaneous cysts Dilated pore Dermoid cyst Cutaneous pits Pitted keratolysis

Squamous cell carcinomas are the second most common cutaneous malignancy.537 They account for about 20% of all skin cancers538 and are the most prevalent skin cancer in blacks.380 Approximately 260,000 new cases of squamous cell carcinoma occur annually.539 The lifetime risk of developing one of these tumors is between 4% and 14%.540 This incidence has been steadily increasing about 4% to 8% per year since the 1960s,537 with a three to fourfold increase over the past 20 to 30 years.541 The case fatality rate for cutaneous squamous cell carcinomas is approximately seven per 1000.542 Between 2000 and 2500 deaths annually are attributed to these neoplasms.537 The death rate for squamous cell carcinomas of the skin is decreasing in most countries but increasing in some. Although typically a disease of older patients, there some evidence suggests that the incidence in children is increasing.543 Risk factors for developing a squamous cell carcinoma include increased age, light skin pigmentation, immunosuppression, and genetic disorders such as xeroderma pigmentosum.538 The most common inciting cause of cutaneous squamous cell carcinomas is cumulative UV radiation (UVR) exposure.537 Sunlight is the greatest source of UVR, with UVB being the most damaging factor.542 The incidence of this malignancy doubles with every 8- to 10-degree decrement in latitude.539 Depletion of the ozone layer may also play a role in susceptibility.540 Patients with a history of sunburns may be particularly prone to developing squamous cell carcinoma. Other etiologic factors include cigarette smoking, therapeutic UV light exposure (including PUVA therapy and tanning bed use), HPV infection (types 16, 31, and 34), arsenic ingestion, polycyclic aromatic hydrocarbon exposure, immunosuppression, diets high in fat and meat, preexisting chronic dermatoses, and ulcer or sinus tract formation.259,537,544-549 Ionizing radiation is well known to induce these malignancies, particularly in patients whose constitutive pigmentation renders them susceptible to sunburn.550 Squamous cell carcinoma of the lip is associated with heavy alcohol intake and smoking and tobacco chewing.538,540,551 Cutaneous conditions associated with the development of squamous cell carcinoma include porokeratosis, lupus erythematosus, lichen planus, lichen sclerosus,

face, and lip are preferred sites of involvement.564 A history of treatment of the lesion is also more common.565 Perineural invasion affects 2.4% to 14% of cutaneous squamous cell carcinomas.540 Acantholytic and spindle cell types disproportionately demonstrate this feature. Lesions are initially painful and later anesthetic.542,563 Muscle weakness is uncommon but is seen in the late stages. Cranial nerves VII and VI (mandibular and maxillary divisions) are most commonly involved.540,541 Extensive perineural invasion may eventuate into direct intracranial extension and death.537 The survival rate of affected persons is usually less than 30%.565 Metastatic disease is uncommon. The overall rate approximates 2% but is between 10% and 15% for lesions on the lips and ears.566 Metastases are more prevalent in tumors that are poorly differentiated, of long standing, and inadequately treated.541,567 Metalloproteinase-2 (gelatinase A) expression has been shown to be upregulated in skin neoplasms demonstrating metastatic spread, and the intensity of staining for this protein correlates with cellular atypia and tumor aggressiveness.568 Eighty-five percent of metastases affect only the lymph nodes, but involvement of lungs, liver, bones, brain, and mediastinum may also occur.541,542 Forty percent of persons who have undergone an organ transplant develop a cutaneous malignancy.540 This risk is approximately 65 times the normal rate, and the incidence increases by 4% each year after transplantation.540,569 Heart transplant recipients have a higher risk of developing cutaneous malignancies than do renal transplant patients. Squamous cell carcinomas outnumber basal cell carcinomas. These cancers are potentially more aggressive, with a higher rate of metastasis and death.540,569 Aggressive lesions are seen more commonly in elderly people, on the head, in recurrent tumors, and with a deeper degree of invasion. These tumors are likely induced by the degree of immunosuppression; however, the role of HPV infection is unclear. HPV types 5 and 8, herpesvirus-like DNA sequences, and Epstein-Barr virus (EBV) proteins have been detected in these malignancies.406,570,571 These findings, however, have been refuted by other investigators.572 Because most lesions arise on sun-exposed skin, cumulative UV light exposure, particularly before age 30 years, is also an important factor.405 Spindle cell variants may demonstrate more aggressive behavior than conven-

tional tumors.408 Squamous cell carcinomas in HIV-positive patients are also more prone to aggressive behavior and metastatic spread.573,574 This proclivity appears unrelated to the degree of immunosuppresion or CD4+ cell count. The presence of anti-p53 peripheral CD8+ T cells in patients with cutaneous squamous cell carcinoma suggests that these immune cells may be directed toward tumor antigens.575 CLINICAL FEATURES Squamous cell carcinomas have varied clinical features. Most tumors are nodules with an overlying scale or scale crust (Fig. 26-27A).542 Lesions are flesh colored, but some may be red to brown, and telangiectasias are present. Exophytic cauliflower-shaped lesions, indurated crusted plaques, ulceration, and subcutaneous nodules, may also be seen. Different histologic types may have more specific clinical features. The surrounding skin usually demonstrates moderate to severe dermatoheliosis. Squamous cell carcinomas of the lip present as rough, scaling papules on the lower lip with frequent ulceration in middle-aged to elderly men.540 The lip mucosa is typically dry and atrophic with leukoplakia and variable pigmentation. Patients’ lips may be chapped or crusted. A history of smoking or tobacco chewing is common, and metastatic disease is more frequent. HISTOPATHOLOGIC FEATURES Squamous cell carcinoma has been divided into four histologic categories: conventional, spindle cell, acantholytic, and verrucous.537 This is a useful paradigm for purposes of classification, but other histologic subtypes also exist. The Broders classification considers the degree of tumor differentiation.576 Grade I tumors are composed of less than 25% undifferentiated cells, grade II have less than 50% undifferentiated, grade III have less than 75% undifferentiated cells, and grade IV have more than 75% undifferentiated cells. Use of this scale for tumor classification, however, is uncommonly used in routine practice. Squamous cell carcinomas arise from precursor lesions, including actinic keratoses, thermal keratoses, arsenical keratoses, chronic radiation keratoses, erythroplasia of Queyrat, epidermodysplasia verruciformis, and Bowen disease.537 Proposals have been put forth suggesting actinic keratoses be considered early squamous cell carcinomas in situ.577 In conventional squamous cell carcinoma, atypical, slightly epithelioid cells emanate from the epidermis and spread into the dermis (Fig. 26-27B). Nuclei are

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

epidermolysis bullosa, erythema ab igne, acrodermatitis chronic atrophicans, ichthyosis, dissecting cellulitis of the scalp, chromoblastomycosis, port wine stain, arteriovenous malformation, nevus sebaceus, linear epidermal nevus, granuloma inguinale, fibroepithelial polyps, acne conglobata, necrobiosis lipoidica, verruciform xanthoma, and lymphogranuloma venereum.537,552-557 PATCHED gene mutations have been reported recently in cutaneous tumors.558 Two specific types of squamous cell carcinoma deserve comment. Marjolin ulcers are squamous cell carcinomas developing in scar tissue or chronic wounds. These include fistulas, venous ulcers, draining sinuses of osteomyelitis, pressure ulcers, vaccination sites, chronic hidradenitis suppurativa, discoid lupus erythematosus, Buruli ulcer, frostbite, and donor sites of skin grafts.540,559 The lesions present as shallow ulcerations with a nodular surface and well-defined peripheral margins. Exophytic nodular excrescences with granulation tissue may also be seen. Although these tumors are well to moderately differentiated histologically, they metastasize to the regional lymph nodes in 36% to 54% of cases.298 Squamous cell carcinomas associated with chronic venous leg ulcers may have a tendency toward more aggressive histologic features and clinical outcome.560 Lesions involving tattoos have also been reported.561 Most squamous cell carcinomas arise on the head and neck.542 The extremities, particularly the hands, are also frequently affected, but the trunk is not commonly involved.537 Men are more often affected than women.541 Deeper skin invasion is associated with increased metastatic disease and recurrence rates.541 Tumors greater than 2 cm in diameter are twice as likely to recur and three times as likely to metastasize.540 Tumor thickness may be measured in millimeters similar to that for melanomas.540 Squamous cell carcinoma, occasionally arising from lesions of bowenoid papulosis, may arise on or near the mucosal surfaces of the anogenital region. These tumors demonstrate evidence of infection with HPV, particularly HPV-16. Other HPVs have also been identified, including types 18, 31, 33, 39, 52, and 67.562 Perineural invasion may be present and lowers the 5-year survival rate.538 These tumors are larger at presentation (most >2 cm in diameter), less well differentiated, and are associated with lymphadenopathy.563 The forehead, central

591

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A

592

B

C

 FIGURE 26-27 Squamous cell carcinoma. (A) Multiple indurated and ulcerated tumors involving the scalp. (B) Atypical keratinocytes spread from the epidermis into the dermis. (C) Tumor cells have enlarged, and hyperchromatic nuclei with prominent mitotic activity are seen.

enlarged and pleomorphic (Fig. 26-27C). Mitotic activity is variable but is usually greater than in basal cell carcinomas. Atypical mitotic figures and keratin pearls are present. Dyskeratotic and prematurely cornifying cells are seen. The depth of dermal invasion is variable. If deep enough the tumor may show lateral spread upon reaching the fascial or capsular plane, muscle, periosteum, or perichondrium.540 The surface of the tumor is often hyperkeratotic with varying amounts of parakeratosis. Granular parakeratosis in the stratum corneum

has been described.462 Perineural invasion shows invasion of the perineurium by atypical squamous cells.540 Involvement of the nerves is suspect in specimens with inflammatory cells around cutaneous nerve twigs.563 Small foci of acantholysis or spindling may be present. Inflammation is seen in ulcerating tumors and typically consists of lymphocytes, plasma cells, and neutrophils.578 Accumulation of inflammatory cells around eccrine ducts simulating lymphoepithelial lesions have been described.579 Tumors demonstrating

dense inflammatory infiltrates consisting of sheets of monomorphous lymphocytes have been reported in patients with underlying chronic lymphocytic leukemia.580 Eosinophils are also frequently present.338 These cells do not seem to impact on prognosis and are unrelated to the etiology, duration, site of the tumor, or patient age. Pigment deposition in and around the tumor with increased numbers of melanocytes is appreciated in a minority of squamous cell carcinomas.581 The presence of giant cells containing remnants of squamous

cells with dermal mucin deposition and tumor retraction associated with morpheaform or infiltrative basal cell carcinoma are absent. Desmoplastic squamous cell carcinomas have a greater propensity to recur and to metastasize compared to more typical tumors. The ear is a common site of occurrence.

Spindle Cell Spindle cell squamous cell carcinomas (SCSCCs) may be associated with previous trauma or radiotherapy.540 They are commonly ulcerated.237,604 Histologically, atypical spindle cells are seen emanating from the epidermis and intermingle with strands of collagen in a whorled fashion.540 They are arranged into intertwining fascicles and bundles (Fig. 26-28).604 The surrounding stroma may be myxoid, and pleomorphic giant cells may be appreciated, but desmoplasia should not comprise more than 30% of tumor volume, as noted in desmoplastic squamous cell carcinomas.237,540 Individual tumor cells are eosinophilic with hyperchromatic, elongated nuclei and multiple nucleoli.540,604 Nuclei may also be pleomorphic and vesicular. Mitotic activity with occasional atypical figures is present.604 Ultrastructurally, myofilaments and tonofilament-associated desmosomes have been noted.540,604,605 Many SCSCCs stain for both cytokeratin and vimentin.604 This gradient between the two tumors may be explained by a metaplastic change with

more mesenchymal differentiation in the SCSCC.604 Previously, spindle cell tumors taking up the vimentin stain were thought to be AFXs, and it is likely that many such tumors have been misdiagnosed. The use of high-molecularweight cytokeratins such as 34βE12 and CK 5/6 has been suggested for lesions failing to take up low-molecular-weight cytokeratin stains.606 A possible subtype of SCSCC is pigmented squamous cell carcinoma.607 These lesions are rare and preferentially affect the oral and conjunctival mucosa in dark-skinned patients. Intratumoral melanocytes are present histologically and may stain with S-100 and HMB45.608-610 Their long-term prognosis does not appear to differ from that of conventional lesions. Such tumors must be distinguished from an even rarer malignancy, the dermal squamous-melanocytic tumor, which demonstrates evidence of biphenotypic differentiation.611,612

Acantholytic These tumors are also called pseudoglandular, adenoid, carcinoma segregans, or adenoacanthoma.537,613 The lesions typically arise on the head and neck as a nodule or ulcer in elderly men.614 They have been associated with recurrent tumors after radiation therapy and portend a better prognosis.540,615 Similar lesions have been described in the orophyarnx, lung, larynx, vulva, and breast.613 The acantholysis is likely an

 FIGURE 26-28 Spindle cell squamous cell carcinoma. Tumor cells are atypical and spindled in a slightly whorled fashion. Mitotic activity is brisk.

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

cell carcinoma after radiation treatment has been described.582 Osteoclast-like giant cells have also been reported in a poorly differentiated tumor; however, these cells were cytokeratin stain negative and CD68 stain positive.583 The presence of increased numbers of melanocytes with pigment deposition may render these neoplasms difficult to differentiate clinically from a melanocytic lesion. Staining with anticytokeratin antibodies is positive for both high- and low-molecular-weight cytokeratins.584 Vimentin may also be positive in poorly differentiated lesions.584 As with basal cell carcinomas, squamous cell carcinomas routinely stain for p53.585,586 A diminished expression of this protein in tumors from sunprotected sites and those more poorly differentiated compared with those from sun-exposed sites has been reported.587 A similar protein, p63, has also been described with enhanced production in more poorly differentiating tumors and is reportedly useful in distinguishing spindle cell variants from histologic mimics, including atypical fibroxanthomas (AFXs) and desmoplastic melanomas.588,589 Immunoperoxidase staining for inducible nitric oxide, cyclooxygenase-2, CEA, c-erbB-2 oncoprotein, bak (bcl-2 homologous antagonist/killer), protein tyrosine phosphatases, human erythrocyte glucose transporter protein, and collagenase3 has been reported.243,586,590-597 The loss of cell-cell adhesion markers, such as desmoglein I, plakoglobin, e-cadherin, βcatenin, and vinculin, may influence the capacity for these tumors to invade and metastasize.598-600 Finally, the expression of the apoptosis-associated proteins Fas and Fas ligand has been found in squamous cell carcinomas.601 Transmembrane receptor kinases, including epidermal growth factor and HER2, although comprising a negative prognostic indicator in extracutaneous squamous cell carcinoma, are expressed either minimally or not at all in tumors from the skin, perhaps accounting for the overall better prognosis in the latter.602 A particularly aggressive form of squamous cell carcinoma, the desmoplastic squamous cell carcinoma, has been recently described.603 These tumors demonstrate aggregates of moderate to poorly differentiated keratinocytes surrounded by desmoplastic stroma, which by definition comprises at least 30% of the tumor volume.298 Tumor cells are oval to spindle shaped with keratin pearls typically appreciable. Perineural invasion is frequently present. Single cell dyskeratosis is present, but basaloid

593

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 594

A

B

 FIGURE 26-29 Acantholytic squamous cell carcinoma. (A) Aggregates of invading atypical keratinocytes demonstrate acantholysis. (B) Enlarged, freefloating keratinocytes are present.

accentuation of the same process seen in actinic keratoses. The tumor is arranged in cords and nests in a glandular (pseudoglandular) or adenoid pattern (Fig. 26-29A). Polygonal cells surround lumen-like spaces containing free-floating, neoplastic keratinocytes (Fig. 26-29B).613 Dyskeratotic cells may be few or abundant and are single or grouped.540 PAS staining may demonstrate abundant glycogen. Syndecan-1 expression is diminished in these tumors compared with conventional squamous cell carcinomas and may account for their capacity to readily invade the dermis.616 Erythrophagocytosis by malignant keratinocytes has been described.617 The signet ring cell squamous cell carcinoma is probably a variant of the acantholytic subtype and is quite rare.618 Tumor cells demonstrate a paranuclear clear zone similar to other signet ring cell malignancies (Fig. 26-30). A second type shows nuclear displacement by a deeply eosinophilic globule resembling the cytoplasm of dyskeratotic cells.618 Whereas the clear zone around the nucleus stains positively for glycogen, the eosinophilic globule is PAS positive but diastase resistant. Keratin stains are strongly positive in concentric rings at the periphery of these cells. Staining for vimentin, actin, and mucin is negative. Ultrastructurally, the vacuoles are formed by dilated cisternae of the rough endoplasmic reticulum.619 These tumors may have a more aggressive clinical course.

Pseudovascular Adenoid This squamous cell carcinoma may be a subtype of the acantholytic variant but tends to show much less acantholysis and more of a glandular appearance.578,613 These tumors are most common in elderly men. They are crusted, heaped-up nodules or ulcers with prominent advancing margins. Metastatic disease and death are common. Histologically, the tumor shows an interanastomosing array of tumor cells

displaying pseudovascular lumen-like features with connection to the overlying epidermis. Tumor cells dissect through dermal collagen and around adnexal structures. The channels and cystic spaces are lined by plump neoplastic cells. Tumor cells are round or polygonal with moderately abundant cytoplasm and “hobnail” features. Nuclei are pleomorphic and hyperchromatic with prominent nucleoli.578 Intracytoplasmic vacuoles

FIGURE 26-30 Signet ring cell squamous cell carcinoma. A paranuclear clear zone has pushed the nuclei aside, forming a “signet ring” appearance.

Subcutaneous These tumors present as asymptomatic subcutaneous nodules on the head and neck.621 The overlying skin is unremarkable. Subcutaneous squamous cell carcinomas show an intradermal collection of atypical epithelioid cells with mitoses, premature cornification, and squamous eddies. Connection to the overlying epidermis is not immediately appreciated but may be found if additional sections are obtained. These tumors have a high incidence of perineural invasion.621 Subcutaneous squamous cell carcinoma is believed to arise as a microscopic focus of epidermal atypia that quickly invades the dermis tethered by a thin stalk.541 This epidermal connection is soon lost, and the tumor appears to be solely confined to the dermis. Some tumors may arise from adnexal epithelium, and the presence of HPV-16 has been reported.621,622 Differentiation from metastatic squamous cell carcinoma may be difficult. A presumably unique form of subcutaneous squamous cell carcinoma has been termed “in-transit” and arises in the skin of solid organ transplant recipients.569 A group of similar tumors consists of squamous cell carcinomas arising from adnexal neoplasms or adnexal epithelium.298,623 Tumors arising in infundibular or epidermoid cysts seem to have a proclivity for periauricular and perineal involvement. Evaluation for HPV infection in these malignancies has been negative.624 Squamous cell carcinomas arising in proliferating pilar cysts commonly arise on the scalp. These neoplasms demonstrate the typical findings of benign pilar differentiation with focal areas of significant atypia, mitotic activity, and stromal invasion.625 Follicular squamous cell carcinomas develop from the upper portion hair follicles, showing full-thickness

atypia and invasion of the adjacent dermis.626 Immunohistochemical studies show positive staining with cytokeratin stains but not for epithelial membrane antigen, CEA, and vimentin. Squamous cell carcinomas arising in eccrine and apocrine hidrocystomas have been described in two patients.622

Papillary Papillary squamous cell carcinomas are more common in elderly women but may also be present in immunosuppressed patients.627,628 They are rapidly growing exophytic tumors with red to tan features. Atypical cells arise atop a fibrovascular stalk with invasion of the underlying dermis.627 The more superficial cells are often clear and demonstrate PAS-positive and diastase sensitive staining.298 Mitoses are widespread, and HPV DNA evaluation has been negative. DIFFERENTIAL DIAGNOSIS The differential diagnosis for squamous cell carcinoma depends on the subtype being considered. Conventional squamous cell carcinoma must be distinguished from pseudocarcinomatous proliferation, metatypical basal cell carcinoma, inflamed seborrheic keratosis, and inflamed warts. Pseudocarcinomatous hyperplasia demonstrates an irregular invasion of the dermis by strands of epithelial cells. These cells may be tapered and proliferate in a poorly circumscribed manner. The cells are typically well differentiated, and mitotic activity and nuclear hyperchromasia are lacking. Inflammatory cell infiltration may also be present. Distinguishing between these two entities may be impossible in some instances. Inflamed seborrheic keratoses do not typically have a significant amount of mitotic activity. Nuclei are also not usually pleomorphic or hyperchromatic. The overall configuration may show the outline of a seborrheic keratosis with acanthosis, spongiosis, and vague papillomatous proliferation. Hyperkeratosis is common and may contain aggregates of serum with inspissated erythrocytes. The typical “flat bottom” of a seborrheic keratosis may also be present, and significant numbers of inflammatory cells may be seen. Metatypical basal cell carcinomas have features intermediate between squamous cell carcinoma and basal cell carcinoma.371 Cells are predominantly basaloid but with some epithelioid features. Slight spindling may be seen along with apoptosis, a moderate mitotic rate, and keratin pearls. Some peripheral palisading and mucinous changes in the

surrounding stroma are occasionally present, but stromal retraction is rare. Ornithine decarboxylase uptake by squamous cell carcinomas is reportedly greater than that of basal cell carcinomas and may assist in differentiation between the two entities.629 Finally, inflamed or resolving warts may be similar to squamous cell carcinomas. Inflamed warts may have increased numbers of mitoses and nuclear enlargement. However, these lesions are not typically endophytic, usually lack nuclear hyperchromatism, are papillomatous, and demonstrate focal areas of hypergranulosis. Additionally, warts have dilated capillaries in the superficial dermis. SCSCCs are easily confused with two other spindle cell malignancies of the skin—spindle cell melanoma and AFX.537,540 Superficial malignant fibrohistiocytomas, sarcomas, and cutaneous metastases may also show similar changes. Spindle cell melanomas usually derive from lentiginous melanomas of chronically sun-exposed skin (historically lentigo malignas) and may have pagetoid spread of atypical melanocytes. Pigment deposition, a comparatively reduced mitotic rate, and nuclear pseudoinclusions may also be present. Whereas these tumors are usually vimentin and S-100 positive but cytokeratin negative, SCSCCs are cytokeratin positive and S-100 negative. Vimentin may be positive in some SCSCCs. AFXs have scattered giant cells with atypical nuclei and bizarre mitotic figures. These tumors are vimentin positive and cytokeratin negative. Strong CD10 expression has been demonstrated in AFXs with weaker and less frequent staining in poorly differentiated squamous cell carcinomas and spindle cell melanomas.630 Electron microscopy analysis for the presence of tonofilaments will help distinguish SCSCCs. Acantholytic squamous cell carcinomas are usually easily distinguished from other acantholytic disorders (eg, HaileyHailey disease, pemphigus vulgaris, transient acantholytic dermatosis) because the acantholysis involves atypical cells and extends deep into the dermis. However, angiosarcoma may be difficult to differentiate from this squamous cell variant. Red blood cell entrapment in some pseudolumina is occasionally present. Immunostaining for cytokeratin and epithelial membrane antigen is positive in acantholytic squamous cell carcinoma but negative in angiosarcomas. The signet ring cell variant of acantholytic squamous cell carcinoma must be differentiated from metastatic gastric and colon cancer. Benign lipoblastoma,

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

mimic primitive vascular lumina. The pseudoglandular spaces are largely empty but contain occasional erythrocytes or detached tumor cells. A spindle cell component has been described in some tumors.620 Mitotic activity may be moderate to marked, and atypical mitoses are seen. Inflammation and peritumoral fibrosis are present. Continuity with dermal blood vessels may be seen.613 Hyaluronic acid is present in many of the pseudovascular structures. The tumors may stain for cytokeratin and epithelial membrane antigens.578,613 Factor VIII and CD34 are negative. Vimentin uptake is present in some lesions. Ultrastructurally, tonofibrils are present, but Weibel-Pelade bodies and other evidence of vascular derivation are not seen.578,620

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 596

Paget disease, signet ring cell basal cell carcinoma, myxoid liposarcoma, and round cell liposarcoma may also demonstrate signet ring cells. Angiosarcoma is in the differential diagnosis for pseudovascular adenoid squamous cell carcinoma. The lining cells in both disorders show “hobnailing” and atypia. Immunostaining is helpful in distinguishing between the two tumors because angiosarcomas are cytokeratin negative but vimentin, Ulex, and CD34 positive. AFXs also possess a spindle cell component but are typically vimentin positive. Subcutaneous squamous cell carcinomas must be differentiated from metastatic disease (Table 26-27). Step sectioning the tissues to search for a connection to the epidermis or adnexal epithelium is useful.

Verrucous Carcinoma Verrucous carcinoma is composed of three entities—oral verrucous carcinoma, plantar verrucous carcinoma, and the Buschke-Loewenstein tumor.631 Oral verrucous carcinoma is also known as panoral verrucous carcinoma, oral florid papillomatosis, and Ackerman tumor and was first described in 1948.632,633 It is rare and comprises only 4% to 12% of oral squamous malignancies.237,634 Tobacco use (especially chewing), betel nut or leaf use, poor oral hygiene, oral lichen planus, chronic candidiasis, and malfitting dentures may induce this tumor.237,634 HPV types 2, 6, 11, 16, and 18 have been associated with these lesions.635 The expression of c-erbB-3 oncogene has been described in oral verrucous carcinoma.636 Plantar verrucous carcinoma is a distinct type of squamous cell carcinoma of the sole.637 This neoplasm is also known as epithelioma cuniculatum, papillomatosis cutis, papillomatosis cutis carcinoides, plantar verrucous carcinoma, and carcinoma cuniculatum.638 “Cuniculatum” means “rabbit burrow” or “rabbit warren,” indicative of the numerous openings these tumors have to the cutaneous surface.633,638 Abundant crypts and sinuses are present. This tumor is slow growing and rarely metastasizes but may display locally aggressive features.633 HPV-11 and -16 infection and increased oncogene activity have been reported in plantar verruous carcinoma.237,639,640 Proliferating cell nuclear antigen studies have suggested that the cells resemble large warts or condylomata.238,641 Most clinicians consider these tumors to be low-grade and

Table 26-27 Squamous Cell Carcinoma

Clinical Features Quickly growing, flesh-colored to red nodules on sun-exposed skin Overlying scale or crusting Lip lesions with atrophy, crusting, and ulceration Most commonly affect the head and neck of elderly patients Usually asymptomatic unless perineural invasion is present Ulcerating, papillomatous, and subcutaneous variants Histopathologic Features Conventional Aggregates of atypical epithelial cells invading the dermis May derive from an actinic keratosis or Bowen disease Variable mitotic activity, keratin pearl formation, premature cornification Focal acantholysis or spindle cell proliferation Nonspecific inflammatory infiltrate with lymphocytes and plasma cells Spindle cell Spindle cells emanating from the basal layer and invading the dermis Mitotic activity and atypia are present Pleomorphic giant cells are occasionally seen Cells are cytokeratin positive and occasionally vimentin positive Acantholytic Lobules and nests of atypical, acantholytic keratinocytes Premature cornification with free-floating neoplastic keratinocytes Signet ring Atypical nuclei are displaced yielding a signet ring appearance Paranuclear clear zone or nuclear displacement by eosinophilic globule Strong staining for glycogen Pseudovascular Proliferation of pleomorphic, atypical cells with “hobnail” appearance Cellular aggregates with vascular appearance Erythrocytes contained in pseudovascular spaces Moderate to marked mitotic activity Subcutaneous Intradermal aggregates of atypical, epithelioid cells Mitotic activity and premature cornification variable Atypical mitoses occasionally seen Connection to epidermis or adnexal structures present on deeper sectioning Differential Diagnosis Conventional Pseudocarcinomatous hyperplasia Inflamed seborrheic keratosis Metatypical basal cell carcinoma Inflamed wart Spindle cell Spindle cell malignant melanoma Atypical fibroxanthoma Acantholytic Acantholytic dermatoses (Hailey-Hailey disease, pemphigus vulgaris, transient acantholytic dermatosis) Angiosarcoma Signet ring Metastatic gastric or colon carcinoma Paget disease Signet ring cell basal cell carcinoma Myxoid liposarcoma Pseudovascular Angiosarcoma Atypical fibroxanthoma Subcutaneous nodular Metastatic squamous cell carcinoma

CLINICAL FEATURES Oral verrucous carcinoma presents as a slowly enlarging white to gray growth on the buccal or gingival mucosa of older men. 237,634 The average age of affected patients is 65 years.634 Invasion into the cheek or mandible may be seen.634 Plantar verrucous carcinoma is a slowgrowing, exophytic or polypoid tumor. It is most common on the heel or ball of the foot but has also been described on the toes, toe web spaces, leg, knee, wrist, finger, hand, axilla, abdominal wall, buttocks, nose, and scalp.638,649,650 Lesions are typically tender, pink to flesh colored, and well circumscribed at their borders.642 Most tumors have been treated as recalcitrant warts or corns for

A

an extended period.638,642 Plantar verrucous carcinoma is more common in middle-age to older men.642 Foul-smelling keratogenous material is excreted through multiple sinus openings. Penetration of the tumor to the dorsum of the foot and involvement of the metatarsal bones have been described.633 Metastases are rare.642 The Buschke-Loewenstein tumor is a cauliflower-like polypoid excrescence that arises on the glans penis in uncircumcised men between the ages of 18 and 86 years.644 The prepuce, coronal sulcus, and perianal mucosa may also be involved. Lesions may ulcerate and form fistulous tracts.631,651 A foul smell is common. Compression of the urethra and other structures may occur. These tumors may involve the genitalia, perineum, and urethra. Perianal tumors have a higher degree of malignant degeneration but no increased mortality.645 Activities such as walking and defecation may become difficult.652 Persons predisposed to these lesions may have a particularly fulminant course.652 Buschke-Loewenstein tumors have a similar appearance in women.644 HISTOPATHOLOGIC FEATURES The epithelium of the oral verrucous carcinoma mimics a low-grade mucosal squamous cell carcinoma. It is moderately verrucous or papillomatous (Fig. 26-31A).644 Hyperkeratosis and parakeratosis overly bulbous rete pegs, which invade the dermis in a “pushing” rather than an infiltrating manner (Fig. 26-31B). These rete pegs are blunt and well polarized. Keratin-lined clefts are seen. Cells are large with prominent cytoplasms and frequent keratinization. Nuclei and nucleoli are enlarged. Mitotic activity is present but is scattered. Parabasal

mitoses are common.634 Formation of keratin pearls is infrequent. An inflammatory infiltrate is seen and may be abundant if the keratin has been extruded into the dermis.634 Plantar verrucous carcinomas show hyperkeratosis with papillomatosis, parakeratosis, and acanthosis.633 There are exophytic and endophytic components to this epidermal proliferation.642 Epithelium-lined crypts are filled with orthokeratotic and parakeratotic material.638,642 The endophytic epithelium forms broad columns and shows minimal atypia with few mitotic figures. Keratogenous cysts and microabscesses are seen.633 Infiltration between bones and muscles may be appreciated. The inflammatory infiltrate is composed of lymphocytes, histiocytes, plasma cells, and rare eosinophils. The stroma is variably edematous with some abscesses.642 Buschke-Loewenstein tumors are hyperplastic and exophytic.644 They have a configuration much similar to that of a condyloma accuminatum and demonstrate koilocytic changes. These may be indistinguishable from those present in condyloma accuminata.652 Hyperkeratosis with parakeratosis and a very prominent granular layer are seen.631,644,652 The epithelium extends broadly into the dermis as blunt-shaped masses forming sinuses and keratinfilled cysts.644 The keratinocytes are well-differentiated squamous cells with little cytologic atypia. The nuclei are enlarged and have prominent nucleoli; however, mitotic activity is infrequent.631,652 Horn pearls, apoptotic cells, and multinucleated keratinocytes are uncommon.644,652 Vascular and lymphatic invasion are not present. An inflammatory infiltrate is present and is identical to that seen in plantar verrucous carcinomas.

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

highly keratinizing squamous cell carcinomas. Low-dose radiotherapy and chronic infection or inflammation may be responsible for these lesions.642 Buschke-Loewenstein tumors appear as exophytic masses involving the anogenital mucosa. They were initially described in 1925 and have also been termed giant malignant condyloma, verrucous carcinoma of the anogenital mucosa, and carcinoma-like condyloma.643,644 Most cases are due to infection with HPV type 6 or 11, although types 16 and 18 have been reported in lesions from HIV-positive patients.645,646 These tumors comprise 5% to 25% of all penile malignancies.644 Some clinicians consider Buschke-Loewenstein tumors to be nothing more than very large condyloma accuminata.647 Most of these lesions pursue a banal course, but metastases to the lymph nodes, skin, and distant sites have been reported.237,648 Destruction and local compression of adjacent structures is more common.

B

 FIGURE 26-31 Oral verrucous carcinoma. (A) The epidermis is verrucous and hyperkeratotic. (B) Rete pegs with atypia “push” into the dermis.

597

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Foci of frank squamous cell carcinoma may occasionally be seen in some tumors and are associated with an increased incidence of nodal involvement and recurrence.644 Consequently, step sectioning through the tumor is important. An entity termed carcinoma cuniculatum, arising on the penis in elderly patients, has also been reported.653 These neoplasms demonstrate a deeply penetrating and burrowing growth pattern typical of that seen in epithelioma cuniculatum.

598

DIFFERENTIAL DIAGNOSIS The differential diagnoses for these three entities are essentially identical (Table 26-28). They must be distinguished from low-grade squamous cell carcinomas, warts, and pseudocarcinomatous hyperplasia.638,644

Table 26-28 Verrucous Carcinoma

Clinical Features Oral verrucous carcinoma Gray or white warty growth on buccal or gingival mucosa More common in older men Plantar verrucous carcinoma Painful, exophytic, verrucous mass on the heel, toe, or ball of foot Extrude foul-smelling keratogenous material Buschke-Loewenstein tumor Polypoid mass on the glans penis in uncircumcised males May ulcerate or form sinus tracts May occlude structures such as the urethra Histopathologic Features Oral verrucous carcinoma Hyperkeratosis with orthokeratosis Rete pegs with pushing well-polarized base Large cells with scattered mitoses Plantar verrucous carcinoma Exophytic and endophytic epithelial proliferation forming crypts and sinuses Hyperkeratosis and parakeratosis Infrequent mitoses Buschke-Loewenstein tumor Hyperplastic, exophytic epithelial proliferation with infrequent mitoses Well-differentiated epidermal proliferation forming crypts and sinuses Hypergranulosis with koilocyte-like changes Differential Diagnosis Low-grade squamous cell carcinoma Warts or condyloma acuminata Pseudoepitheliomatous hyperplasia

Squamous cell carcinomas typically have a substantial amount of apoptosis, premature cornification, squamous eddy formation, and mitotic activity. These are absent in most examples of verrucous carcinoma with the exception of those Buschke-Loewenstein tumors with foci of frank squamous cell carcinoma. The presence of atypical mitoses suggests a squamous cell carcinoma. A recently described entity, the warty carcinoma, is a variant of squamous cell carcinoma with features similar to verrucous carcinoma, but it demonstrates papillomatosis with greater degrees of cytologic atypia and mitotic activity.654 Condyloma accuminata and verruca vulgares may demonstrate the papillomatosis present in tumors of BuschkeLoewenstein and plantar verrucous carcinoma. Koilocytic changes may also be seen. However, warts are not typically endophytic with broad columns of epidermis and do not usually show the same degree of mitotic activity. It is important to inquire about recent application of topical podophyllin because this medication may produce atypical mitotic features similar to a squamous cell carcinoma. Pseudoepitheliomatous hyperplasia demonstrates asymmetric epithelial proliferation with a prominent granular layer and minimal, if any, atypia. The invading epithelium is also more “pointed” than blunt.

Adenosquamous Carcinoma Adenosquamous carcinoma is a rare tumor that arises in the skin, lung, female genital tract, salivary gland, and submucosal glands of the head and neck.655,656 Primary cutaneous tumors are rare. These tumors are of sweat gland origin and arise from the pleuripotential cells in or around the acrosyringium.655 Affected patients have a poor prognosis with low 5-year survival rates.657 CLINICAL FEATURES These neoplasms present as asymptomatic nodules on the head and neck of elderly men. Men are more commonly affected.658 Adenosquamous carcinomas are typically aggressive neoplasms with a high rate of tumor recurrence and metastatic spread to the lymph nodes. HISTOPATHOLOGIC FEATURES Adenosquamous carcinomas are composed of nests and islands of atypical squamous cells infiltrating the dermis. The tumors form glandular and cystic spaces lined by mucin secreting epithelium.656 Some islands of cells undergo keratinization.655

Goblet and signet ring cells are not appreciated. The mucin stains with PAS, mucicarmine, and Alcian blue at a pH of 2.5.655,656 It is hyaluronidase resistant and sialidase sensitive, meaning that it is an epithelial mucin. 655 Areas of glandular differentiation stain for CEA.655,656,658 Staining for gross cystic disease fluid protein-15 has been reportedly negative.659 DIFFERENTIAL DIAGNOSIS Adenosquamous carcinomas should be differentiated from adenosquamous carcinomas arising in other sites such as the salivary glands (Table 26-29). Other carcinomas, such as eccrine epithelioma, microcystic adnexal carcinoma, and sebaceous carcinoma, should be distinguished as well. Eccrine epitheliomas also show cystic spaces with Alcian blue–positive mucin deposition. However, the tumor cells are not squamous appearing, the stroma is more fibrous, and the glandular elements are not as prominent but more tubular or ductal. Microcystic adnexal carcinomas have a more tubular or ductal appearance but no mucin deposition. Sebaceous carcinomas are formed by proliferation of cells with sebaceous differentiation. The glandular appearance is less prominent, and pagetoid spread of atypical epithelial cells is seen.

Mucoepidermoid Carcinoma These tumors are identical to those arising in the major salivary glands, and differentiation from metastatic disease may be difficult.657,660 Mucinous metaplasia of routine squamous cell carcinomas may be responsible for the histopathologic changes within these lesions. Tumors

Table 26-29 Adenosquamous Carcinoma

Clinical Features Asymptomatic nodules on the head and neck in elderly men Histopathologic Features Atypical keratinizing squamous cells with proliferating glandular structures Alcian-blue–positive mucin formation within the glands and cystic spaces No goblet cells or signet ring cells Differential Diagnosis Adenosquamous carcinoma from other sites (eg, salivary gland, submucosal gland) Eccrine epithelioma Microcystic adnexal carcinoma Sebaceous carcinoma

considered “high grade” are likely identical to adenosquamous carcinomas.661

carcinomas form tumor islands and nests but do not have goblet cells.

CLINICAL FEATURES Mucoepidermoid carcinomas do not have characteristic clinical features.657 Most lesions have arisen as flesh-colored nodules with occasional ulceration on the sun-exposed surfaces of elderly patients. A case on the scalp of a child has also been reported.662

Carcinosarcoma

DIFFERENTIAL DIAGNOSIS Mucoepidermoid carcinoma must be differentiated from sebaceous carcinomas and adenosquamous carcinomas (Table 26-30). Sebaceous carcinomas typically show aggregates of basaloid cells with clear features. However, pagetoid spread and evidence of sebaceous differentiation are seen with these tumors. Adenosquamous

Table 26-30 Mucoepidermoid Carcinoma

Clinical Features Flesh-colored nodules on sun-exposed skin in middle-aged or older patients Histopathologic Features Tumors with two cell types: polygonal squamous cells and goblet cells Atypia is seen with occasional mitoses Connection to the epidermis and adnexal structures is present Differential Diagnosis Sebaceous carcinoma Adenosquamous carcinoma

CLINICAL FEATURES Tumors appear as eroding and ulcerating nodules on the skin of older patients. Rapid growth has been reported by some patients.666 Death from metastatic spread has been described, although cutaneous lesions seem to pursue a less aggressive course than visceral malignancies.666,670,671 Lesions larger than 40 mm reportedly demonstrate a worse clinical outcome.669 Patients with the nevoid basal cell carcinoma syndrome and Brooke-Spiegler syndrome have been described.672,673 HISTOPATHOLOGIC FEATURES Basaloid and squamoid cells with stromal retraction, peripheral palisading, and mucin deposition form the superficial aspects of these tumors.665 In the deeper dermis, sarcomatous changes appear and consist of spindled cells with nuclear atypia and mitotic activity.665 These two cell populations are usually easily distinguished. The basaloid and squamoid cells are cytokeratin positive, but the sarcomatous cells are not. Similarly, sarcomatous cells are vimentin positive, but epithelial cells are negative.670 These mesenchymal components are believed to represent sarcomatous metaplasia of malignant epithelial cells.671 Poorly differentiated epithelial components can be found in some tumors and may reportedly be highlighted using a p63 stain.674 Basal cell carcinoma, squamous cell carcinoma, malignant eccrine spiradenoma, cylindrocarcinoma, and eccrine porocarcinoma have been described in carcinosarcomas.669,670,672,675 The mesenchymal portion of these neoplasms most often demonstrates osteogenic (80%) and cartilagenous (40%) differentiation; however, rhabdomyoblastic, angiosarcomatous, fibrosarcomatous, and atypical fibrous histiocytoma-like features have been described as well.670,671,676 Tumors derived from the epidermis (basal cell

DIFFERENTIAL DIAGNOSIS Carcinosarcomas should be differentiated from malignant mixed tumors of the skin and malignant fibrous histiocytomas (Table 26-31). Malignant mixed tumors of the skin show deposition of mucoid and cartilaginous stroma with proliferating ducts and tubules. These epithelial elements may be atypical with mitotic activity.518 Lobular growth is also present, but the proliferating atypical spindle cells are not seen. Malignant fibrous histiocytomas do not involve the upper dermis and show no basaloid or squamoid proliferation. However, they may stain for both vimentin and cytokeratin, potentially causing some confusion.

Lymphoepithelioma-like Carcinoma This tumor was first described by Swanson et al.678 It is similar to lymphoepitheliomas, occurring primarily in the nasopharyngeal region. These neoplasms may also be found in the salivary gland, breast, larynx, thyroid, thymus, lung, prostate, tonsil, and uterine cervix.679-681 They are called “lymphoepithelioma-like” because lymphoepitheliomas are associated with EBV virus infection, but the former have consistently been EBV negative.682-685 Investigations of lymphoepitheliomalike carcinomas for HPV and simian virus 40 have also shown no evidence of infection with these microbes.685 Some

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

HISTOPATHOLOGIC FEATURES The tumor is composed of two different cell populations. The first is that of large polygonal squamous cells with vesicular, hyperchromatic nuclei that have been shifted to the periphery of the cell. The mitotic activity is variable. The second group of cells is that of the goblet cells. These demonstrate vacuolated cytoplasm and are located at the periphery of tumor lobules. Occasional mitoses are present. The goblet cells contain mucin, which stains for PAS, mucicarmine, and Alcian blue and is hyaluronidase resistant.657,663 Positive staining for epithelial membrane antigen and CEA has been reported.661,664 Tumor lobules are surrounded by a nonspecific lymphohistiocytic inflammatory infiltrate. Keratinocyte atypia is present in some acrosyringia, suggesting that these tumors differentiate from sweat gland structures. Connection to the epidermis and adnexal structures may be seen in some foci.

Carcinosarcomas, also termed metaplastic carcinomas and biphasic sarcomatoid carcinomas, are rare tumors with both malignant epithelial and mesenchymal elements.665-667 They are seen in the bladder, breast, kidney, cervix, and gallbladder.665 These neoplasms may be sarcomatoid carcinomas with variable degrees of differentiation.665 Metaplastic changes in malignant epithelial cells may form the neoplastic mesenchymal cells.668,669

carcinoma and squamous cell carcinoma) reportedly arise more commonly in older patients and have a better 5-year diseasefree survival than those with adnexal components.677

Table 26-31 Carcinosarcoma

Clinical Features Solitary nodules with epidermal ulceration and breakdown on the skin of elderly patients Histopathologic Features Two types of cellular proliferation: basaloid or squamoid cells with palisading, retraction, and surrounding fibromucinous stroma (cytokeratin positive and vimentin negative) Second cell type composed of atypical spindle-shaped cells (cytokeratin negative and vimentin positive) Differential Diagnosis Malignant mixed tumor of the skin Malignant fibrous histiocytoma

599

authors believe these tumors differentiate from adnexal, particularly follicular, epithelium because sebocytes have been noted in some tumors.682 Other investigators consider them merely a growth pattern of a squamous cell carcinoma.681

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

CLINICAL FEATURES Tumors are typically on the face and scalp in older patients.682,683 They are flesh-colored, dome-shaped, long-standing nodules. Surface changes such as ulceration are uncommon.237 The lesions may metastasize, and fatalities have been reported.682,685,686

600

HISTOPATHOLOGIC FEATURES The tumor masses have minimal, if any, connection to the epidermis or follicular epithelium and appear as nodules in the reticular dermis.682 They are asymmetric and poorly circumscribed and form a somewhat “follicular” pattern. Tumor cells are epithelioid and of moderate size with vacuolated cytoplasms. The nuclei are vesicular and contain prominent, eosinophilic nucleoli. There is a high nuclear-to-cytoplasm ratio to these cells. A tumor with spindle cell differentiation has been reported.687 Mitoses are common and may be atypical.680,682 Tumor nodules are surrounded by enveloping masses of T cells and occasional plasma cells.679,680,682,683,688 Small lymphoid follicles, neutrophils, and eosinophils may also be present.237,681 The tumor cells are cytokeratin and epithelial membrane antigen positive but S-100, CEA, and leukocyte common antigen negative.679,680,682,688 Most of the surrounding inflammatory cells stain with T-cell markers and are believed to be aggregating secondary to immunologic stimuli or chemotactic factors produced by the tumor cells.237 Factor XIIIa–staining cells in the surrounding stroma have been described and may contribute to the overall better prognosis of these lesions.684 DIFFERENTIAL DIAGNOSIS Lymphoepithelioma-like carcinomas should be differentiated from lymphomas, pseudolymphomas, cutaneous lymphadenomas, primary neuroendocrine carcinoma, and metastatic lymphoepithelioma (Table 26-32).680,682,689,690 Cutaneous lymphomas may show a follicular proliferation, but tumor cells are not typically this vesicular or large and are not cytokeratin positive. Analysis for lymphocyte antigens such as UCHL-1 and L26 are positive in cutaneous lymphomas. Likewise, pseudolymphomas may have plasma cells, eosinophils, and

Table 26-32 Lymphoepithelioma-Like Carcinoma

Clinical Features Flesh-colored nodules on the face and scalp of elderly patients Histopathologic Features Intradermal nodules of epithelioid cells with vesicular nuclei and vacuolated cytoplasm Mitotic activity and prominent nucleoli are seen Tumor cells are cytokeratin positive and leukocyte common antigen negative Surrounding lymphocytes and plasma cells are present Differential Diagnosis Cutaneous lymphomas/pseudolymphomas Cutaneous lymphadenoma Primary neuroendocrine carcinoma Metastatic lymphoepithelioma

a follicular proliferation but do not stain for cytokeratin and epithelial membrane antigen. Cutaneous lymphadenomas are intradermal lobular proliferations of cytokeratin-positive cells with infiltrating lymphocytes and a stromal reaction. However, they have a basaloid appearance with peripheral palisading and lack investing lymphocytes and plasma cells. Primary neuroendocrine carcinoma (Merkel cell carcinoma) displays a distinct paranuclear punctate uptake of cytokeratin 20 stain with expression of

neuroendocrine markers such as neuronspecific enolase, chromogranin A, and synaptophysin. Finally, metastatic disease from distant lymphoepitheliomas, most likely otorhinolaryngologic, must be ruled out as well.

MISCELLANEOUS “TUMORS”

Cutaneous Horn These tumors, also known as cornu cutaneum, are defined as lesions with a height at least half that of their width.288,691 The stratum corneum forms a cohesive mass of cornified material that protrudes from the cutaneous surfaces.288 CLINICAL FEATURES Cutaneous horns present as a yellow to gray protrusions of keratinized material that is organized in the shape of a horn or spike.288,691 They are more common in women than men, but men are more likely to have a malignant cause for their tumors. Larger lesions and those arising on older patients are also more likely to be malignant. Cutaneous horns are most common on the face, ears, dorsum of the hands, and scalp. HISTOPATHOLOGIC FEATURES The stratum corneum is compact and exaggerated (Fig. 26-32). It may be lamellated or composed of parakeratotic squames. This parakeratosis may be intermittent, forming a vertical “skip” pattern. Cutaneous

 FIGURE 26-32 Cutaneous horn. This cutaneous horn demonstrates compact hyperkeratosis and parakeratosis with underlying squamous cell carcinoma in situ.

DIFFERENTIAL DIAGNOSIS Hyperkeratotic lesions with compact keratinization must be distinguished from cutaneous horns. These include warts and inflamed seborrheic keratoses (Table 26-33). Warts are typically hyperkeratotic with intermittent parakeratosis, but the keratin is usually not compact or conical and is limited in scope. Inflamed seborrheic keratoses may demonstrate hyperkeratosis with parakeratosis. These tumors, however, show intermittent serum deposition within the stratum corneum and infiltrating inflammatory cells.

Stucco Keratosis Stucco keratoses have also been called verruca dorsi manus et pedis705 and were

initially described by Kocsard in 1958.706 Similar lesions have been reported in pitch and tar workers.705 Their etiology is unclear but may be due to heat or chemical exposure.707 They are more common in Australia than England perhaps due to the amount of sun exposure in these countries.708 HPV has been detected in these lesions.709 CLINICAL FEATURES Stucco keratoses are typically multiple and involve the lower extremities below the knee.705 They may also affect the upper extremities but spare the palms and soles. Symptoms are rare. They are discrete gray to white keratotic papules 1 to 4 mm in diameter with a “stuck-on” appearance.705,707 They have a flat or convex surface and are dry and rough in texture. Most patients are older, and men are affected more than women.708 Approximately 20% of the populace develop these lesions.

Clavus (Corn) Clavi (corns) are hyperkeratotic lesions of the feet and are seen only in people who wear shoes.710 They are a consequence of persistent frictional injury and are typically painful.711 Women are affected more often than men. Underlying bony prominences and other orthopedic abnormalities exert pressure through the skin.

HISTOPATHOLOGIC FEATURES The epidermis has a “church spire” configuration with papillomatosis and loose hyperkeratosis.705,707,708 Modest acanthosis is seen, but parakeratosis and horn pseudocysts are absent. The granular layer is thickened, and the base of the tumor is evenly flat. Atypia is not appreciated. Perivascular inflammation may be present but is minimal.705

CLINICAL FEATURES Lesions are yellow to brown with a central core.710 Hard corns are burnished with a smooth surface. Soft corns are macerated and sodden.

DIFFERENTIAL DIAGNOSIS Stucco keratoses must be differentiated from seborrheic keratoses, actinic keratoses, and large cell acanthomas (Table 26-34).705 The tumor known as acrokeratosis verruciformis of Hopf is essentially indistinguishable from stucco keratoses. Seborrheic keratoses, particularly the papillomatous variant, are hyperkeratotic with papillomatosis. Unlike stucco

DIFFERENTIAL DIAGNOSIS These tumors should be differentiated from warts, calluses, and porokeratosis (Table 26-35). Warts may show a concave depression, but the granular layer is usually accentuated rather than diminished. Calluses also demonstrate concave depression and typically show less parakeratosis. Porokeratomas are hyperkeratotic with

Table 26-33 Cutaneous Horn

Clinical Features Hyperkeratotic gray to yellow masses on the face, scalp, hands, and ears The lesion’s height is at least half the diameter of the base Histopathologic Features Compact stratum corneum in a conical formation Lamellated with occasional parakeratosis Underlying lesions are typically actinic keratoses, warts, squamous cell carcinomas, or seborrheic keratoses Differential Diagnosis Wart Inflamed seborrheic keratosis

keratoses, however, they may show parakeratosis, horn pseudocysts, and basal layer hyperpigmentation. Actinic keratoses have atypical cells with mitotic activity and are rarely papillomatous. Large cell acanthomas, which some investigators believe are variants of actinic keratoses, may appear similar to stucco keratoses but demonstrate large nuclei with occasional mitotic activity.517

HISTOPATHOLOGIC FEATURES Tumors are endophytic with a cup-shaped depression. A thick parakeratotic plug is seen. The spinous and granular layers are decreased.

CHAPTER 26 ■ TUMORS OF THE EPIDERMIS

horns arising from tricholemmomas show a trichilemmal form of keratinization rather than epidermal. The most common causes of cutaneous horns are actinic keratoses (37%), warts (23%), squamous cell carcinomas (18%), and seborrheic keratoses (16%).288 Other tumors that cause these lesions include trichilemmal cyst, keratoacanthoma, Bowen disease, molluscum contagiosum, benign lichenoid keratosis, infundibular cyst, sebaceous adenoma, dermatofibroma, angiokeratoma, epidermolytic acanthoma, pyogenic granuloma, papillary eccrine adenoma, pilomatricoma, subepidermal calcified nodule, nevus sebaceous, syringocystadenoma papilliferum, basal cell carcinoma, arsenical keratosis, verrucous epidermal nevus, onychomatricoma, lichen simplex chronicus, condyloma accuminatum, sebaceous carcinoma, malignant melanoma, trichilemmal carcinoma, and penile verrucous carcinoma.288,691-704

Table 26-35 Clavus (Corn) Table 26-34 Stucco Keratosis

Clinical Features White to gray keratoses with a “stuck-on” appearance arising on the extremities Most patients are middle age to older Histopathologic Features Regular, even papillomatosis with hyperkeratosis Parakeratosis, horn pseudocysts, basal layer hyperpigmentation, and atypia are absent Differential Diagnosis Papillomatous seborrheic keratosis Actinic keratosis Large cell acanthoma

Clinical Features Yellow to brown hyperkeratotic lesion on the feet May be hard with a smooth surface (hard corn) or macerated and sodden (soft corn) Women more commonly affected than men Histopathologic Features Concave, cup-shaped depression with hyperkeratosis and parakeratosis Spinous and granular layer decreased Differential Diagnosis Wart Callus Porokeratoma

601

coronoid lamellae. However, these lesions are not endophytic and demonstrate focal areas of dyskeratotic keratinocytes.

Callus

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

These are hyperkeratotic lesions due to chronic friction or pressure.712 They may be seen on the palms and soles but are more common on the feet. They result from poorly fitting shoes or clothes and bony deformities. Calluses affect persons of all ages but are most typical on persons whose skin is exposed to consistent and constant friction.712

602

CLINICAL FEATURES Calluses may be preceded by blisters and inflammation.712 Fully developed lesions are yellow to brown or flesh colored. They are typically hard and dry but rarely painful. They do not possess a central core. The overlying skin markings may be accentuated. HISTOPATHOLOGIC FEATURES The stratum corneum is compact, hyperkeratotic, and variably parakeratotic.712 The granular and spinous layer are accentuated. Tumors may be concave with a cupshaped depression. Perivascular inflammation is present but is not abundant. DIFFERENTIAL DIAGNOSIS Calluses should be distinguished from clavi (corns) and warts (Table 26-36). Clavi also show a concave depression but a diminished granular layer and more parakeratosis. Warts are also concave with a prominent granular layer but may have koilocytic change and increased vascularity.

Punctate (Mechanical) Keratoses Punctate keratoses are also known as keratosis punctata palmaris et plantaris

Table 26-36 Callus

Clinical Features Flesh-colored to yellow or brown hyperkeratotic lesions on the palms and soles Elevated, hard, dry, and usually asymptomatic Histopathologic Features Hyperkeratotic stratum corneum with variable parakeratosis Cup-shaped depression with hypergranulosis and accentuated spinous layer Differential Diagnosis Clavus Wart

and punctate keratosis of the palm and soles.713 This condition is inherited as an autosomal dominant trait. Eleven percent of the population is affected.714 Lesions usually appear in adolescence.713 Punctate keratoses have been described in association with atopy, dioxin intoxication, and ichthyosis vulgaris.715-717 There is a subcategory of this disease affecting black men in which the lesions are confined to the palmar creases.718-720 CLINICAL FEATURES Punctate keratoses are small, hyperkeratotic papules 2 to 10 mm in diameter.713 They are firm and round to oval.721 Lesions appear on the palms and soles, particularly the medial aspects.715 The keratotic plug may be removed, leaving a small pit behind. Punctate keratoses are usually asymptomatic but may occasionally be painful.713,715 HISTOPATHOLOGIC FEATURES The epidermis shows a small cup-shaped depression filled with hyperkeratotic stratum corneum.713,718-722 This plug of hyperkeratotic material is conical or wedge shaped with its apex at the depth of the depression.721 Parakeratosis is usually absent but may be seen in small amounts in a vertical configuration. The surrounding rim of normal epidermis is also hyperkeratotic. The epidermis beneath the keratin plug may be compressed. The granular layer is accentuated in some cases and thinned in others.714,720 Mild spongiosis may be present. Occasional acantholysis and dyskeratosis have been described.722 A mild perivascular inflammatory infiltrate may be present in the dermis.713,721 Blood vessels may be slightly dilated with mild dermal edema. Occluded blood and lymph vessels have been reported.714 Ultrastructurally, keratohyaline granules, membrane-coating granules, and desmosomes appear normal.713 Membrane-coating granules are also normal but may be present in diminished numbers. This scarcity may prevent normal keratinocyte desquamation.721 DIFFERENTIAL DIAGNOSIS Punctate keratoses should be differentiated from punctate porokeratosis, perforating diseases, and calluses (Table 26-37). Porokeratomas, particularly the punctate variant, are hyperkeratotic with columns of parakeratosis (coronoid lamellae). These tumors have dyskeratotic cells underlying the coronoid lamellae. Perforating diseases may show a conical shaped mass of hyperkeratotic material, but this mass is basophilic and contains inflammatory cells. The dermis is inflamed and fibrotic. Calluses are also

Table 26-37 Punctate (Mechanical) Keratosis

Clinical Features Onset in childhood or adolescence in persons with an atopic diathesis Multiple, hard, hyperkeratotic papules on the palms and soles Crateriform pits when the hyperkeratotic mass is removed Histopathologic Features Wedge-shaped hyperkeratotic plug depressing the epidermis Parakeratosis and width of the granular layer are variable Perivascular inflammation and vascular dilatation are present Differential Diagnosis Punctate porokeratosis Perforating disorders Callus

parakeratotic endophytic lesions. These may be differentiated from punctate keratoses by the relative confluence of the parakeratosis (not columnar), the lack of a conical configuration to the hyperkeratotic mass, and the increased granular layer.

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51. Unna PG: The Histopathology of the Diseases of the Skin. New York: Macmillan Cl; 1896:1148. 52. Altman J, Mehregan AH: Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1971;104:385-389. 53. Morag C, Metzker A: Inflammatory linear verrucous epidermal nevus: report of seven new cases and review of the literature. Ped Dermatol. 1985;3:15-18. 54. de Jong EMGJ, Rulo HFC, de Kerkhof PCM: Inflammatory linear verrucous epidermal nevus (ILVEN) versus linear psoriasis. Act Derm Venereol (Stockh). 1991;71:343-346. 55. Adams BB, Mutasim DF: Adult onset verrucous epidermal nevus. J Am Acad Dermatol. 1999;41:825-826. 56. Rulo HFC, van de Kerkhof PCM: Treatment of inflammatory linear verrucous epidermal nevus. Dermatologica. 1991;182:112-114. 57. Kawaguchi H, Takeuchi M, Ono H, Nakajima H: Adult onset of inflammatory linear verrucous epidermal nevus. J Dermatol. 1999;26:599-602. 58. Al-Enezi A, Huber AM, Krafchik BR, et al: Inflammatory linear verrucous epidermal nevus and arthritis: a new association. J Pediatr. 2001;138: 602-604. 59. Menni S, Restano L, Gianotti R, et al: Inflammatory linear verrucous epidermal nevus (ILVEN) and psoriasis in a child? Int J Dermatol. 2000;39:30-32. 60. Hofer T: Does inflammatory linear verrucous epidermal nevus represent a segmental type1/type 2 mosaic of psoriasis? Dermatology. 2006;212:103-107. 61. Vissers WH, Muys L, Erp PE, et al: Immunohistochemical differentiation between. inflammatory linear verrucous epidermal nevus (ILVEN) and psoriasis. Eur J Dermatol. 2004;14:216-220. 62. Dupre A, Christol B: Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1977;113:767-769. 63. Kofmann S: Ein fall von seltener lokalisation und verbreitung von komedonen. Arch Derm Syph. 1895;32:177-178. 64. Nabai H, Mehregan AH: Nevus comedonicus. Acta Dermato Venereol (Stockh). 1973;53:71-74. 65. Cestari TF, Rubim M, Valentini BC: Nevus comedonicus: case report and brief review of the literature. Ped Dermatol. 1991;8:300-305. 66. Dudley K, Barr WG, Armin A, et al: Nevus comedonicus in association with widespread, well-differentiated follicular tumors. J Am Acad Dermatol. 1986;15: 1123-1127. 67. Kim SC, Kang WH: Nevus comedonicus associated with epidermal nevus. J Am Acad Dermatol. 1989;21:1085-1088. 68. Grimalt R, Caputo R: Posttraumatic nevus comedonicus. J Am Acad Dermatol. 1993;28:273-274. 69. Vasiloudes PE, Morelli JG, Weston WL: Inflammatory nevus comedonicus in children. J Am Acad Dermatol. 1998;38: 834-836. 70. Aloi FG, Molinero A: Nevus comedonicus with epidermolytic hyperkeratosis. Dermatologica. 1987;174(3):140-143. 71. Kirtak N, Inaloz HS, Karakok M, et al: Extensive inflammatory nevus comedonicus involving half of the body. Int J Dermatol. 2004;43:434-436.

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11. Tsubota A, Akiyama M, Sakai K, et al: Keratin 1 gene mutation detected in epidermal nevus with epidermolytic hyperkeratosis. J Invest Dermatol. 2007;127: 1371-1374. 12. Cambiaghi S, Brusasco A, Grimalt R, et al: Acantholytic dyskeratotic epidermal nevus as a mosaic form of Darier’s disease. J Am Acad Dermatol. 1995;32:284-286. 13. Youn M, Hann SK, Moon TK, Lee MG: Acantholytic dyskeratotic epidermal nevus induced by ultraviolet B radiation. J Am Acad Dermatol. 1998;39:301-304. 14. Rosen T: Keratoacanthomas arising within a linear epidermal nevus. J Dermatol Surg Oncol. 1982;8:878-880. 15. Crovato F, Desirello G, Rebora A: Is Dowling-Degos disease the same disease as Kitamura’s reticulate acropigmentation? Br J Dermatol. 1983;109:105-110. 16. Rebora A, Crovato F: The spectrum of Dowling-Degos disease. Br J Dermatol. 1984;110:627-630. 17. Cox NH, Long E: Dowling-Degos disease and Kitamura’s reticulate acropigmentation: support for the concept of a single disease. Br J Dermatol. 1991;125: 169-171. 18. Kershenovich J, Langenberg A, Odom RB, et al: Dowling-Degos’ disease mimicking chloracne. J Am Acad Dermatol. 1992;27:345-348. 19. Ostlere L, Holden CA: Dowling-Degos disease associated with Kitamura’s reticulate acropigmentation. Clin Exp Dermatol. 1994;19:492-495. 20. Schnur RE, Heymann WR: Reticulate hyperpigmentation. Sem Cutan Med Surg. 1997;16:72-80. 21. Oiso N, Tsuruta D, Ota T, et al: Spotted and rippled reticulate hypermelanosis: a possible variant of Dowling-Degos disease. Br J Dermatol. 2007;156:196-198. 22. Legoupil D, Demasson G, Davaine AC, et al: Bowen’s disease and squamous cell carcinoma in Haber’s syndrome: two cases. Ann Dermatol Venereol. 2007; 134:59-61. 23. Lestringant GG, Masouye I, Frossard PM, et al: Co-existence of leukoderma with features of Dowling-Degos disease: reticulate acropigmentation of Kitamura spectrum in five patients. Dermatology. 1997;195:337-343. 24. Kikuchi I, Crovato F, Rebora A: Haber’s syndrome and Dowling-Degos disease. Int J Dermatol. 1988;27:96-97. 25. Erel A, Gurer MA, Edali N: Reticulate acropigmentation of Kitamura: two case reports. Int J Dermatol. 1993;32:726-727. 26. Wilson-Jones E, Grice K: Reticulate pigmented anomaly of the flexures. Arch Dermatol. 1978;114:1150-1157. 27. Braun-Falco M, Volgger W, Borelli S, et al: Galli-Galli disease: an unrecognized entity or an acantholytic variant of Dowling-Degos disease. J Am Acad Dermatol. 2001;45:760-763. 28. Braun-Falco M, Ring J: Enhanced cytoplasmic expression of desmocollin 3 in epidermal rete ridges of Dowling-Degos disease. Br J Dermatol. 2003;149:1293-1295. 29. Pollitzer S: Acanthosis nigricans, in Unna PG, Morris M, Besnier E, et al (eds). International Atlas of Rare Skin Diseases. London: HK Lewis & Co; 1890:1-3. 30. Curth HO: The necessity of distinguishing four types of acanthosis nigricans, inJadassohn W, Schirren CG, (eds). XIII

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72. Morillo V, Manrique P, De Miguel E, et al: Nevus comedonicus with epidermolytic hyperkeratosis. Eur J Derm. 2007;17: 176-177. 73. Kurokawa I, Nakai Y, Nishimura K, et al: Cytokeratin and filaggrin expression in nevus comedonicus. J Cutan Pathol. 2007;34:338-341. 74. Resnik KS, Kantor GR, Howe NR, et al: Dilated pore nevus. Am J Dermatopathol. 1993;15:169-171. 75. Carneiro SJC, Dickson JE, Knox JM: Familial dyskeratotic comedones. Arch Dermatol. 1972;105:249-251. 76. Van Geel NAC, Kockaert M, Neumann HAM: Familial dyskeratotic comedones. Br J Dermatol. 1999;140:956-959. 77. Leppard BJ: Familial dyskeratotic comedones. Clin Exp Dermatol. 1982;7:329-332. 78. Price M, Jones RR: Familial dyskeratotic comedones. Clin Exp Dermatol. 1985;10: 147-153. 79. Hall JR, Holder W, Knox JM, et al: J Am Acad Dermatol. 1987;17:808-814. 80. Hallermann C, Bertsch HP: Two sisters with familial dyskeratotic comedones. Eur J Dermatol. 2004;14:214-215. 81. Sutton RL: A fissured granulomatous lesion of the upper labioalveolar fold. Arch Dermatol. 1932;26:425-427. 82. Epstein EE: Granuloma fissuratum of the ears. Arch Dermatol. 1965;91:621-622. 83. Farrell WJ, Wilson JW: Granuloma fissuratum. Arch Dermatol. 1968;97: 34-37. 84. Barnes HM, Calnan CD, Sarkany I: Spectacle from acanthoma. Trans St. Johns Dermatol Soc. 1974;60:99-102. 85. MacDonald DM, Martin SJ: Acanthoma fissuratum-spectacle frame acanthoma. Acta Dermato Venereol (Stockh). 1975;55: 485-488. 86. Cerroni L, Soyer HP, Chimenti S: Acanthoma fissuratum. J Dermatol Surg Oncol. 1988;14:1003-1005. 87. Kennedy CM, Dewdney S, Galask RP: Vulvar granuloma fissuratum: a description of fissuring of the posterior fourchette and the repair. Obstet Gynecol. 2005;105:1018-1023. 88. Fretzin DF: Granuloma fissuratum of the ears. Arch Dermatol. 1966;93:448-449. 89. Hyde W: Diseases of the Skin, 8th ed. New York: Lea & Febiger; 1909:174-175. 90. Payne CMER, Wilkinson JD, McKee PH, et al: Nodular prurigo—a clinicopathological study of 46 patients. Br J Dermatol. 1985;113:431-439. 91. Perez GL, Peters MS, Reda AM, et al: Mast cells, neutrophils and eosinophils in prurigo nodularis. Arch Dermatol. 1993;129:861-865. 92. Nahass GT, Penneys NS: Merkel cells and prurigo nodularis. J Am Acad Dermatol. 1994;31:86-88. 93. Neri S, Ierna D, D’Amico RA, et al: Helicobacter pylori and prurigo nodularis. Hepato Gastroenterol. 1999;46:2269-2272. 94. Matthews SN, Cockerell CJ: Prurigo nodularis in HIV-infected individuals. Int J Dermatol. 1998;37:401-409. 95. Sonkoly E, Muller A, Lauerma AI, et al: IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Aller Clin Immunol. 2006;117:411-417. 96. Mattila JA, Vornanen M, Katila ML: Histopathological and bacteriological findings in prurigo nodularis. Acta Derm Venereol. 1997;77:49-51.

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119. Newland JR, Leventon GS: Warty dyskeratoma of the oral mucosa. Oral Surg. 1984;58:176-183. 120. Niren NM, Waldman GD, Barsky S: Warty dyskeratoma. Cutis. 1982;29:79-81, 94. 121. Tanay A, Mehregan AH: Warty dyskeratoma. Dermatologica. 1969;138:155-164. 122. Panja RK: Warty dyskeratoma. J Cutan Pathol. 1977;4:194-200. 123. Brownstein MH: Acantholytic acanthoma. J Am Acad Dermatol. 1988;19: 783-686. 124. Megahead M, Scharffetter-Kochanek K: Acantholytic acanthoma. Am J Dermatopathol. 1993;15:283-285. 125. Barnette DJ, Cobb M: A solitary, erythematous, hyperkeratotic papule. Arch Dermatol. 1995;131:211-212, 214-215. 126. O’Connell BM, Nickoloff BJ: Solitary labial papular acantholytic dyskeratoma in an immunocompromised host. Am J Dermatopathol. 1987;9:339-342. 127. Ko CJ, Iftner T, Barr RJ, et al: Changes of epidermodysplasia verrucifomis in benign skin lesions: the EV acanthoma. J Cutan Pathol. 2007;34:44-48. 128. Baer RL, Garcia RL, Partsalidou V, et al: Papillated squamous cell carcinoma in situ arising in a seborrheic keratosis. J Am Acad Dermatol. 1981;5:561-565. 129. Freudenthal W: Verruca senilis und keratoma senile. Arch Dermatol Syph. 1926;152:505-528. 130. Heaphy MR, Millns JL, Schroeter AL: The sign of Leser-Trelat in a case of adenocarcinoma of the lung. J Am Acad Dermatol. 2000;43:386-390. 131. Williams JV, Helm KF, Long D: Chemotherapy-induced inflammation in seborrheic keratoses mimicking disseminated herpes zoster. J Am Acad Dermatol. 1999;40:643-644. 132. Schwartz RA: Sign of Leser-Trelat. J Am Acad Dermatol. 1996;35:88-95. 133. Czarnecki DB, Rotstein H, O’Brien TJ, et al: The sign of Leser-Trelat. Australas J Dermatol. 1983;24:93-99. 134. Garcia RL, Bishop ME: The rapid onset of seborrheic keratosis of the breasts during pregnancy. J Assoc Mil Dermatol. 1977;3:13-14. 135. Kilmer SL, Berman B, Morhenn VB: Eruptive seborrheic keratoses in a young woman with acromegaly. J Am Acad Dermatol. 1990;23:991-994. 136. Williams MG: Acanthoma appearing after eczema. Br J Dermatol. 1956;68: 268-271. 137. Brown J, Winkelmann RK: Acanthosis nigricans: a study of 90 cases. Medicine. 1968;47:33-51. 138. Winkelmann RK: Superficial spreading (and disappearing) seborrheic keratosis. Cutis. 1999;63:235-237. 139. Kapasi Y, Khopkar U, Raj S,, et al: Weary-Kindler syndrome with multiple seborrheic keratoses. Int J Dermatol. 1993;32:444-445. 140. Ellis DL, Kafka SP, Chow JC, et al: Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelat, and multiple acrochordons: a possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. N Engl J Med. 1987;317:1582-1587. 141. Nanney LB, Ellis DL, Levine J, et al: Epidermal growth factor receptors in idiopathic and virally induced diseases. Am J Pathol. 1992;140:915-925.

163. Gurbuz O, Hurwitz RM: Keratotic melanocytic nevus. Int J Dermatol. 1990; 29:713-715. 164. Wagner RF: Benign pigmented tumor with combined features of seborrheic keratosis and compound nevus. Cutis. 1991;48:463-464. 165. Chun SI, Im S: An epidermoid cyst with a seborrheic verruca-like cyst wall. J Dermatol. 1990;17:260-263. 166. Hoshina D, Akiyama M, Hata H, et al: Eccrine porocarcinoma and Bowen’s disease arising in a seborrhoeic keratosis. Clin Exp Dermatol. 2007;32:54-56. 167. Yakar JB, Sagi A, Mahler D, et al: Malignant melanoma appearing in seborrheic keratosis. J Dermatol Surg Oncol. 1984;10:382-383. 168. Zabel RJ, Vinson RP, McCollough ML: Malignant melanoma arising in a seborrheic keratosis. J Am Acad Dermatol. 2000;42:831-833. 169. Kwittken J: Keratoacanthoma arising in seborrheic keratosis. Cutis. 1974;14: 546-547. 170. Smith KJ, Skelton HG, Palominon NJ: Adenocarcinoma arising in a seborrheic keratosis. Arch Dermatol. 1991;127: 1738-1739. 171. Bahcekapili D, Buyukbabani N, Saglik E, et al: Seborrhoeic dermatosis arising on a nevus sebaceous. J Eur Acad Dermatol Venereol. 2006;20:875-877. 172. Monteagudo JC, Jordan E, Terencio C, et al: Squamous cell carcinoma in situ (Bowen’s disease) arising in seborrheic keratosis: three lesions in two patients. J Cutan Pathol. 1989;16:348-352. 173. Al-Daraji WI, Al-Dawoud A: Primary cutaneous ganglioneuroma arising within a seborrheic keratosis: a rare association. Clin Exp Dermatol. 2005;30: 137-140. 174. Rahbari H: Bowenoid transformation of seborrhoeic verrucae (keratoses). Br J Dermatol. 1979;101:459-463. 175. Vun Y, De’Ambrosis B, Spelman L, et al: Seborrhoeic keratosis and malignancy: collision tumour or malignant transformation. Aust J Dermatol. 2006;47: 106-108. 176. Zhao Y, Lin Y, Luo R, et al: Human papillomavirus (HPV) infection in seborrheic keratosis. Am J Dermatopathol. 1989;11:209-212. 177. Leonardi CL, Zhu WY, Kinsey WH, et al: Seborrheic keratoses from the genital region may contain human papillomavirus DNA. Arch Dermatol. 1991;127: 1203-1206. 178. Jacyk WK, Dreyer L, de Villiers EM: Seborrheic keratoses of black patients with epidermodysplasia verruciformis contain human papillomavirus DNA. Am J Dermatopathol. 1993;15:1-6. 179. Gushi A, Kanekura T, Kanzaki T, et al: Detection and sequences of human papillomavirus DNA in nongenital seborrhoeic keratosis of immunopotent individuals. J Dermatol Sci. 2003;31: 143-149. 180. Googe PB, King R: Herpesvirus infection of seborrheic keratoses. Am J Dermatopathol. 2001;23:146-148. 181. Nakamura S, Nisioka K: Enhanced expression of p16 in seborrhoeic keratosis: a lesion of accumulated senescent epidermal cells in G1 arrest. Br J Dermatol. 2003;149:560-565.

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666. Brown TJ, Tschen JA. Primary carcinosarcoma of the skin: report of a case and review of the literature. Dermatol Surg. 1999;25:498-500. 667. Ram R, Saadat P, Peng D, et al: Case report and literature review: primary cutaneous carcinosarcoma. Ann Clin Lab Sci. 2005;35:189-194. 668. McKee PH, Fletcher CDM, Stavrinos P, et al: Carcinosarcoma arising in eccrine spiradenoma. Am J Dermatopathol. 1990; 12:335-343. 669. Bigby SM, Charlton A, Miller MV, et al: Biphasic sarcomatoid basal cell carcinoma (carcinosarcoma): four cases with immunohistochemistry and review of the literature. J Cutan Pathol. 2005;32: 141-147. 670. Izaki S, Hirai A, Yoshizawa Y, et al: Carcinosarcoma of the skin: immunohistochemical and electron microscopic observations. J Cutan Pathol. 1993;20: 272-278. 671. McCluggage WG, Fon LJ, O’Rourke D, et al: Malignant eccrine spiradenoma with carcinomatous and sarcomatous elements. J Clin Pathol. 1997;50:871-873. 672. De Francesco V, Frattasio A, Pillon B, et al: Carcinosarcoma arising in a patient with multiple cylindromas. Am J Dermatopathol. 2005;27:21-26. 673. Bhattacharjee P, Leffell D, McNiff JM: Primary cutaneous carcinosarcoma arising in a patient with nevoid basal cell carcinoma syndrome. J Cutan Pathol. 2005;32:638-641. 674. Suh KY, Lacouture M, Gerami P: p63 in primary cutaneous carcinosarcoma. Am J Dermatopathol. 2007;29:374-377. 675. Patel NK, McKee PH, Smith NP, Fletcher CDM: Primary metaplastic carcinoma (carcinosarcoma) of the skin. A clinicopathologic study of four cases and review of the literature. Am J Dermatopathol. 1997;19:363-372. 676. Kantrow SM, Boyd AS: Primary cutaneous metaplastic carcinoma: report of a case involving angiosarcoma. Am J Dermatopathol. 2007;29:270-273. 677. Tran TA, Muller S, Chaudahri PJ, et al: Cutaneous carcinosarcoma: adnexal vs. epidermal types define high- and lowrisk tumors. Results of a meta-analysis. J Cutan Pathol. 2005;32:2-11. 678. Swanson SA, Cooper PH, Mills SE, et al: Lymphoepithelioma-like carcinoma of the skin. Mod Pathol. 1988;1:359-365. 679. Walker AN, Kent D, Mitchell AR: Lymphoepithelioma-like carcinoma in the skin. J Am Acad Dermatol. 1990; 22:691-693. 680. Wick MR, Swanson PE, LeBoit PE, et al: Lymphoepithelioma-like carcinoma of the skin with adnexal differentiation. J Cutan Pathol. 1990;18:93-102. 681. Lind AC, Breer WA, Wick MR: Lymphoepithelioma-like carcinoma of the skin with apparent origin in the epidermis—a pattern or an entity. Cancer. 1999;85:884-890. 682. Requena L, Sanchez Yus E, Jimenez E, et al: Lymphoepithelioma-like carcinoma of the skin: a light-microscopic and immunohistochemical study. J Cutan Pathol. 1994;21:541-548.

683. Axelsen SM, Stamp IM: Lymphoepithelioma-like carcinoma of the vulvar region. Histopathology. 1995; 27:281-283. 684. Ferlicot S, Plantier F, Rethers L, et al: Lymphoepithelioma-like carcinoma of the skin: a report of 3 Epstein-Barr virus (EBV)–negative additional cases. Immunohistochemical study of the stroma reaction. J Cutan Pathol. 2000; 27(6):306-311. 685. Kazakov DV, Nemcova J, Mjkyskova I, et al: Absence of Epstein-Barr virus, human papillomavirus and simian virus 40 in patients of central european origin with lymphoepithelioma-like carcinoma of the skin. Am J Dermatopathol. 2007;29:365-369. 686. Hall G, Duncan A, Azurdia R, et al: Lymphoepithelioma-like carcinoma of the skin: a case with lymph node metastases at presentation. Am J Dermatopathol. 2006;28:111-125. 687. Clarke LE, Ioffreda MD: Lymphoepithelioma-like carcinoma of the sin with spindle cell differentiation. J Cutan Pathol. 2005;32:419-423. 688. Carr KA, Bulengo S, Weiss LM, et al: Lymphepitheliomalike carcinoma of the skin. Am J Surg Pathol. 1992;16:909-913. 689. Santa Cruz DJ, Barr RJ, Headington JT: Cutaneous lymphadenoma. Am J Surg Pathol. 1991;15:101-110. 690. Rosso R, Paulli M, Carnevali L: Neuroendocrine carcinoma of the skin with lymphoepithelioma-like features. Am J Dermatopathol. 1998;20:483-486. 691. Yu RCH, Pryce DW, MacFarlane AW, Stewart TW: A histopathological study of 643 cutaneous horns. Br J Dermatol. 1991;124:449-452. 692. Thornton CM, Hunt SJ: Sebaceous adenoma with a cutaneous horn. J Cutan Pathol. 1995;22:185-187. 693. Schwartz JJ: HIV-related molluscum contagiosum presenting as a cutaneous horn. Int J Dermatol. 1992;31:142-144. 694. Perrin C, Goettmann S, Baran R: Onychomatricoma: clinical and histopathologic findings in 12 cases. J Am Acad Dermatol. 1998;39:560-564. 695. Khaitan BK, Sood A, Singh MK: Lichen simplex chronicus with a cutaneous horn. Acta Derm Venereol. 1999;79:243. 696. Agarwalla A, Agrawal CS, Thakur A, et al: Cutaneous horn on condyloma accuminatum. Acta Derm Venereol. 2000;80:159. 697. Wen Y: Syringocystadenoma papilliferum presenting as a cutaneous horn. Br J Dermatol. 2000;142:1242-1244. 698. Song MG, Min HG, Jung SY, et al: Trichilemmal carcinoma with a cutaneous horn. Br J Dermatol. 2000;143:646-647. 699. Pilomatrical horn: a new superficial variant of pilomatricoma. Am J Dermatopathol. 2006;28:426-428. 700. Kitagawa H, Mizuno M, Nakamura Y, et al: Cutaneous horn can be a clinical manifestation of underlying sebaceous carcinoma. Br J Dermatol. 2007;156:180-182. 701. Zhu JW, Luo D, Li CR, et al: A case of penile verrucous carcinoma associated with cutaneous horn. Clin Exp Dermatol. 2007;32:213-214. 702. Blasini W, Hu S, Gugic D, et al: Papillary eccrine adenoma in association with

703. 704.

705. 706.

707. 708. 709.

710. 711. 712. 713.

714.

715. 716.

717.

718. 719.

720. 721.

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cutaneous horn. Am J Clin Dermatol. 2007; 8:179-182. Critobal MC, Urbina F, Espinoza A: Cutaneous horn malignant melanoma. Dermatol Surg. 2007;33:997-999. Arvas L, Livaoglu M, Karacal N, et al: Giant cutaneous horn with naevus sebaceus. J Plast Reconst Aesth Surg. 2007; 60:1168-1169. Willoughby C, Soter NA: Stucco keratosis. Arch Dermatol. 1972;105:859-861. Kocsard E, Ofner F, Coles JF, et al: Senile changes in the skin and visible mucous membranes of the Australian male. Australas J Dermatol. 1958;4:216-223. Shall L, Marks R: Stucco keratoses: a clinico-pathological study. Acta Derm Venereol. 1991;71:258-261. Scott O, Ward J: Stucco keratosis. Br J Dermatol. 1971;64:376-379. Stockfleth E, Rowert J, Arndt R, et al: Detection of human papillomavirus and response to topical 5% imiquimod in a case of stucco keratosis. Br J Dermatol. 2000;143:846-850. Waisman M: Clavus (corn), in Deis DJ (ed). Clinical Dermatology. Philadelphia: Lippincott-Raven; 1995:Unit 1-45. Cure for the corn. Br Med J. 1976;1:113. Waisman M: Callus, in Deis DJ (ed). Clinical Dermatology. Philadelphia: Lippincott-Raven; 1995:Unit 1-43. Patterson J: Palmar and plantar hyperkeratosis, in Deis DJ (ed). Clinical Dermatology. Philadelphia: Lippincott-Raven; 1995:Unit 1-31. Rustad OJ, Vance JC: Punctate keratoses of the palms and soles and keratotic pits of the palmar creases. J Am Acad Dermatol. 1990;22:468-476. Anderson WA, Elam MD, Lambert WC: Keratosis punctata and atopy. Arch Dermatol. 1984;120:884-890. Geusau A, Jurecka W, Nahavandi H, et al: Punctate keratoderma-like lesions on the palms and soles in a patient with chloracne: a new clinical manifestation of dioxin intoxication? Br J Dermatol. 2000;143:1067-1071. Just M, Ribera M, Bielsa I, et al: Keratosis punctata of the palmar creases: report of two cases associated with ichthyosis vulgaris. Br J Dermatol. 1999;141:551-553. Schwartz RA, Rojas-Corona RR, Yu GSM, et al: Keratosis punctata of the palmar creases. Cutis. 1983;32:75-77. Orget M, Sanchez-Conejo-Mir J, Quintana del Olmo J, et al: Keratosis punctata of the palmar creases. J Cutan Pathol. 1989;16:109-111. Weiss RM, Rasmussen JE: Keratosis punctata of the palmar creases. Arch Dermatol. 1980;116:669-671. Rubenstein DJ, Schwartz RA, Hansen RC, et al: Punctate hyperkeratosis of the palms and soles. J Am Acad Dermatol. 1980;3:43-49. Caputo R, Carminati G, Ermacora E, et al: Keratosis punctata palmaris et plantaris as an expression of focal acantholytic dyskeratosis. Am J Dermatopathol. 1989; 11:574-576.

CHAPTER 27 Tumors of Melanocytes Raymond L. Barnhill

CIRCUMSCRIBED PIGMENTED LESIONS COMPOSED OF BASILAR MELANOCYTES

Solar Lentigo Synonyms: Lentigo senilis, liver spot, “ink spot” lentigo Solar lentigo occurs on sun-exposed skin1,2 in more than 90% of the white population older than age 60 years but may be observed in much younger individuals as well.1 Solar lentigines are distinguished from common freckles by their persistence despite absence of sun exposure. Solar lentigines are prominent in xeroderma pigmentosum. The

I. Location of melanocytes in the skin (depth) A. Superficial –Intraepidermal –Papillary dermis –Upper half of reticular dermis B. Deep –Lower half of reticular dermis –Subcutaneous –Fascial II. Disposition of melanocytes A. Intraepidermal 1. Basilar melanocytes (single cell pattern) a. Normal numbers b. Increased frequency –With elongated rete (lentiginous) –Without elongated rete 2. Pagetoid pattern 3. Nested pattern –With lentiginous pattern –Without lentiginous pattern B. Dermal 1. Diffuse, interstitial 2. Patchy perivascular, periadnexal, perineurial 3. Wedge pattern (deep apex of nests, fascicles of melanocytes extend into reticular dermis or subcutaneous fat) 4. Plexiform pattern (discreet nests, fascicles associated with neurovascular or adnexal structures of reticular dermis with intervening normal dermis) 5. Bulbous aggregates, nodules (cellular nests or fascicles with rounded contours, usually extending into reticular dermis, subcutis) 6. Alveolar pattern 7. Maturation or differentiation III. Stroma –Desmoplasia, sclerosis IV. Cell type –Small round or oval cells –Fusiform or spindle cell –Epithelioid cell (abundant cytoplasm, overall enlarged) –Dendritic cell (lengthy, delicate cellular processes) –Intermediate, difficult to classify cell types –All with varying degrees of melanization

photochemotherapy-induced (PUVA) lentigo has been observed in patients receiving long-term methoxypsoralen PUVA for psoriasis.3 Carriers of one or two of the melanocortin-1-receptor (MC1R) gene variants have a 1.5- to 2fold increased risk for the development of numerous solar lentigines.4 CLINICAL FEATURES Solar lentigines are well-circumscribed, round, oval, or irregularly bordered macules of yellow, tan, or brown color, varying in size from about 1 to 3 cm in diameter, with a tendency to confluency.1,2 Solar lentigines occur on sun-exposed areas, predominantly the dorsal aspects of hands and forearms, the face, and the upper chest and back.

CHAPTER 27 ■ TUMORS OF MELANOCYTES

The recognition of the various types of benign, intermediate, and malignant cutaneous melanocytic lesions and their differential diagnoses remain formidable challenges to histopathologists. The gravity of this diagnostic problem is rather extreme because cutaneous melanoma may be lethal, metastases may develop immediately or only after the passage of 15 to 25 years, and there is currently no effective treatment for advanced melanoma, whereas early melanoma is potentially curable by surgical resection. The reasons for the inordinate difficulty of melanocytic lesions relate to the basic lack of knowledge about their biology, their considerable heterogeneity and thus the fact that melanoma may closely mimic many benign melanocytic tumors and the converse, and consequently the lack of reliable criteria for discriminating melanoma from other melanocytic (and sometimes nonmelanocytic) lesions in some proportion of cases. The goals of this chapter are to provide histopathologic and other criteria for the interpretation of melanocytic lesions (Table 27-1), to provide a pragmatic approach to interpretation so that melanoma is recognized if possible but not over-diagnosed, and at the same time that other biologically significant melanocytic neoplasms are not neglected to insure the appropriate management of patients.

Table 27-1 Histologic Criteria for the Classification of Melanocytic Nevi

The “sunburn,” hypermelanotic, or “ink spot” solar lentigo is characterized by a striking jet-black color and a stellate outline.5 The PUVA lentigo has a close clinical resemblance to the solar lentigo, particularly the hypermelanotic type.3,4 HISTOPATHOLOGIC FEATURES In general, the solar lentigo is notable for elongated, club-shaped epidermal rete ridges, basal layer hyperpigmentation most prominent at the tips of the rete, and an increased frequency of basilar melanocytes; however, the melanocytes may not be increased in number (Fig. 27-1).1,2 The epidermis between rete ridges is usually flattened. On occasion, there is slight cytologic atypia of basilar melanocytes.6 There may

615

point such that a lentigo, junctional nevus, or compound nevus may persist indefinitely.14

Lentigo Simplex Synonyms: Simple lentigo, nevoid lentigo

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

 FIGURE 27-1 Solar lentigo. Note the elongated, club-shaped epidermal rete with basal layer hyperpigmentation.

also be hyperkeratosis and rather prominent elongation and anastomosis of rete. Solar elastosis is almost always present. The solar lentigo may show transitions to reticulated seborrheic keratosis, large cell acanthoma, and lichenoid keratosis.7,8 Some solar lentigines develop an associated lichenoid dermatitis and hence are termed lichenoid or lichen planuslike keratosis. Similar to solar lentigines, the PUVA lentigo exhibits lentiginous melanocytic hyperplasia, and low-grade cytologic atypia of melanocytes is occasionally noted.3 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes solar intraepidermal melanocytic proliferations (SIMPs or socalled “lentigo maligna”) with atypia involving sun-exposed skin and pigmented actinic keratosis. In general, SIMP, particularly when present on the central face, in contrast to solar lentigo, is characterized by absence or diminution of the epidermal rete pattern. In addition, in SIMP (lentigo maligna), as compared with solar lentigo, there is usually a greater frequency of basilar melanocytes, occasional junctional nests, and prominent involvement of adnexal epithelium by the lentiginous proliferation of melanocytes. Finally, SIMP is characterized by greater cytologic atypia of basilar melanocytes than should be seen in solar lentigo. Nonetheless, on occasion, one may encounter lesions transitional between solar lentigo and SIMP.

Lentigines And Acquired Melanocytic Nevi

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Lentigines and melanocytic nevi are thought to represent progressive stages of melanocyte migration and proliferation in the skin (see Table 27-1).9-11 Melanoblasts or a related precursor cell are believed to migrate from the neural crest and take

residence in the epidermis early in development.12,13 Proliferation of these cells in the basilar epidermis may give rise sequentially to lentigo and the three subsequent stages of the melanocytic nevus. The proliferation of melanocytes as clusters or nests within the epidermis defines the junctional nevus.11,14,15 The term nevus cell describes the cells within these nests or clusters. These cells are closely related to melanocytes but perhaps functionally somewhat altered by the aggregative pattern of growth.16 These cells tend to lose the dendritic processes that are characteristic of solitary basilar melanocytes and to assume a more rounded morphology. In general, these cells have more abundant cytoplasm, somewhat larger nuclei, and somewhat more prominent nucleoli compared with the basilar melanocyte. Ultrastructurally, nevus cells contain single melanosomes in all stages of development similar to melanocytes.16 Thus, many authors consider nevus cells to be melanocytes and dismiss the need for alternative nomenclature. The presumptive natural history of melanocytic nevi includes proliferation within the epidermis as junctional nests and subsequent migration or “dropping off” of nevus cells into the papillary dermis, where proliferation results in nests of cells.14 According to this hypothesis, eventually all intraepidermal proliferation of melanocytes ceases and the nevi become entirely intradermal.14,15 Nevus cells entering the dermis have a reduction in both proliferation and metabolic activity except for the formation of melanosomes.14,15,17 Thus, the cellularity of a nevus tends to decrease with age; because of this cessation of replication, the nevus cells are gradually replaced by mesenchymal elements—fibrous matrix, mucin, and fat.15 Most dermal nevi are believed to undergo progressive involution, perhaps via acrochordons and eventual shedding.18 This developmental sequence may be arrested at any

CLINICAL AND HISTOPATHOLOGIC FEATURES The simple lentigo is a regular, well-circumscribed macule measuring 1 to 5 mm in diameter and having a uniform light brown, brown, or dark brown color.19 The simple lentigo may occur in a localized or in a widespread pattern as in lentiginosis profusa or in association with certain syndromes, as for example, LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness), multiple lentigines, LAMB (lentigines, atrial myxomas, cutaneous papular myxomas, blue nevi), or Peutz-Jeghers.19 The simple lentigo is defined histologically by three features: (1) increased frequency of basilar melanocytes compared with adjacent normal skin, (2) elongated, club-shaped epidermal rete, and (3) basilar hyperpigmentation of the epidermis (Fig. 27-2) that may extend into the upper portion of the epidermis and stratum corneum.9,11,20 There is increased melanin and an increased frequency of melanocytes at the tips of the elongated epidermal rete with diminished frequency proceeding upward along the sides and between the rete. DIFFERENTIAL DIAGNOSIS Simple lentigo must be discriminated from a freckle and solar lentigo. Simple lentigo differs from freckles because of elongated epidermal rete ridges and an increased frequency of basilar melanocytes. The simple lentigo does not usually have rete ridges as elongated and showing anastomosis or solar elastosis to the degree observed in solar lentigo. In addition, melanocytic hyperplasia may not be present in solar lentigo. A common dilemma is differentiating a simple lentigo from a typical melanocytic nevus or dysplastic nevus. The melanocytic nevus is distinguished by the presence of junctional nests.13

Melanotic Macules and Lentigines of Mucocutaneous Sites Certain pigmented macules may involve mucosal sites such as the conjunctiva, oral mucosa, the vermillion border of

other sites, progressively greater clinical atypicality raises concern about atypical histologic changes and melanoma. Histologically, atypical melanocytic lesions and melanoma on mucosae are characterized by progressively greater frequency of basilar melanocytes and prominent cytologic atypia. In the case of melanoma, the basilar melanocytes often reach confluence along the basal layer in a lentiginous pattern. The melanocytes exhibit continuous marked cytologic atypia. Pagetoid spread is variable and may be absent, minimal, or prominent.

the lip, and genitalia.20-22 Multiple lentigines may involve the oral mucosa and vermillion border as part of the PeutzJeghers syndrome.23,24 CLINICAL FEATURES These lesions are usually solitary or multiple macules measuring 1 to 5 mm and are often characterized by uniform light to dark brown or black homogeneous color.21,22 The borders are generally regular and well defined. Occasional lesions on the genitalia in particular are notable for a mottled appearance and large size, measuring up to 50 mm in greatest diameter.21 The latter clinical appearance suggests melanoma, but such lesions generally do not show atypical changes histologically or eventuate in melanoma.21

HISTOPATHOLOGIC FEATURES The histologic spectrum of these lesions may vary from slight acanthosis of epithelium, the presence or absence of club-shaped rete, and the presence or absence of basilar melanocytic hyperplasia21 (Fig. 27-3). The lesions without melanocytic hyperplasia may be designated as a melanotic macule or melanosis. Lesions with melanocytic hyperplasia are best termed lentigines. As with other simple lentigines, hyperpigmentation of the basilar epithelium is present. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes melanocytic nevi of mucosal sites, atypical melanocytic proliferations, and melanoma. In general, as with melanocytic lesions located on

 FIGURE 27-3 Penile lentigo. There are slightly increased numbers of basilar melanocytes.

COMMON ACQUIRED MELANOCYTIC NEVI The developmental biology and natural history of acquired melanocytic nevi remain poorly understood.14,17,18 The overriding importance and significance of studying benign melanocytic nevi (among all benign melanocytic lesions in general) is their relationship to melanoma. Benign melanocytic nevi are closely linked to melanoma in three important ways; they may be (1) clinical and histologic mimics of melanoma, (2) precursors to melanoma, or (3) clinical and histologic markers of increased risk for melanoma. The prevalence of nevi is related to age, race, and genetic and environmental factors. 25-34 Very few nevi are present in early childhood, but they increase in number, reaching a peak in the third decade of life, and tend thereafter to disappear with increasing age.32 There is a period of particularly rapid development of nevi at puberty. In general, the greatest numbers of nevi are noted among individuals age 20 to 29 years,32 and there are no substantial differences between men and women.32 Whites, in general, have greater numbers of nevi than do darker-skinned groups such as blacks and Asians.33 Furthermore, a greater prevalence of nevi is associated with lighter skin color in whites.34 The frequency of melanocytic nevi on the palms and soles, nail beds, and conjunctivae is also related to race; nevi on these surfaces are more prevalent in blacks than in whites.35 Common acquired nevi range from small, well-circumscribed pigmented macules to raised, flesh-colored lesions, defined by the location of aggregations of “nevus cells” in the skin: junctional nevi have intraepidermal collections of nevus cells, dermal (intradermal) nevi have nevus cells in the dermis, and compound nevi have nevus cells in both areas.19,20

CHAPTER 27 ■ TUMORS OF MELANOCYTES

 FIGURE 27-2 Lentigo simplex. There are elongated epidermal rete and basal layer hyperpigmentation, most prominently involving the lowermost aspects of the rete.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 618

The factors determining the baseline histological phenotype of common acquired nevi include age and programmed natural history; regional microanatomy; genetic factors; physiologic, hormonal, and immunologic factors; environmental factors such as sun exposure, trauma, and other insults; and other poorly understood factors. Owing to the lack of sufficient study as to the spectrum of baseline histology of melanocytic nevi in general, the relationships and attributes shared among banal acquired nevi, nevi of particular anatomic (“special”) sites, and atypical (so-called “dysplastic”) nevi have not been adequately defined. CLINICAL FEATURES Melanocytic nevi are well-circumscribed round or ovoid lesions, generally measuring from 2 to 6 mm in diameter (Table 27-2).19 Although many nevi display slight asymmetry, the borders are usually regular and well defined. The natural history is believed to be a progression from a

Table 27-2 Common Acquired Melanocytic Nevi

Clinical Features Onset childhood, adolescence, third decade, or later 3-6-mm macule, papule (slight to clear elevation), often dome shaped, globoid, polypoid, or papillomatous Round, oval Symmetric Well-defined regular borders Homogenous tan, brown, dark brown Slight accentuation of skin cleavage lines with oblique lighting Histopathologic Features Symmetry Well-circumscribed Regular arrangement of junctional nests of nevus cells, if present Fairly uniform size, shape, position of nests Nests usually at tips of epidermal rete Usually cohesive nests Generally no pagetoid spread Nevus cells usually confined to papillary dermis or superficial reticular dermis Usual transition or maturation from epithelioid to lymphocytoid to spindled nevus cells Mitotic figures uncommon or rare in dermis Usually only minimal nuclear pleomorphism Differential Diagnosis Lentigo Atypical (dysplastic) nevus Melanoma

junctional nevus to a compound nevus and then to a dermal nevus and subsequent involution.14,17,18,20 The junctional nevus is macular with slight accentuation of skin markings visible with side lighting. Junctional nevi display a uniform medium to dark brown color. Compound nevi show variable elevation and in general somewhat lighter shades of brown than do junctional nevi. Dermal nevi are usually more elevated and show lighter shades of brown or even flesh tones compared with compound nevi. However, there is clinical overlap among the three types of nevi.19 Dermal nevi and, to a lesser degree, compound nevi may be dome shaped or papillomatous. Nevi may have a verrucous surface simulating that of seborrheic keratosis. Many nevi contain hairs that are coarser and darker than those in the surrounding skin. HISTOPATHOLOGIC FEATURES Melanocytic nevi are usually symmetric and well circumscribed (Fig. 27-4A). The junctional component as a general rule does not extend peripherally beyond a dermal component,14 if present. The surface profile may vary from being almost flat to dome shaped, polypoid, or papillomatous20 and tends to correlate with type of nevus; for example, junctional nevi are relatively flat, compound nevi are slightly raised, and dermal nevi are often dome shaped, polypoid, or papillomatous (Figs. 27-4 and 27-5). This surface configuration also correlates with anatomic location. Most nevi on acral sites are relatively flat or slightly raised junctional or compound nevi.13,17,18,23,36 In contrast, many nevi on the head and neck, and to a lesser extent on the trunk, are dome shaped or polypoid. The junctional nevus has nesting of nevus cells within the epidermis.17,18,20 A junctional nest or thèque contains five or more nevus cells in close apposition that are cohesive and usually above the basement membrane (see Fig. 27-4B).13,36 The size, shape, location, and spacing of these nests tend to be regular.20 The junctional nests are usually located on the tips of elongated rete rather than on the sides or between rete. Whereas the compound nevus has nevus cells within the dermis as well as junctional nesting, the dermal (or intradermal) nevus has no intraepidermal component (see Fig. 27-4A and Table 27-2).17 Most nevi are compound; on serial sectioning, 80% of apparent dermal nevi have junctional nests.36 Common acquired nevi are generally confined to the adventitial dermis (the finely textured collagenous stroma comprising the papillary dermis

and surrounding adnexal structures and blood vessels).17 Dermal nevi mainly proliferate in and expand the papillary dermis, resulting in progressive elevation of nevus contours commensurate with the volume of nevus cells (see Fig. 27-5).

Maturational Sequence and Cytology of Nevus Cells Nevus cells within junctional nests or the superficial dermis exhibit cohesive rounded nesting, a tendency to synthesis of melanin, and cytologic characteristics of epithelial cells and have been termed epithelioid or type A cells (see Figs. 27-4B and 27-5B).14,17,18,20,,37,38 The latter features refer to the abundant pinkish cytoplasm and the rounded or polygonal configuration of the cells. In general, the nuclei are slightly larger than those of basilar melanocytes.20 The nuclei have a uniform deposition of chromatin, generally with a ground glass basophilic appearance and delicate nuclear membranes.17,19,20,37 Small nucleoli may also be observed. Type B nevus cells in the papillary dermis, usually subjacent to the type A cells, resemble lymphocytes (Fig. 27-5C).20,37 This is caused by a smaller amount of cytoplasm and the tendency to form more compact cords and nests of cells. Generally, the latter nevus cells do not synthesize melanin or form rounded nests.17,19,20,37 The final stage of maturation is that of type C nevus cells with elongated or spindle-shaped morphology and separation by delicate fibrous tissue (see Fig. 27-5D).17,19,20,37,38 The latter cells have considerable resemblance to fibroblasts or Schwann cells. Giant cells are observed in melanocytic nevi and melanoma.17 Nevus giant cells are principally of two types. One type contains tightly packed nuclei with scant cytoplasm and has been called a “mulberry” type giant cell. The molding of nuclei may lead to misinterpretation as a bizarre, atypical nevus cell. This cell type is often in the dermal component of a nevus. The second type has a peripheral, wreathlike arrangement of nuclei with central pink or slightly bluish cytoplasm. The latter cell type may closely simulate or on occasion be identical to a Touton giant cell. This particular giant cell is commonly observed in junctional nests. Another common feature, the pseudonuclear inclusion,37 is an invagination of cytoplasm that on cross-section seems to lie within the nucleus and has the same staining properties as the nevus cell cytoplasm, often a pale or “dusty” ground glass appearance.

A

B

A

C

CHAPTER 27 ■ TUMORS OF MELANOCYTES

 FIGURE 27-4 (A) Lentiginous compound nevus. The epidermis shows lentiginous and junctional nested patterns of melanocytes. (B) Junctional nevus. Dyscohesive nest of epithelioid (type A) nevus cells.

B

D

 FIGURE 27-5 (A) Dermal nevus. There is progression maturation with depth as illustrated by the transition (or differentiation) of melanocytes in B through D. (B) Nests of epithelioid (type A) nevus cells in superficial dermis. (C) Type B (lymphocytoid) nevus cells in dermis. The cells contain minimal cytoplasm and uniform round or oval nuclei. (D) Type C (spindled) nevus cells. The cells resemble Schwann cells and are separated by delicate connective tissue.

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VARIANTS OF ACQUIRED MELANOCYTIC NEVI

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Balloon Cell Nevus

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CLINICAL AND HISTOPATHOLOGIC FEATURES The balloon cell nevus is a rare variant of melanocytic nevus in which more than half of the nevus cell population is composed of balloon nevus cells.39-41 The balloon cells are admixed with typical nevus cells and cells transitional between ordinary nevus cells and balloon cells.39-41 The balloon cells are enlarged with clear, foamy, or vacuolated cytoplasm39 and contain relatively small centrally located, small, round nuclei with uniform basophilic chromatin. Multinucleate balloon giant cells are commonly observed. Electron microscopy of balloon cells has demonstrated progressive vacuolization of melanocytes resulting from the enlargement and lysis of melanosomes. The latter phenomenon is considered to be a degenerative process, but the pathogenesis for these changes has not been established. DIFFERENTIAL DIAGNOSIS The primary entity to be distinguished from balloon cell nevus is balloon cell melanoma (BCM) (see Balloon Cell Melanoma). In contrast to balloon cell nevus, BCM occurs in older patients and is histologically characterized by prominent cytologic atypia and mitotic activity. Other entities entering into the differential diagnosis include xanthomas, granular cell tumors, and clear cell adnexal tumors such as sebaceous neoplasms.39,40

The natural history of halo nevi has not been well documented. However, in general, the hypopigmentation is thought to develop over weeks to months.42-47 The central nevus may persist, or more likely, undergoes involution over months to years. The depigmentation has been ascribed to (1) an immune response against antigenically altered (perhaps atypical) nevus cells 45 or to (2) cell-mediated or humoral (antibody-mediated) reaction against nonspecifically altered melanocytes and possible cross-reactivity with melanocytes at a distant site or sites. 47 CLINICAL FEATURES The central melanocytic nevus may be relatively flat or raised and dark brown to pink (Table 27-3)19,42, and exhibits surface scale or crusting. The central nevus is surrounded by a well-circumscribed annulus of hypo- or depigmented skin, commonly measures 3 to 6 mm in longest diameter, has regular and welldefined borders, and has a homogeneous coloration.19,42 The subsequent course of a halo nevus is variable. Both the central nevus and the halo may persist or regress completely. 42-47 The central nevus may not change or may become irregularly pigmented or pink or red. Probably more than half of all halo nevi undergo complete regression. The period of time associated

HISTOPATHOLOGIC FEATURES The halo nevus may be junctional, compound, or dermal.20,42,44 In the fully evolved stages, the central nevus is associated with a well-circumscribed, dense, almost bandlike infiltrate of mononuclear cells, almost exclusively lymphocytes and histiocytes, that occupies the papillary dermis and permeates nests of nevus cells (Figs. 27-6A and 27-6B; see also Table 27-4). It is often difficult to distinguish nevus cells from surrounding mononuclear cells. Degenerating nevus cells can sometimes be identified in this zone. Homogeneous eosinophilic (apoptotic) bodies, representing degenerated cells, are often observed near the dermal-epidermal junction. Occasional nevus cells within the infiltrate show prominent eosinophilic cytoplasm and enlarged nuclei and may sometimes be pleomorphic. In some instances, the melanocytes closely resemble the cells in Spitz nevi, and thus such lesions may be confused with a Spitz nevus. Although most halo nevi demonstrate no obviously

Table 27-3 Comparison of Halo Nevus and Malignant Melanoma

Clinical Features

Halo Nevus Synonyms: Leukoderma acquisitum centrifugum, Sutton’s nevus, perinevoid vitiligo, perinevoid leukoderma The halo nevus is surrounded by a white (hypo- or depigmented) band or halo and histologically has a dense mononuclear cell infiltrate filling the papillary dermis.42-47 The nevus is almost always acquired, but any type of nevus or melanocytic lesion may develop a clinical halo or histologic halo reaction.42-47 Halo nevi generally affect individuals younger than age 20 years,42,43 and the overall incidence is probably less than 1%. There is no difference in incidence between males and females. Approximately 20% of individuals with halo nevi have vitiligo, and halo nevi have an association with melanoma and atypical (dysplastic) nevi.47

with nevus regression varies from months to as long as several years. Halo nevi are most typically located on the upper back but may be found in any location.19,20,42 Approximately 25% to 50% of affected individuals have two or more halo nevi.

Histopathologic Features

HALO NEVUS

MELANOMA

Central nevus 3-6 mm in size Symmetry of central nevus and halo Regular borders Uniform color of central nevus—tan, brown, or pink—and halo; hypo- or depigmentation Symmetry Usually well circumscribed Mononuclear cell infiltrate orderly with well-defined inferior margin Maturation or differentiation of nevus elements Apoptosis of nevus cells common

Usually >6 mm Asymmetry Irregular borders Haphazard or irregular color

Rete ridges maintained Little or no cytologic atypia commonly Few mitoses in dermal component Atypical mitoses usually absent

Asymmetry Poorly circumscribed Often variation in pattern of infiltrate Usually little or no maturation Apoptosis may be observed Effaced rete ridges common Prominent cytologic atypia Mitoses in dermal component frequent Atypical mitoses may be observed

B

 FIGURE 27-6 Halo nevus. (A) Scanning magnification shows dense mononuclear cell infiltrate that obscures junctional and papillary dermal nests of nevus cells. (B) Note maturation of nevus cells in dense infiltrate.

atypical nevus cells, some display varying degrees of cytologic atypia potentially ranging from slight to severe.20 The cytologic alteration is often reactive, but legitimate neoplastic halo nevi occur. Occasional mitoses are observed in the dermal component of halo nevi and should prompt careful study to exclude melanoma. The peripheral zones of the nevus, corresponding to the clinical halo, show diminished or absent basilar melanocytes and melanin in the basal layer; the central part of the lesion may also show the latter features.42 The papillary dermis in this annulus may also demonstrate slight reparative alteration of the stroma, but

Table 27-4 Recurrent Melanocytic Nevus

Clinical Features Onset ~6 weeks to 6 months after previous surgery Macular pigmentation Limited to scar 4-6 mm (usually <1.5 cm) Often some irregularity of borders Histopathologic Features Effacement of epidermis Dermal scar Intraepidermal melanocytic proliferation limited to area above scar Lentiginous or nested pattern of intraepidermal melanocytes Variable cytologic atypia, usually low grade Differential Diagnosis Atypical (dysplastic) nevus Melanoma

usually no inflammatory cell infiltrates are found. 42 With complete regression, all nevus cells are destroyed, with resulting thickening of the papillary dermis, occasional delicate fibroplasia and frequent mucinous alteration, vascular ectasia, variable residual mononuclear cell infiltrates, and melanophages. There may be complete depigmentation of the epidermis. Occasional nevi with typical hypopigmented halos do not exhibit cellular infiltrates. Most of the infiltrating cells in halo nevi are T lymphocytes and monocytes or macrophages.20,44 There are approximately equal numbers of helper or inducer (CD4+) and cytotoxic or suppressor (CD8+) T cells. The nevus cells also express class I human leukocyte antibody (HLA) antigens to a much greater extent than class II HLA antigens. These findings suggest a specific cell-mediated immune response in halo nevi.44 DIFFERENTIAL DIAGNOSIS The halo nevus must primarily be distinguished from melanoma. This distinction is not a significant problem for halo nevi showing little or no cytologic atypia (see Table 27-3). Such halo nevi generally are small (ie, <5-6 mm), symmetric, display maturation, and have an orderly appearance compared with melanoma. Halo nevi are notable for the symmetry and welldefined inferior margin of the mononuclear cell infiltrate contained in the papillary dermis. An important feature is the maturation of nevus cells. Although mitotic figures may be noted in the dermal component of any melanocytic lesion, including halo nevi, more than a

few mitoses, mitoses in the deepest dermal cells, and atypical mitoses are of particular concern.

Lentiginous Junctional Nevus (Nevoid Lentigo; “Jentigo”) Lentiginous Compound Nevus These nevi show a prominent lentiginous pattern of the epidermis, that is, elongated epidermal rete, lentiginous melanocytic hyperplasia, and basal layer hypermelanosis (see Fig. 27-4).20 The degree of junctional nesting may vary from almost none (nevoid lentigo) to prominent nesting.

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DIFFERENTIAL DIAGNOSIS Lentiginous nevi must be distinguished from atypical (dysplastic) nevi, SIMP, and solar melanoma in situ. Lentiginous nevi lack the increased frequency of melanocytic proliferation and the cytologic atypia found in atypical (dysplastic) nevi, SIMP, and solar melanoma in situ. In addition, SIMP and solar melanoma in situ often exhibit an effacement of the epidermal rete and pronounced involvement of adnexal structures in contrast to lentiginous nevi.

Neural Nevus (Neurotized Nevus) This term indicates complete or nearly complete neurotization (maturation to type C cells) of a dermal nevus (see Fig. 27-5D).17,18,20,37 In some instances, it may not be possible to distinguish this lesion from a solitary cutaneous neurofibroma. However, nesting of cells suggests a nevus.

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Nevus Spilus (Speckled Lentiginous Nevus)

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

The nevus spilus is a slightly hyperpigmented (tan) macular lesion that contains hyperpigmented foci or speckles that may be either flat or raised.19,20,48-53 The nevus spilus may be congenital or acquired and often becomes more prominent after solar exposure.20 There are several reports of melanoma arising in association with a nevus spilus.53 CLINICAL AND HISTOPATHOLOGIC FEATURES The tan macular area commonly varies from less than 1 cm to 10 or 20 cm in greatest diameter.20,48-53 The hyperpigmented speckles are approximately 1 to 6 mm in greatest diameter and may be macular or papular. Large nevi spili may be unilateral, segmental, or zosteriform (speckled zosteriform lentiginous nevus).20 The tan macule or patch exhibits lentiginous melanocytic hyperplasia associated with elongated epidermal rete ridges. Whereas the hyperpigmented macular foci show lentiginous melanocytic hyperplasia, or junctional nevus, the papular foci contain junctional or compound nevus elements. The histologic changes of Spitz nevi have been noted in the raised speckled area. Varying degrees of architectural disorder or cytologic atypia may be observed in nevus spilus.52,53 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis includes large or congenital lentigo, congenital nevus, and

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atypical (dysplastic) nevus. Unless the dark speckles, which usually show junctional or compound nevus, are present in the biopsy, the histology of nevus spilus may be indistinguishable from lentigo. The clinical features should enable one to recognize nevus spilus.

Recurrent Melanocytic Nevus Synonyms: Pseudomelanoma, persistent or recurrent melanocytic nevus The recurrent melanocytic nevus shows pigmentation at the site of previous nevus removal or biopsy.54,55 Most of the recurrences have followed a shave excision. Approximately 50% of cases recur within 6 months.54,55 This phenomenon is thought to result from an intraepidermal proliferation of residual melanocytes, possibly from nearby sweat ducts, hair follicles, or intraepidermal melanocytes.55 CLINICAL FEATURES These lesions are characterized by circumscribed hyperpigmentation within a scar from the previous surgical procedure for nevus removal (see Table 27-4).19,54,55 The lesion is usually macular and exhibits variable irregularity of borders and pigment pattern.54,55 Most recurrent nevi measure 4 to 6 mm in diameter and almost all are smaller than 1.5 cm. HISTOPATHOLOGIC FEATURES Histologic examination usually reveals intraepidermal melanocytic proliferation confined to the area above a dermal scar (Fig. 27-7A;

Table 27-5).54,55 There is effacement of the epidermal rete ridge pattern and variable lentiginous or nested intraepidermal proliferation of melanocytes (Fig. 27-7 B). The melanocytes often contain abundant melanin and relatively uniform nuclei but occasionally exhibit low-grade cytologic atypia. Dysplastic nevi tend to recur with fairly similar grades of cytologic atypia compared with the original lesion removed. Frequently, residual dermal nevus cells are seen beneath the superficial dermal scar. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes recurrent atypical (dysplastic) nevus, lentiginous melanocytic proliferations developing in melanoma scars, and recurrent melanoma. In general, recurrent melanocytic nevus is usually but not always confined to the area of the surgical scar, appears within 6 months of surgery, and exhibits well-defined margins and a banal histologic picture. Recurrent atypical (dysplastic) nevi may have greater cytologic atypia than conventional recurrent nevi. Clinical features suggesting melanoma include irregular pigmentation, recurrence beyond the confines of the surgical scar, and a longer interval to recurrence (>6 months). Review of the previous biopsy is mandatory to rule out an atypical proliferation, particularly melanoma. Reexcision of a recurrent nevus is not necessary unless abnormal features are present, for example, extension of the lesion beyond the surgical scar or substantial cytologic atypia.

B

 FIGURE 27-7 Recurrent melanocytic nevus. (A) Scanning magnification shows regenerative melanocytic proliferation along and subjacent to the effaced epidermis. A dermal scar lies between the epidermis, the regenerative superficial melanocytic dermal elements, and the original dermal nevus component previously biopsied (lower center of the field). (B) There is irregular single-cell and nested melanocytic proliferation at the dermal-epidermal junction. However, significant cytologic atypia of melanocytes is absent.

Table 27-5 Unusual Genital or Flexural Melanocytic Nevus

MELANOCYTIC NEVI FROM PARTICULAR ANATOMIC SITES (MELANOCYTIC NEVI FROM “SPECIAL SITES”) The anatomic location of melanocytic nevi influences their histopathology and importantly may introduce particular histological properties that require distinction from melanoma.14,56-72 Over the past two decades, acral and vulvar nevi have received the most detailed study in this regard. However, recent reports have suggested that melanocytic nevi from practically every anatomic region exhibit histologic properties that mark them as unique. Unfortunately, at present, there are no sufficiently large, comprehensive and rigorously controlled studies that provide any definitive conclusions about the differences in baseline histology among nevi from many different anatomic sites in relationship to age, gender, the considerable heterogeneity of nevi, and other factors. Because the latter data are lacking, one

Melanocytic Nevus of Acral Skin Synonym: Melanocytic acral nevus with intraepidermal ascent of cells (MANIAC) Melanocytic nevi of acral skin (atypical melanocytic nevi [AMN]) may be defined as to their localization to glabrous (non–hair bearing) skin, the entire surface of the hands and feet (including hair-bearing dorsal aspects), or potentially inclusive of other sites such as the elbows and knees.56-60 Recently an additional subset of atypical lesions comprised predominately of atypical nevi from the distal lower extremities with features of acral nevi has been described.61 Without question, the histology of acral nevi involving glabrous skin is influenced by the dermatoglyphics (the ridges and furrows of skin lines), the thick stratum corneum, the concentration of eccrine glands, absence of hair follicles, and other factors such as repetitive mechanical trauma. The major clinical concern with AMN is their distinction from acral melanoma. CLINICAL FEATURES Acral melanocytic nevi are usually acquired macular or only slightly elevated, uniform brown or dark brown lesions commonly indistinguishable from simple lentigines.14,56-60 They may exhibit striking striate appearances (linear pigment patterns) corresponding to the dermatoglyphics (ie, the skin lines of glabrous skin). They are usually relatively small (<5-7 mm), well-circumscribed, and symmetrical lesions with regular borders. Nonetheless, congenital and atypical clinical variants occur and show a spectrum of abnormalities, including larger diameter, asymmetry, irregular borders, and variation in pigment patterns that require histologic distinction from melanoma. HISTOPATHOLOGIC FEATURES At scanning magnification, the most typical AMNs usually measure 2 to 8 mm (mean,

~5 mm) in diameter, are symmetrical, well-circumscribed, and have a relatively flat or slighty elevated topography (Fig. 27-8A).56-60 The vast majority are junctional or compound nevi, and a small proportion is entirely dermal. AMN usually show regular junctional nesting of melanocytes with absent to low-grade cytologic atypia. Junctional nests may be large, vertically oriented, and show transepidermal elimination (Figs. 27-8B and 27-8C). A characteristic property of AMN is the presence of vertically oriented melanin columns (in ≤61% of palmar and plantar nevi) in the stratum corneum.60 The dermal components, if present, are usually limited to the papillary and superficial reticular dermis. Importantly, AMN may commonly exhibit features that raise suspicion for melanoma such as large diameter (>6-7 mm), asymmetry (≤44%), poor circumsciption (≤63%), lentiginous melanocytic proliferation (≤54%), pagetoid melanocytosis (up to 86.5%), architectural disorder (5.4% in one study), and moderate to severe cytologic atypia (Figs. 27-8C and 27-8D).56-61 It is of interest that the abnormal features of asymmetry, poor circumsciption, and absence of melanin columns correlate with plane of section of AMN parallel to skin lines (versus symmetry, sharp circumsciption, and the presence of melanin columns correlating with plane of section perpendicular to skin lines). DIFFERENTIAL DIAGNOSIS As with all melanocytic nevi, there is considerable heterogeneity of AMN, and a number of variants are observed on a regular basis, including lentiginous AMN, AMN with architectural variation and cytologic atypia, congenital pattern nevi, pigmented spindle cell nevi, and Spitz nevi or tumors. Suffice to say that AMN, as with all nevi, exhibit a broad spectrum of architectural and cytologic phenotypic variations that have not been sufficiently studied to establish their biologic significance. The fundamental problem is the distinction of AMN and their (many and atypical) variants from acral melanoma. Multiple standard criteria are needed because no single criterion is sufficient for this distinction, and there are exceptions to every criterion. Thus, the greatest diameter (eg, <5-6 mm vs >7 mm), symmetry versus asymmetry, sharp circumscription versus poor circumscription, degree of irregular and discohesive junctional nesting patterns, degree of lentiginous melanocytic proliferation, degree and proportion of lesion involved by

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Clinical Features Occurrence in premenopausal women (range, 14-40 years of age) Often enlarged, ≤ 10 mm in diameter Other features not well studied Histopathologic Features Symmetry Usually well circumscribed Enlarged junctional nests with diminished cohesion Lentiginous melanocytic proliferation Confluence of cells, nests along dermalepidermal junction Variation in size, shape, position of junctional nests Extension of intraepidermal component along adnexal epithelium Generally no pagetoid spread Generally no lateral extension Fibroplasia common, often lamellar Lymphocytic infiltrates Cytologic atypia, often slight to moderate Somewhat enlarged intraepidermal melanocytes, often abundant cytoplasm Multinucleate nevus giant cells Maturation of nevus cells common Differential Diagnosis Vulvar melanoma Spitz nevus Atypical nevus

again has the fundamental problem of defining how common acquired (or banal) nevi, clinically and histologically atypical nevi, and nevi from “special sites” differ. Ultimately, the issue is clarifying and quantifying the biologic significance of the various phenotypic properties of melanocytic nevi. Many of the studies reported thus far have not addressed inherent biases such as the origin of study subjects (eg, population based versus various referral biases), how nevi have been selected for removal, and insufficient numbers of study subjects.

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C

D

 FIGURE 27-8 Compound nevus of acral skin. (A) Scanning magnification shows an overall symmetry and fairly regular nesting pattern of melanocytes in at the dermal-epidermal junction and in the superficial dermis. (B) Note the rather large, well-defined, vertically oriented junctional nests. (C) The melanocytes in junctional nests show slight nuclear enlargement and pleomorphism. (D) This field shows lentiginous melanocytic proliferation and focal upward migration of melanocytes in the epidermis.

pagetoid melanocytosis, nondisruption of epidermis versus effacement and obliteration of epidermis, degree of cytologic atypia of melanocytes, and degree of host response present are among the most important criteria. Particular features favoring an acral nevus are small size (<5 mm), symmetry, sharp circumscription, large and vertically oriented junctional nests, transepidermal elimination of junctional nests, lentiginous melanocytic proliferation confined to (and not contiguous between) the epidermal retia, only limited degrees of pagetoid scatter, discrete melanin columns in the cornified layer, and absent or only slight to moderate cytologic atypia. On the other hand, acral melanomas usually exhibit size larger than 7 mm, asymmetry, poor circumscription, contiguous lentiginous melanocytic

proliferation, more developed pagetoid spread, and high-grade cytologic atypia compared with acral nevi. The dendritic processes of melanocytes often extend throughout the epidermis and reach the granular layer. It is important to realize that a small proportion of acral melanocytic lesions prove to be so difficult that they cannot be confidently interpreted as benign or malignant. Such lesions should be reported descriptively and excised with adequate margins, and the patients should be followed cautiously for lesional recurrence.

Unusual (or Atypical) Melanocytic Nevi of Genital Skin Synonyms: Atypical melanocytic nevi of the genital type, atypical genital nevi

Melanocytic nevi, including conventional acquired, congenital, Spitz, blue nevi, and so on, involving the vulva have been detected in about 2.3% women undergoing routine examination.62 Particular melanocytic nevi occurring on the vulva estimated to comprise about 5.1% of vulvar nevi in one study, the male genitalia such as the scrotum (and in other flexural locations such as the umbilicus and axillae) are thought to have distinctive histopathologic features compared with most nevi from nongenital sites.62-65 As with all melanocytic lesions, how such nevi are selected for removal may influence these observations. In fact, one may observe these features in nevi from any site, although probably much less commonly. The significance of the clinical and histologic features of such genital nevi in terms of melanoma risk and association

CLINICAL FEATURES Such nevi are observed in women age 6 to 54 years (median, 26 years) in one study. Vulvar nevi range in size from 2 to 20 mm (mean, 6 mm; median, 5 mm) and commonly involve

the labium majus, mons pubis, labium minus, clitoris, and perineum.62-65 They are often relatively flat, but not necessarily so; they generally have fairly regular borders; and often have a complex mahogany color, that is, an admixture of tan, brown, and red (see Table 27-5). Among 56 recently reported genital nevi, 45% were judged to be clinically atypical.65 HISTOPATHOLOGIC FEATURES In general at scanning, these atypical genital nevi (AGN) possess an overall symmetry and are well circumscribed (Table 27-6).62-65 The most notable features include enlarged junctional nests; variation in the size, shape, position, and reduced cohesion of junctional nests; often horizontal confluence and bridging of nests; and intraepidermal melanocytes are commonly slightly enlarged with abundant eosinophilic cytoplasms resembling the epithelioid cells in Spitz nevus (Figs. 27-9). Cytologic atypia of melanocytes is usually present and generally of slight to moderated degree in about 80% of cases but may be severe on occasion.64,65 Focal pagetoid melanocytosis and lentiginous melanocytic proliferation are noted uncommonly. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes genital melanoma, conventional acquired nevi, and Spitz tumors. Although abnormal architecture

Table 27-6 Uncommon Findings in or Presentations of Melanocytic Nevi Agminated (speckled) lentiginosis or melanocytic nevi74

Amyloid deposition75 Angiomatous, pseudovascular pattern76

Cockarde (Cockade) nevus77

Keratinous cyst rupture, folliculitis, abscess formation78,79 Meyerson nevus80,81 Nevus (osteonevus) of Nanta82 Perinevoid alopecia83

Psammoma bodies84

Circumscribed grouping of hyperpigmented macules or papules equivalent to nevus spilus but with absence of background macule. Hyperpigmented foci are lentigines, junctional, or compound nevi Degenerative nevus cells Nevus cell pattern resembles vascular or lymphatic spaces, possibly secondary to tissue shrinkage, processing Peripheral pigmented halo (junctional nevus usually) with intervening nonpigmented annulus about central nevus (junctional or compound nevus) Enlargement, change in color suggesting melanoma Subacute eczematous epidermal changes associated with nevus, often forming eczematous halo Bone formation in nevus (metaplastic ossification) Hair loss associated with scalp nevi Inflammatory reaction resembling halo nevus but associated with hair follicles Probably associated with degenerative nevus cells

and cytologic atypia may be present in AGN, these features are not as developed as in melanoma. Melanoma usually demonstrates larger diameter, asymmetry, poor circumscription, contiguous proliferation of basilar intraepidermal melanocytes, prominent pagetoid spread, greater cytologic atypia, and more developed host response. Moreover, vulvar melanoma is rare and occurs in older women (average age, ~65 years) compared with these AGN (see Table 27-6). Although AGN are not considered “dysplastic” by many, such a distinction may lack credibility for many lesions because of commonly shared features. Thus, in a general sense, both AGN and “dysplastic” nevi qualify as nevi exhibiting architectural disorder and cytologic atypia. Spitz nevi and tumors are recognized by typical architecture and enlarged monomorphous epithelioid or fusiform cells.

Melanocytic Nevi of Flexural Skin, the Breast, and Milkline Some proportion of melanocytic nevi involving flexural surfaces such as the umbilicus, axillary and inguinal folds, perianal areas, breast, and milkline are believed to show histological properties shared with genital melanocytic nevi.66,67 In general, these nevi have not been sufficiently studied to rigorously characterize their histologic phenotype versus that of other nevi. In a study of 40 flexural nevi, 55.5% demonstrated enlarged junctional nests with variations in size, shape, and position of nests and frequent discohesion of melanocytes (Fig. 27-10).66 Cytologic atypia judged to be of slight to moderate degree was noted in a majority of cases. Umbilical nevi are often distinctive because of dermal scarring. Because of their localization to skin folds, axillary nevi commonly have polypoid or papillomatous surface topographies.

CHAPTER 27 ■ TUMORS OF MELANOCYTES

with an atypical nevus phenotype has not been completely elucidated and requires further study. Some of the unusual genital nevi previously reported exhibit features intermediate between ordinary nevi and melanoma, and thus, share features with so-called “dysplastic” nevi. Irrespective of site or nomenclature, particular nevus phenotypic characteristics such as diameter larger than 8 mm, irregular borders, irregular coloration, and moderate to severe cytologic atypia of melanocytes are established risk factors for melanoma. However, of critical importance is the knowledge that such peculiar genital nevi may exhibit features that may result in misinterpretation as melanoma with potential catastrophic consequences for children, adolescents, and women of any age. Although there are insufficient data at present to be certain as to the biologic potential of such nevi, there is no evidence of either documented progression to melanoma or metastases from such lesions. In only one instance has local recurrence occurred after removal of a vulvar nevus with positive surgical margins.65

Melanocytic Nevi of the Scalp and Nearby Sites Although data are limited, about 0.5% of melanocytic nevi are estimated to involve the scalp. Because the first report of atypical-appearing nevi on the scalps of children,68 there has been ongoing debate as to the biologic significance of these lesions and their relationship to “dysplastic” nevi and melanoma.69,70 The importance of scalp nevi directly relates to (1) the development of atypical nevi in the scalps of children may be among the first manifestations of an atypical nevus phenotype and increased risk for melanoma; (2) the

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C  FIGURE 27-9 Compound nevus of the vulva. (A) The nevus is large and shows a protuberant (“mushroom-like”) topography with bulky dermal component. (B) Note the large confluent nests of nevus cells along dermal-epidermal junction. (C) The melanocytes are enlarged epithelioid cells with abundant cytoplasms and display some nuclear enlargement and variation in nuclear contours. Multinucleate forms are present.

scalp is among the most common sites of pediatric melanoma; and (3) because of the latter considerations and striking histologic features suggesting melanoma, such scalp nevi are overinterpreted as melanoma on a regular basis. (RL Barnhill, personal observations, 2009). Without question, melanocytic nevi on the head and neck in more or less close proximity to the scalp show comparable histologic features. Thus, for example, nevi from the auricular area have been reported to show many of the same histologic attributes as scalp and other nevi from other “special sites”.71,72 CLINICAL FEATURES Such nevi are observed in all age groups and range in size from 2 to more than 20 mm (mean, ~5 mm). They are often symmetrical, relatively flat, generally have fairly regular borders, and often have fairly uniform tan to brown colors. However, a proportion of scalp nevi are clinically

atypical, as evidenced by diameter larger than 5 mm, asymmetry, irregular and illdefined borders, and complex coloration. A clinical variant, the “eclipse” nevus (with a tan center and an irregular brown peripheral rim), often involves the scalp.73 HISTOPATHOLOGIC FEATURES At scanning magnification, scalp nevi (SMN) are usually symmetrical and well circumscribed, and the epidermal rete are usually elongated in a regular pattern (Fig. 27-11A).69,70 However, the most notable characteristics that mark these nevi include large junctional nests of melanocytes; variation in the size, shape, position, and reduced cohesion of junctional nests often with horizontal confluence and bridging; nests on melanocytes closely associated with or infiltrating skin appendages; nevus cell infiltration of the reticular dermis (in a “congenital” pattern); and confluent

dermal nests often without conventional maturation (Fig. 27-11B). Rarely, dermal mitotic activity is present. The melanocytes are commonly enlarged round or ovoid cells with abundant pale, eosinophilic, or “dusty” pigmented cytoplasms (see Fig. 27-11). The nuclei are often enlarged with some pleomorphism, readily observed nucleoli, and occasionally some hyperchromatism. Thus, based on the latter findings, cytologic atypia is judged present in many of these nevi and generally of slight to moderate degree. Focal pagetoid melanocytosis and lentiginous melanocytic proliferation are noted uncommonly. Papillary dermal fibroplasia and lymphocytic infiltrates are seen with some frequency. DIFFERENTIAL DIAGNOSIS Differentiation of SMN from melanoma is critical and cannot be overemphasized, particularly in children and adolescents. Although,

A

CHAPTER 27 ■ TUMORS OF MELANOCYTES

 FIGURE 27-10 Compound nevus from the umbilicus. The lesion shows some effacement of the epidermis and strikingly confluent and hypercellular junctional nesting of melanocytes. The melanocytes exhibit nuclear enlargement and pleomorphism. The nevus otherwise shows maturation and no other characteristics suggesting melanoma.

as mentioned, the scalp is a common site of pediatric melanoma, one must always bear in mind that childhood melanoma is so rare as to be almost nonexistent. Thus, the pathologist must have overwhelming criteria for melanoma in this age group and the concordance of one or more experts. Despite the deceptive features suggesting melanoma mentioned above— large, confluent and irregular junctional nesting and enlarged and atypicalappearing melanocytes—SMN are usually small (<5 to 6 mm), fairly symmetrical, and sharply circumscribed; usually exhibit a regular nondisrupted appearance of the epidermis and a distinctly nevus-like nested architectural configuration with some maturation; and usually fail to show significant pagetoid scatter (the melanocytes are actually fairly uniform, and dermal mitoses are lacking). Melanoma usually demonstrates larger diameter, asymmetry, poor circumscription, effacement, and obliteration of the epidermis, contiguous proliferation of intraepidermal melanocytes, prominent pagetoid spread, greater cytologic atypia, and a more developed host response. It is clear from the above accounts that many SMN, whether considered “atypical” or deviant or not, show considerable, if not complete, overlap with “dysplastic” nevi. Thus, many are one and the same, and the question then becomes one of nomenclature and biologic significance. An empirical approach, as suggested throughout this chapter, is to consider all melanocytic nevi as part of a biologic continuum and to try to ascertain what properties (if any) they exhibit are important with respect to melanoma risk and that may reliably predict progression to melanoma.

Uncommon Findings in or Presentations of Melanocytic Nevi Unusual findings in or presentations of melanocytic nevi41,74-84 are described in Table 27-6.

B  FIGURE 27-11 Compound nevus from the scalp. (A) The nevus demonstrates large confluent nests of nevus cells along dermal-epidermal junction with bridging and prominent cellularity. The lesion also characteristically shows involvement of the reticular dermis and follicular epithelium by nests of melanocytes suggesting a “congenital pattern.” However, the nevus fails to show pagetoid melanocytosis, effacement of the epidermis, or dermal mitoses. (B) The melanocytes are enlarged, round to ovoid cells with some nuclear enlargement and pleomorphism.

CONGENITAL MELANOCYTIC NEVI AND ASSOCIATED NEOPLASMS: CONGENITAL AND CHILDHOOD MELANOMA The term congenital nevus denotes presence at birth.85,86 However, congenital melanocytic nevi (CMN) also frequently differ from common acquired nevi because of overall size, depth of involvement by nevus cells, adnexal or vascular

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involvement, and diversity of neurocristic differentiation.87 Most melanocytic nevi greater than 1.5 cm in diameter are probably congenital.85 However, smaller CMN may be indistinguishable from acquired nevi.86,88,89

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Incidence and Melanoma Risk

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The significance of CMN, particularly the larger varieties, relates to their risk for progression to melanoma and cosmetic disfigurement.90-94 There is considerable controversy surrounding the melanoma risk and management of CMN. Accurate estimates of melanoma risk associated with CMN are difficult to obtain. The potential risk is probably related to the size of the CMN; that is, the larger the nevus, the greater the risk.95-98 The prevalence of relatively small CMN is approximately 1%; consequently, these nevi are fairly common.90,96 However, one particular problem associated with estimating melanoma risk in these nevi is the lack of specificity of histologic features for CMN of this size.88 At present, melanoma risk associated with small- and medium-sized CMN is thought to be low.96 Giant CMN are rare, with an incidence of approximately one in 20,000 births.99 Very high estimates of melanoma risk associated with large or giant CMN are partially explained by referral bias. On the other hand, a number of studies confirm substantial melanoma risk linked to large or giant (>20 cm) CMN. A lifetime risk of approximately 6.3% has been estimated from the Danish Birth Registry.106,107 A recent prospective study involving 92 patients with large or giant CMN demonstrated a cumulative 5-year life-table risk of 4.5% and a standardized morbidity ratio of 239 for the development of melanoma.97 CLINICAL FEATURES The clinical characteristics of CMN are related to size and age.14,85,86,90,91 Small congenital nevi smaller than 1.5 cm in greatest diameter may be indistinguishable from common acquired nevi, and documentation at birth may be the only means of confirming a congenital origin. In general, CMN in the range of 1.5 to 10 or 20 cm in diameter have a well-circumscribed, elongated or oval morphology and an orderly distribution of pigment (Table 27-7).85 Most of these nevi are brown but range in color from tan to dark brown or black. A speckled or mottled appearance is also common, and many have coarse, terminal hair follicles. Giant CMN often involve a large portion of the dorsal surface of the individual

Table 27-7 Small- and Medium-Sized Congenital Nevi

Table 27-8 Large or Giant Congenital Nevi

Clinical Features May occur anywhere, but head and neck common Symmetry <1.5-20 cm Round, oval, elongated Tan, brown, dark brown, often mahogany, or black Slightly raised plaque Pebbled or rugose surface Often coarse hairs Histopathologic Features Often lentiginous melanocytic hyperplasia Junctional, compound, or dermal Small congenital nevi (<1.5 cm) Involvement of upper half of reticular dermis common –Interstitial pattern –Perivascular, periadnexal pattern Medium-sized congenital nevi (1.5-20 cm) Involvement of reticular dermis, particularly lower half –Diffuse dermal involvement by nevus cells –Interstitial pattern –“Inflammatory” pattern Nevus cells within appendages, blood vessels, nerves Differential Diagnosis Becker nevus Atypical (dysplastic) nevus Epidermal nevus Congenital lentigo Melanoma

Clinical Features Symmetry >20 cm Involvement of major anatomic area, segmental Often dorsal involvement Occasional congenital deformities Well-defined borders Brown, dark brown, black “Animal pelt” feature, rugose, doughy Soft tissue hypertrophy Hypertrichosis Scattered satellite nevi distant from giant nevus Involvement of meninges common for head and neck nevi Histopathologic Features Lentiginous melanocytic hyperplasia common Usually compound or dermal Reticular dermal involvement, usually superficial and deep –Diffuse –Interstitial –Perivascular, periadnexal Subcutaneous involvement, septal >> lobular Maturation Neural differentiation, neuroid, or neurofibromalike pattern on occasion Wagner-Meissner–like corpuscles Fascial or muscle involvement Cellular nodules in reticular dermis on occasion Blue nevus component on occasion Spindle and epithelioid cell nevus component on occasion Hamartomatous elements –Cartilaginous differentiation –Adipose differentiation Differential Diagnosis Becker nevus Neurofibromatosis Melanoma Peripheral nerve sheath tumors

and are most commonly raised and exhibit a variably papular, lumpy, rugose, or even verrucous surface (Table 27-8). The skin surface may be shiny or contain numerous terminal hairs. Soft tissue hypertrophy may mimic changes found in neurofibromatosis. The color is most often dark brown or black, but considerable variegation of pigment is often noted. Giant CMN are also remarkable for scattered, smaller satellite nevi on the skin surface beyond the garment nevus.90,91 HISTOPATHOLOGIC FEATURES The histologic characteristics observed in CMN are related primarily to the size of the nevus and to a lesser degree to the age of the individual (see Tables 27-7 and 27-8).20,86,88,89,92,94,102,103 Evidence now suggests that the depth of nevus cell involvement throughout the dermis and subcutis is established early and remains for the most part unchanged.103 However, the superficial (intraepidermal

and superficial dermal) components of a CMN may mature in some instances. It is believed that immature, disordered patterns such as pagetoid spread, large irregular nests, and cytologic atypia do diminish (or mature) with time.103,104 However, the latter conclusion must be made with some circumspection because of the rather prominent morphologic heterogeneity throughout many CMN.103 HISTOPATHOLOGIC FEATURES OF RELATIVELY SMALL CMN Small CMN may display considerable heterogeneity.86,88 Some may be entirely junctional and indistinguishable

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CHAPTER 27 ■ TUMORS OF MELANOCYTES

from acquired nevi.86,103,105 Many small nevi, particularly those measuring less than 1.5 cm in diameter, also demonstrate what has been termed a superficial pattern89,103 (ie, junctional nests alone or a compound or entirely dermal pattern with aggregates of nevus cells extending to no greater depth than the upper half of the reticular dermis). Such a pattern may be seen in a significant percentage of acquired nevi. Up to 28% of acquired nevi may also exhibit nevus cells extending into the lower two-thirds of the reticular dermis.88 Histologic features considered characteristic of CMN85,88,89 include involvement of the lower third of the reticular dermis by nevus cells, close association of nevus cells with or within appendageal structures, and neurovascular structures at the mid-reticular dermal level or deeper (Figs. 27-12).85 In contradistinction to acquired nevi, CMN are notable for nevus cells being disposed, “fanning out,” or splaying collagen bundles of the reticular dermis as single cells, files, sheets, and cords of cells (two cells in tandem). CMN also show a typical pattern of maturation of nevus cells from superficial to deep dermis. Near the epidermal surface, nevus cells tend to be aggregated in nests and may exhibit epithelioid cell features.85,105 With increasing depth, the nevus cells often demonstrate greater separation (ie, splaying) and slightly diminished cellular and nuclear sizes. Extension of nevus cells into the subcutaneous fat is also a common feature, particularly in larger varieties of congenital nevi.89,99 With increasing sizes of CMN, there is greater tendency for deep dermal, appendageal structures, and neurovascular involvement.88,89,94,103 However, even some congenital nevi less than 1.5 cm in diameter tend to involve eccrine and follicular units at the mid-reticular dermal level or deeper, much more commonly than acquired nevi. Because of histologic overlap between small CMN and acquired nevi, there are no features with 100% specificity and 100% sensitivity for recognition of small CMN.88 Nonetheless, the presence of nevus cells in the lower half of the reticular dermis, in an appendageal or neurovascular pattern, or both will enable one to detect a majority of small CMN.88 Absence of the latter features does not preclude a congenital origin.88,106 Giant CMN, most medium-sized CMN, and a small percentage of nevi less than 10 cm in diameter tend to exhibit distinctive features (see Table 27-8). Probably the most characteristic feature

B

C  FIGURE 27-12 (A) Small congenital nevus. Discrete nests of nevus cells are present in the dermis. (B) Giant congenital nevus. Nevus cells diffusely infiltrate dermis with some maturation. (C) At higher magnification, the nevus cells show small, fairly uniform nuclei.

is the diffuse proliferation of nevus cells throughout the reticular dermis with frequent extension into the subcutaneous fat.85,89,90,94,103 There is usually a grenz zone separating the epidermis from the dermal infiltration of nevus cells85,94;

however, junctional nests may be noted. The nevus cells tend to infiltrate collagen in an orderly and uniform pattern. The nevus cells also often extend along the fibrous trabeculae of the subcutaneous fat and occasionally infiltrate fat

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

lobules.85,103 Aggregates of nevus cells also tend to cuff or infiltrate follicular epithelium, sebaceous glands, eccrine ducts and glands, the perineurium of nerve twigs, and the walls of vascular structures.85 The perivascular and periadnexal cuffing by nevus cells may closely resemble an inflammatory process such as a gyrate erythema. Foci of hypercellularity are also sometimes noted within the dermal population of cells.103 A subset of large or giant CMN are also characterized by spindle cell or neuroidal differentiation resembling a neurofibroma (neuroid CMN).90,107 The constituent cells have a wavy configuration and are embedded in a delicate stroma. Neural differentiation resembling neural tubules or pseudo-Meissnerian structures may also occur.85,90,107 Such nevi may be associated with congenital anomalies such as club foot and spina bifida.107 Large CMN may also show a variety of other patterns, suggesting that they are indeed hamartomas of neural crest differentiation.102 Such nevi may contain heterologous elements such as cartilage, bone, adipose tissue, vascular malformation,

Congenital Nevi with Atypical Features ARCHITECTURAL DISORDER AND CYTOLOGIC ATYPIA All varieties of congenital nevi may exhibit varying degrees of architectural and cytologic atypia of both the intraepidermal and dermal components (Table 27-9).102,103 Perhaps one of the most common findings is lentiginous melanocytic proliferation, which may occur with or without variation in junctional nesting or cytologic atypia of the intraepidermal melanocytes.103 INTRAEPIDERMAL PAGETOID SPREAD OF MELANOCYTES Another common finding, particularly in CMN in individuals younger than age 10 years, especially in the first year of life, is upward migration of intraepidermal melanocytes.104 Although the latter changes may be alarming, the proliferation

Table 27-9 Intraepidermal and Dermal Proliferations Developing in Large/Giant Congenital Nevi BENIGN 1. Epithelioid cell Intraepidermal Pagetoid spread in nevi Dermal Expansile nodule of epithelioid cells Epithelioid schwannoma 2. Pigmented spindle cell Dermal Expansile nodule of spindle cells 3. Spindle cell with schwannian or perineurial differentiation Dermal Neurofibroma-like tumor Schwannoma 4. Small round cell Dermal Expansile nodule of small cells 5. Specific mesenchymal (“ectomesenchymal”) differentiation Cartilage Lipoma Hemangioma 6. Neuronal elements Ganglioneuroma 7. Unclassified or undifferentiated neoplasms

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hemangioma, lymphangioma, mastocytoma, and schwannoma.85,90,102,107 Foci suggesting blue nevus, cellular blue nevus (CBN), Spitz nevus, and other nevus variants are occasionally noted.

SOURCE: Adapted from Hendrickson and Ross.108

is usually orderly, often confined to the lower half of the epidermis, and with cytologic atypia absent or of low grade.109 One may encounter a spectrum of atypicality within the intraepidermal component, ranging from little or no atypia to frank melanoma in situ. DERMAL NODULAR PROLIFERATIONS Large or giant CMN may give rise to dermal or subcutaneous nodular melanocytic proliferations (Fig. 27-13; see Table 27-9). Such proliferations may occur superficially or deeply and be composed of epithelioid, spindled, or small cells.102,103,108-110 Varying degrees of cytologic atypia; mitotic activity; and, occasionally, necrosis may be observed. Most of these cellular aggregates tend to blend with the surrounding nevus. The vast majority of such proliferations, particularly in the neonatal period, are biologically benign, despite their atypical histologic features. Small round cell tumors should be evaluated especially carefully for malignancy. Many of these nodular proliferations are composed of enlarged epithelioid or spindled cells containing granular cytoplasmic melanin. Usually, the melanin does not have the finely divided (“dusty”) character observed in melanoma cells. The nuclei also tend to be uniform compared with the pleomorphism and clumped chromatin of melanoma cells.103

INDETERMINATE OR MALIGNANT

Melanoma Developing in Congenital Nevi Pagetoid melanoma Melanoma, epithelioid cell type Malignant epithelioid schwannoma

Melanoma, pigmented spindle cell type

Malignant peripheral nerve sheath tumor

Small cell melanoma (“lymphoblastic” type melanoma)

Rhabdomyosarcoma

Ganglioneuroblastoma Undifferentiated sarcoma

Conventional melanoma originating from an intraepidermal location occurs most commonly in relatively small CMN (see Table 27-9).94,108 Such melanomas are usually of the pagetoid or nodular type. However, such melanomas are uncommonly observed in large and giant CMN.108,109 The great majority of melanomas developing in the latter setting are dermal and composed of epithelioid cells, spindle cells, or small round cells resembling malignant lymphoma (Figs. 27-14; see Table 27-9).90,102,108-110 Some melanomas may have the characteristics of malignant blue nevus (MBN) or malignant epithelioid schwannoma.108,111 Such tumors usually manifest cohesive cellular nodules distinctly different from the surrounding nevus, substantial nuclear pleomorphism, necrotic cells, mitotic activity, and striking cellularity.114-116 Interpretation of such tumors may be exceedingly difficult, and a final diagnosis of benign or malignant tumor may not be possible. Melanomas developing in newborns and infants younger than 1 year of age are extremely rare, and

B

 FIGURE 27-13 Atypical dermal nodular melanocytic proliferation in present in congenital nevus of a child. (A) Note asymmetry and hypercellular aggregates of relatively small melanocytes. However, there is some maturation. (B) The melanocytes have a monomorphous appearance and exhibit some nuclear enlargement and pleomorphism, and nucleoli are present.

such a diagnosis must always be seriously questioned. Furthermore, the vast majority of epithelioid and spindle cell nodular proliferations developing in CMN, particularly in young individuals, are benign or not aggressive. A prudent approach is to ensure complete surgical removal of such nodular lesions and to carefully monitor the patient for recurrence

A

or metastasis. On the other hand, many of the true biologic melanomas arising in giant CMN are of the small cell type.90,102,108-110 The cells are disposed in sheets in a delicate myxoid stroma. The cells are closely crowded; have minimal cytoplasms; and contain small round or slightly oval nuclei with dense, uniformly dispersed chromatin. The cells

take on the appearance of lymphoblastic lymphoma or comparable “blastic” tumors. Mitotic figures and nuclear debris are also commonly observed.

Other Mesenchymal Tumors Giant CMN may exhibit specific mesenchymal differentiation and rarely give

CHAPTER 27 ■ TUMORS OF MELANOCYTES

A

B

 FIGURE 27-14 Small cell (verrucous) melanoma. (A) Diffuse sheet of small cells in the dermis. (B) Uniform population of cells resembling lymphoma. The patient died of metastases.

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rise to hamartomatous mesenchymal tumors containing cartilage, vascular channels, and other elements.108 Rarely, liposarcoma, rhabdomyosarcoma, ganglioneuroblastoma, and other primitive sarcomas have been reported to arise in giant congenital nevi.102,108

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Leptomeningeal Melanocytosis

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Synonym: Neurocutaneous melanosis CMN, not necessarily large or giant, involving the scalp, neck, or posterior midline may be associated with melanocytic proliferations localized to the cranial or spinal leptomeninges or both.90,102,112 Histologically, aggregates of melanocytes are present in the basal subarachnoid cisterns. The latter lesion may be asymptomatic or result in hydrocephalus (either the communicating or noncommunicating type) seizures, mental retardation, other neurologic signs, or leptomeningeal melanoma. Meningeal biopsy may be necessary to confirm a diagnosis of leptomeningeal melanocytosis.

Focal Melanocytic Aggregates in Skin, Placenta, and Lymph Nodes Associated with Large or Giant Congenital Nevi There have been occasional reports of melanocytic lesions or satellites identified in the skin, placenta, and lymph nodes of patients with large or giant CMN.113,114 Explanations for these peculiar lesions include arrested or aberrant migration of neural crest elements during embryogenesis and benign metastases from the large CMN. DIFFERENTIAL DIAGNOSIS The differential diagnosis for small CMN less than 1.5 cm in diameter is primarily that of acquired melanocytic nevi and atypical (dysplastic) nevi. Because there are no specific histologic features for small CMN, the distinction from acquired nevi often rests on documentation at birth. Acquired atypical nevi are superficial proliferations that often involve the papillary dermis, resulting in a compound nevus. One particular problem associated with CMN is the presence of prominent upward migration of melanocytic cells throughout the epidermis in congenital nevi of children and particularly neonates. These proliferations suggest melanoma in situ or even invasive melanoma. However, in general, the pattern within the epidermis has an orderly character, and many of the cells do not

reach the granular layer. Furthermore, careful examination reveals low-grade or no cytologic atypia of these cells. In the author’s experience and in the experience of others, virtually all of these proliferations are benign. Another diagnostic difficulty is the distinction of tumoral dermal nodules in large CMN from melanoma. Relatively small nodules, generally measuring less than 1 cm in greatest diameter, are common in giant CMN. These nodules exhibit compact cellularity, and the constituent cells are usually larger and exhibit variable degrees of cytologic atypia. The distinction from melanoma relates to the gradual blending of the cellular nodule with the surrounding nevus. Necrotic cells, significant cytologic atypia, and easily found mitotic activity are also features suggesting melanoma. Age is a significant factor to be considered in the evaluation of these proliferations. A diagnosis of melanoma should be made with extreme caution in children younger than age 1 year.99,109,110

Congenital Melanoma Melanoma at birth is exceedingly rare and may be classified into three varieties.115,116 The first type of which only a few cases have been reported (reviewed by Trozak et al115) is characterized by maternal melanoma metastatic to the fetus. Neonates usually present at birth with widespread visceral metastases and are dead of disease within days to months. The placenta usually shows metastatic melanoma. Primary congenital melanoma may develop de novo or in association with a giant congenital nevus. Only a small number of cases of either type has been reported.116-118 Because of the extreme rarity of these lesions, a diagnosis of congenital or neonatal melanoma must be viewed with considerable skepticism.103,109,110 Virtually all such lesions are biologically benign.

Childhood Melanoma The incidence of melanoma increases with age but is exceptionally rare in prepubertal individuals (estimated incidence, ~0.4% among all melanomas)115,118 and uncommon under the age of 20 years (incidence approximately 2%).117,119 With the realization that many cases of childhood melanoma in the past had been considered to be Spitz nevi or atypical proliferations in CMN, it has become evident that melanoma is much less common and may have no better prognosis in children compared with adults.110,115-123 Analysis

of melanomas in individuals younger than age 20 years seems to show fairly similar clinical and histologic features compared with melanomas in adults.120 However, probably too few cases of melanoma have been reported in prepubescent children to make any definitive statements about melanomas in this age group. Recent studies from Children’s Hospital in Boston and from Europe describe three variants of childhood melanoma: (1) adult or conventional variants, (2) small cell variants, and (3) Spitz-like melanomas (including metastasizing Spitz tumors).118,121,122 It will be necessary to obtain additional information from multiple centers or through a central registry.

SPITZ NEVUS AND VARIANTS Synonyms: Spitz nevus, Spitz tumor, spindle and epithelioid cell nevus of large spindle and/or epithelioid cells, spindle cell nevus, juvenile melanoma, benign juvenile melanoma Spitzoid melanocytic proliferations have occupied a special niche in the melanocytic neoplastic system for many years, and increasing evidence suggests that they are a biologically unique melanocytic neoplasm. Yet there are still many unresolved questions with respect to the biologic nature, natural history, and biologic potential of spitzoid melanocytic lesions in general. For example, do malignant spitzoid lesions exist as such? Do they exist in particular age groups such as prepubertal children or even in older individuals? Do they have a unique molecular genotype? Do they have a different biologic potential, possibly less aggressive, than conventional melanomas? The Spitz nevus (or Spitz tumor) has been recognized for well over a century but was first definitively characterized in 1948 by Sophie Spitz.124-132 Spitz believed that such lesions represented juvenile counterpart of melanomas occurring in adults. Spitz tumors are usually acquired but may be congenital. The characteristics that set this nevus apart from other nevi are large epithelioid or spindle cells in varying proportions and frequent misdiagnosis as melanoma. CLINICAL FEATURES Spitz nevi most often present as a solitary; asymptomatic; red, pink, or flesh colored; hairless; domeshaped; smooth nodule measuring less than 1 cm in diameter (Fig. 27-15A; Table 27-10).14,22,96,130,131 Some lesions

B

C

D

E

F

CHAPTER 27 ■ TUMORS OF MELANOCYTES

A

 FIGURE 27-15 Spitz nevus. (A) Reddish brown symmetrical nodule. (B) Note the small diameter, dome-shaped morphology, striking symmetry from side to side, and sharp lateral demarcation. (C) Large epithelioid cells and spindle cells in the papillary dermis. Note the angular contours of the cells; some are triangular, some are rhomboidal, and some are polygonal in morphology. The cytoplasm is pink with a ground glass appearance. Many nuclei contain prominent nucleoli. (D) Fascicles of spindle cells with abundant cytoplasms. Note the striking uniformity of the spindle cells. The cells have abundant pink cytoplasms. Also note uniformity of nuclei with evenly dispersed chromatin. (E) Superficial portion of Spitz tumor demonstrating vertically oriented, predominately spindled melanocytes and progressive dispersion (maturation) of the melanocytic aggregates with depth. (F) Base of Spitz tumor shows orderly infiltration of collagen by individual cells (maturation). (Figure 27-15A: Courtesy of P Guitera and SW Menzies, Sydney Melanoma Diagnostic Centre and Dermatology Department, Royal Prince Alfred Hospital, NSW, Australia.)

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Table 27-10 Spitz Nevus or Tumor

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Clinical Features Configuration: plaque, papule, or nodule, often dome shaped Size: small (usually <1 cm) Profile: smooth surface topography Color: pink or red; darker forms occur Age: majority in children and adolescents Location: face and extremities most common Number: usually solitary; rare multiple forms occur Symptoms: commonly asymptomatic; rarely pruritic History of growth: months; usually <1 year Histopathologic Features Cytologic features Spindle or epithelioid cell typea Overall monomorphous population of cellsa Occasional striking pleomorphism in a minority of cells Architectural features Symmetrya Sharp lateral demarcationa Zonation in depth (eg, “maturation”)a Orderly nondisruptive infiltration of collagen by Spitz nevusa cells Other helpful diagnostic features Absent or rare, but not atypical, mitoses in deep partsa Giant nevus cells Irregular contours of growth at deep margina Kamino bodies Paucity or absence of single cell upward spread Junctional clefts Loss of cohesion between cells (retraction spaces) Perivascular or diffuse inflammatory infiltrate Superficial distribution of pigmentation Telangiectasia and edema Epidermal hyperplasia Differential Diagnosis Melanocytic lesions Malignant melanoma Atypical nevi with features of Spitz nevus Variants of nevi with spindle or epithelioid cells Pigmented spindle cell nevus Desmoplastic Spitz nevus Plexiform spindle cell nevus or deep-penetrating nevus Cellular blue nevus Various “combined” nevi Nonmelanocytic lesions Juvenile xanthogranuloma Epithelioid cell histiocytoma Reticulohistiocytoma Cellular neurothekeoma a

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Most helpful features

may be tan, brown, or even black in color. Pedunculated and polypoid forms occur.128 Spitz nevi may involve any site; however, there is a predilection for the face and the extremities. They may be slightly more common in females. Multiple Spitz nevi

may occur in either a grouped (agminate) or disseminated pattern.132 The disseminated type is characterized by numerous, up to hundreds of Spitz tumors all over the body, typically sparing the palms, soles, and mucous membranes.

The vast majority of lesions with characteristics of Spitz nevi are benign. However, because of the histologic resemblance of Spitz nevi to some melanomas, the presence of atypical variants, and rare metastases from such lesions, there is some justification for the belief that melanoma may uncommonly or rarely develop in association with Spitz nevi. The exact nature and classification of these lesions awaits definitive study. HISTOPATHOLOGIC FEATURES Spitzoid lesions, similar to other melanocytic lesions, occur along a histologic continuum of benign, atypical, and malignant and must be evaluated using all clinical, histopathologic, and other criteria available. After examination, one can usually assign a given lesion to one of three categories: (1) Spitz nevi or tumors without appreciable abnormality; (2) Spitz tumors with one or more atypical features (atypical Spitz tumor), including those with indeterminate biologic or malignant potential; and (3) malignant melanoma. The author believes that it is overly simplistic to impose an (often arbitrary) interpretation of either “Spitz nevus” or malignant melanoma on every spitzoid lesion. This approach is not satisfactory for patient care and does not provide a realistic methodology for dealing prospectively with such a difficult problem. Such an exercise undoubtedly results in both the overdiagnosis of melanoma and under-recognition of atypical or ambiguous lesions requiring more medical attention. Patients may unfairly suffer the psychological burden of a grave diagnosis and be subjected to overly aggressive and potentially harmful therapies. Conversely, some proportion of patients will have the false and unjustified assurances of a benign diagnosis and may not receive appropriate treatment and follow-up. Figure 27-15 illustrates the histopathologic features of Spitz nevi. The majority of Spitz nevi (≥66% or more) are compound, 5% to 10% are junctional, and 12% to 20% are dermal.128-131 The most distinctive histologic features and an absolute prerequisite for diagnosis are large epithelioid or spindle-shaped melanocytes (see Figs. 27-15B and 27-15C and Table 27-10).130 The epithelioid cells are large, round, oval, polygonal, rhomboidal, or polyangular cells with distinct cellular borders (see Fig. 27-15B) with nuclei similar to those in the spindle cells but also sometimes irregularly shaped or lobulated. Multi-nucleated

MATURATION (ZONATION) Maturation (zonation) refers to the appearance of layers of differing morphology from “top to bottom.”20 There is transition from larger nests at the dermoepidermal junction to smaller nests and single cells near the deep margin of the nevus. With this transition from top to bottom, the cellular elements exhibit a nondisruptive insinuation among collagen bundles without induction of new stroma (see Fig. 27-15). The distribution of pigment may also be zonal. If

melanin is present in Spitz nevi, it is largely confined to cells immediately subjacent to the epidermis.130 The cytologic features of the spindle or epithelioid cells may change from above downward, leading to a gradient in cell size and shape, such as from large, plump cells at the top to smaller or more slender cells at the bottom. ABSENT OR RARE MITOSES IN DEEP PARTS Mitoses are variable; they may be numerous, rare, or absent. Mitoses most commonly occur in the upper portion of the lesion and are usually bipolar. Although an occasional mitosis in the deeper parts of the lesion or a rare atypical mitosis may be observed, they should nonetheless prompt careful evaluation for melanoma.20,131 KAMINO BODIES Eosinophilic amorphous globules, either singly or in aggregates, at the dermoepidermal junction occur frequently in Spitz nevi137,138 and are useful because they are found less frequently in patients with melanoma. However, they are nonspecific.138 Ultrastructurally, Kamino bodies are composed of amorphous masses and bundles of filaments. Immunohistochemically, they contain basement membrane components, including collagen types IV and VII, as well as laminin.139 Degenerate material derived from melanocytes and keratinocytes may also be present.

PAGETOID SPREAD Pagetoid spread of single melanocytes occurs less often in Spitz nevus than in melanoma (Fig. 27-16).20,130,131 Upward migration of melanocytes in Spitz nevus usually takes the form of transepidermal elimination of nests of two or more cells. JUNCTIONAL CLEAVAGE At the dermoepidermal junction, the fascicles of spindle cells are often separated by a cleftlike retraction space from the adjacent epidermis, a result of tissue shrinkage during processing.130 ADNEXAL INVOLVEMENT Spitz nevi and its variants have a propensity to involve hair follicles and eccrine ducts. In most instances, intraepidermal fascicles of cells track along the adventitial sheaths of appendageal structures into the papillary dermis and often into the reticular dermis. PERIVASCULAR OR DIFFUSE INFLAMMATORY INFILTRATE The distribution of the inflammatory infiltrate tends to be perivascular but may be diffuse in some Spitz nevi.128 EPIDERMAL HYPERPLASIA Epidermal hyperplasia is a common finding in Spitz nevi.

 FIGURE 27-16 Pagetoid Spitz nevus. Pagetoid spread suggests melanoma in situ. Note the characteristic cytologic details of Spitz nevus cells. The cells are polyangular and contain abundant ground glass cytoplasm, and the nuclei have dispersed chromatin.

CHAPTER 27 ■ TUMORS OF MELANOCYTES

cells are often seen when epithelioid forms constitute the predominant cell type. The spindle cells are elongated, fusiform, and often plump (see Fig. 27-15C) and may exhibit dendrites. The cells possess centrally located nuclei, comparable in size to or even larger than the nuclei of keratinocytes. The nuclear contours are typically smooth and regular. The chromatin pattern is usually finely dispersed or slightly vesicular. Typically, a distinct, single, centrally located, round eosinophilic or amphophilic nucleolus is present. The spindle cells are arranged in fascicles or elongated nests, characteristically in vertical orientation or concentric arrangements within nests. The cytoplasm of the spindle and epithelioid cells is usually abundant with a homogeneous eosinophilic or bluish, sometimes “ground glass” appearance. Melanin is typically absent or scarce. The two cell types may be admixed in varying proportions, but either may occur alone. Regardless of the proportion of spindle or epithelioid cells, one of the most characteristic features of Spitz nevus is the uniformity of the cells and nuclei. From side to side in horizontal zones, the cells tend to show a strikingly uniform appearance and size. In all age groups, Spitz nevi with predominant spindle cell morphology are the most common type and are especially prevalent in adults.127-131 Spitz nevi of the epithelioid cell type are observed mainly in children. Although spindle or epithelioid cells are a prerequisite for diagnosis, they must appear in an appropriate architectural arrangement. The major architectural criteria include symmetry, sharp lateral demarcation, size (generally <1 cm), maturation (zonation), lack of deep extension, and lack of significant pagetoid spread. These and other criteria, such as few or no deeply located mitoses and the lack of significant cytologic atypia, which are thought to reflect ordered growth, favor benignancy.20

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Spitz Nevus or Tumor with Atypical Features (Atypical Spitz Nevus or Tumor)

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Table 27-11 Spitz Nevus or Pigmented Spindle Cell Nevus with Atypical Features I. Intraepidermal variant A. Architectural disorder 1. Disordered intraepidermal melanocytic proliferation:a a. Lentiginous or single-cell patterna b. Disordered junctional nestinga Variation in size, shape, orientation, spacing, cellular cohesion of nests Horizontal confluence and bridging of nests c. Pagetoid spread 2. Asymmetry 3. Poorly circumscribed 4. Lateral extension of intraepidermal component (“shoulder phenomenon”) B. Cytologic atypiaa 1. Nuclear pleomorphism 2. Variation in nuclear chromatin patterns 3. Nuclear enlargement 4. Variation in nucleoli C. Host response 1. Patchy to bandlike mononuclear infiltrates in papillary dermis 2. Fibroplasia II. Dermal variant A. Architectural disordera 1. Expansile nodules 2. Increased cellularity 3. Loss of cellular cohesion 4. Asymmetry 5. Deep extension 6. Lack of maturation or orderly infiltration of collagen 7. Ulceration 8. Necrosis B. Cytologic atypia (as above) C. Mitotic activity 1. Numerous mitoses 2. Mitoses at base of lesion 3. Atypical mitoses D. Host response 1. Prominent mononuclear cell infiltrates 2. Formation of tumor stroma

Spitz nevi or tumors with atypical features are not uncommon yet remain controversial because there is no consensus concerning standardized criteria for recognizing or categorizing such lesions.20,131,133-135 In general, atypical features may be subdivided into those involving primarily the epidermis or the dermis or subcutis (Table 27-11). A grading protocol for evaluating Spitz tumors with atypical features in children and adolescents was proposed by Spatz et al (Table 27-12).140 The grading scheme attempts to estimate potential risk for metastases based on cumulative scores from quantifiable or objective parameters, including diameter (< or >1 cm), the presence or absence of ulceration, depth, mitotic rate per mm2, and age (younger than or older than age 10 years).140 Molecular techniques also have been used recently in an effort to shed more light on the biologic nature of Spitz tumors. In particular, gains on chromosome 11p (by comparative genomic hybridization), mutations in the HRAS gene by fluorescence in situ hybridization,141,142 and loss of heterozygosity on chromosome 9p have been described,143,144 suggesting some evidence of tumor progression in some Spitz nevi.

Atypical Features of the Intraepidermal Component Spitz nevi (and pigmented spindle cell nevi) may show abnormal morphologic features observed in conventional atypical nevi (see Table 27-11 and Fig. 2717A).20,131,133-135 The essential criteria for diagnosis are (1) large diameter (>1 cm), asymmetry, ulceration, irregular patterns including asymmetry, effacement (or “consumption”) of the epidermis, disordered architectural patterns of the intraepidermal component (ie, lentiginous melanocytic proliferation or significant variation in junctional nesting, including variation in size, shape, orientation, spacing of junctional nests; horizontal confluence and bridging of nests; diminished cellular cohesion of nests); and (2) cytologic atypia of melanocytes beyond what is considered acceptable for a Spitz nevus (admittedly a subjective assessment) (see Fig. 27-17A).

a

Essential criteria for diagnosis.

Intraepidermal or Mainly Intraepidermal Spitz Nevi with Prominent Pagetoid Spread (Pagetoid Spitz Nevus) A distinctive variant is the mainly intraepidermal subtype with a prominent pagetoid pattern.145 This variant may occur anywhere but is most commonly encountered on the lower extremities of young women. The most important reason for recognizing this lesion is its frequent misdiagnosis as in situ or microinvasive melanoma. Most lesions measure less than 5 or 6 mm.145 Scanning magnification usually discloses a mainly intraepidermal proliferation of enlarged epithelioid cells usually

devoid of melanin (see Fig. 27-16) with an overall symmetry from side to side and reasonably well-defined margins.145 However, some lesions have ill-defined margins. Many of these lesions show a combination of both a single cell and nested proliferation of epithelioid melanocytes. The single-cell proliferative pattern is often both basilar and pagetoid and commonly varies within the lesion. Typical junctional nests of epithelioid cells with associated clefting are also usually present and may be quite small in size. Nests of cells or single Spitz nevus cells may or may not be present in the papillary dermis. Often, the degree of pagetoid spread is focal or limited; however, it may be prominent in some lesions, raising the possibility of melanoma in situ.

Table 27-12 Assessment of Atypical Spitz Tumors in Children and Adolescents for Risk for Metastasis PARAMETER

SCORE 0 1 0 1

0 2

A

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Age (years) 0-10 11-17 Diameter (mm) 0-10 >10 Involvement of subcutaneous fat Absent Present Ulceration Absent Present Mitotic activity (mm2) 0-5 6-8 >9 Total score and risk for metastasis: 0-2: Low risk 3-4: Intermediate risk 5-11: High risk

0 2 0 2 5

Atypical Features of the Dermal Component As already alluded to, abnormal properties of the dermal component include large diameter; asymmetry; cohesive cellular nodules; increased cellularity; asymmetry; deep extension into the lowermost dermis or subcutis; lack of maturation or orderly infiltration of collagen; cytologic atypia; and mitotic activity especially deep (see Fig. 27-17A, B and C).20,135,140 Because of the rarity of such lesions and the lack of sufficient follow-up in many instances, the significance of these various features has not been elucidated. There is little question that the cumulative presence of these various features in any given lesion is highly worrisome for melanoma and that as these features increase in number and severity, the likelihood of malignancy increases. In evaluating such lesions, a number of factors should be weighed in the final interpretation (see Tables 27-11 and 27-12). Clinical factors such as the age of the patient, location of the tumor, clinical appearance, history of recent change in a long-standing stable lesions, size larger than 1 cm, and family history of melanoma should be carefully considered. The older the patient, especially

B

C  FIGURE 27-17 Compound Spitz tumor with atypical features. (A) The lesion demonstrates large diameter, asymmetry, involvement of the deep dermis and subcutis, and hypercellular nesting of melanocytes. (B) The lesion infiltrates the dermis and superficial subcutaneous fat without maturation. (C) The base of the lesion prominent cellularity, the lack of maturation, and deeply located mitoses.

individuals older than age 30 years, the greater the likelihood of malignancy. As a general rule, one’s threshold for diagnosing melanoma in such lesions should correlate inversely with the age of the

patient, that is, a high threshold for very young individuals and a lower threshold for elderly individuals. The location of atypical tumors on sites less commonly involved by Spitz nevus, such as the

637

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back, is also another such factor suggesting careful scrutiny of the lesion for melanoma. If after weighing these factors, a clear-cut diagnosis of melanoma cannot be made, a practical approach is to communicate this situation to the clinician and patient.

638

DIFFERENTIAL DIAGNOSIS The intraepidermal or junctional variants of Spitz nevi must first be discriminated from in situ or early invasive melanoma. These intraepidermal Spitz nevi often show relatively small size, symmetry, evidence of growth control, and sharp circumscription compared with melanoma. Of particular importance are the cytologic characteristics of the epithelioid cells; they tend to be fairly monotypic with abundant pinkish cytoplasm that has a ground glass appearance rather than the granular cytoplasm often observed in melanoma cells. The nuclei of Spitz nevus cells are also fairly uniform with evenly dispersed chromatin versus the pleomorphism of melanoma cells. Compound and dermal Spitz nevi and their atypical variants must also be discriminated from invasive melanoma. The features outlined above and listed in Tables 27-11 and 27-12 provide guidelines for this distinction. However, many Spitz lesions show atypical features. The absence or incomplete development of major diagnostic features, such as symmetry or sharply demarcated lateral borders, are of concern and should prompt a careful search for features of melanoma. Even if symmetry and sharp lateral demarcation are observed, the presence of extensive pagetoid spread, the lack of maturation in depth, prominent cellularity of the dermal component, nuclear pleomorphism of more than a small proportion of cells, cohesive cellular nodules in the dermis, or deeply located (albeit rare) mitoses are worrisome. Detailed knowledge of diagnostic criteria and their relative weight are critical in the histologic assessment of such atypical lesions. When an atypical lesion is present, it is appropriate to indicate whether the lesion is low grade (ie, only limited abnormal features are present) or high grade (ie, whether its features approach malignancy). Depending on the severity of the atypia, one should acknowledge that melanoma cannot be completely excluded. A diagnosis of malignancy should not be made unless there is sufficient histologic and other evidence so that overtreatment and undue psychological burden for the patient can be avoided.

Nonmelanocytic lesions that need to be considered in the differential diagnosis include juvenile xanthogranuloma, cellular neurothekeoma, epithelioid cell histiocytoma, and reticulohistiocytoma.

Spitz Tumors and Lymph Node Involvement Melanocytic lesions classified as Spitz nevi have been reported to spread to regional (including sentinel) lymph nodes.118,133-135,140 These metastasizing melanocytic lesions, albeit resembling in many ways Spitz nevi, often tend to be unusually large, deep, and ulcerated, and possibly also show other atypical features (Table 27-12).118,133-135,140 Further studies are needed to clarify the nature of these tumors; however, until definitive information is available, such tumors must be considered aggressive, potentially malignant, and managed on a case by case basis.

Sentinel Lymph Node Biopsy The application of sentinel lymph node biopsy (SLNB) to atypical spitzoid melanocytic lesions as a means of obtaining more information about the biologic characteristics of such lesions may appear at first to have some rational basis. However, upon closer scrutiny, there are several fundamental questions that must be addressed before one can begin to have any meaningful data on this issue: one must have a much better understanding of the metastatic process in general versus nonmalignant cellular migration and spread and other possible explanations for the presence of ectopic cells in lymph nodes and other sites; the nature and significance of SLN deposits associated with all melanocytic lesions requires much more rigorous study and analysis; and finally, only the study of sufficient numbers of patients with long-term follow-up will provide the data to definitively know the biologic nature of many SLN deposits associated with various spitzoid lesions, if they are inherently different from conventional melanomas, and if they potentially have better prognoses. Thus, without such data, it is impossible to know, in general, the true biologic significance of spitzoid deposits in SLN. However, some data are available from the 69 patients thus far been reported in the literature.146152 Among these 69 patients, mostly children and adolescents, who have undergone sentinel lymph biopsy for spitzoid melanocytic tumors (probably a heterogeneous group of typical and atypical spitzoid lesions and possibly some true

melanomas), 30 patients have shown positive SLNB. In most instances, the tumor deposits have been microscopic and generally have involved the parenchyma or subcapsular sinuses of the SLN. With completion lymphadenectomy, only four of 30 patients showed any further nodal involvement, usually only a single additional node being involved. None of the 69 patients have shown any further disease progression with follow-up ranging from months to several years. Although these data are preliminary and not yet conclusive due to lack of consensus interpretation of the primary spitzoid neoplasms and sufficient long-term followup, the patients appear to show no progression of disease, and thus the positive SLN does not correlate with risk of further metastatic disease. As a result, the data suggest that many SLN deposits from spitzoid tumors are probably benign or at least biologically indeterminate. Consequently, atypical Spitz tumor deposits in SLNs may possibly have a different biology or significance than metastases from conventional melanoma.

Desmoplastic Spitz Nevus Synonyms: Sclerosing desmoplastic nevus

Spitz

nevus,

CLINICAL FEATURES Although the desmoplastic Spitz nevus is considered by many to be an unusual variant of Spitz nevus,20,153 some authors maintain that this lesion is a distinct entity.154,155 In fact, both of the latter perspectives are correct because desmoplastic or sclerosing nevi may be composed of varying proportions of enlarged epithelioid cells, spindle cells, or smaller conventional nevus cells. Desmoplastic Spitz nevus typically presents as a firm, dome-shaped, fleshcolored papule or nodule, measuring up to 1 cm in greatest diameter; is most often located on the extremities; and suggests a dermatofibroma (Table 27-13).153 This variant of Spitz nevus primarily affects adults, with a peak incidence in the third decade of life. HISTOPATHOLOGIC FEATURES The desmoplastic Spitz nevus is a poorly circumscribed growth of large polygonal or elongated melanocytes in a collagen-rich stromal background (see Table 27-13 and Figs. 27-18A and 27-18B).20,153 It is usually a wholly intradermal lesion. The desmoplastic changes in Spitz nevi may make up the entire lesion or any portion of it. In the superficial dermis, melanocytes may be grouped in nests or aggregates,

Table 27-13 Desmoplastic Spitz Nevus

but in the deeper parts of the lesions, they tend to infiltrate singly between typically thickened collagen bundles (see Fig. 27-18B). The latter phenomenon

A

DIFFERENTIAL DIAGNOSIS The major differential diagnostic problem with desmoplastic Spitz nevus is its distinction from desmoplastic melanoma (DM) (Table 27-14). The desmoplastic Spitz nevus may present in a similar fashion to DM, that is, an indurated amelanotic or slightly pigmented nodule. However, in other respects, the desmoplastic Spitz nevus is different from DM. There is a predilection for the extremities of young individuals versus the head and neck of elderly persons in DM. Histologically, whereas desmoplastic Spitz nevi tend to be small, well-circumscribed, superficial lesions, DMs are often larger, poorly demarcated, and characterized by deep involvement of the dermis or subcutis. The desmoplastic variant of Spitz nevus also shows maturation, that is, isolation of individually smaller cells with

increasing depth versus little or no such transition in DM. The cell types in the two processes tend to be rather different. Whereas desmoplastic Spitz nevi contain typical large epithelioid or fusiform cells, DM is notable for pleomorphic spindle cells often with hyperchromatic nuclei. Although the blue nevus may have pronounced sclerosing features, it is usually a more ill-defined melanocytic lesion than desmoplastic Spitz nevus and is composed of a more slender and more diffusely pigmented melanocytic population than the plumper cells of Spitz nevus. Nonmelanocytic dermal spindle cell lesions that may share morphologic features of desmoplastic Spitz nevus are dermatofibroma, reticulohistiocytoma, and epithelioid cell histiocytoma.

Other Variants of Spitz Nevus Other rare or noteworthy variants of Spitz nevus reported in the literature include angiomatoid (related to desmoplastic Spitz nevus and characterized by prominent vascularity),156 hyalinizing (hyalinized dermis),157 halo (dense lymphoid infiltrates),158 plexiform,159 recurrent or persistent (may have tumoral dermal component suggesting melanoma),160 and tubular (prominent intracellular vacuoles, possibly an artifact) variants.161

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Clinical Features Firm papule or nodule Adults (peak incidence in third decade of life) Most commonly located on extremities Histopathologic Features Spindle or epithelioid cells Predominantly intradermal location of melanocytes Sometimes junctional component Dermal stroma with increased collagen Usually circumscribed, but with ill-defined borders Often vaguely wedge shaped Usually diffuse distribution of cells with low cell density Typically small nests and single melanocytes Maturation often present Mitoses absent or rare Multinucleate giant cells not uncommon (usually superficial) Melanin usually sparse or absent Differential Diagnosis Desmoplastic melanoma Sclerosing blue nevus Dermatofibroma Epithelioid cell histiocytoma

is maturation. Scattered multinucleated giant cells or large pleomorphic forms may be present. Cytologically, the melanocytes of desmoplastic Spitz nevi are characterized by nuclei that are often hyperchromatic with clumped or finely dispersed chromatin. Nucleoli are commonly inconspicuous but may be prominent, especially in larger cells. The size of the nuclei tends to diminish as melanocytes approach the base of the lesion, which is usually ill defined. Mitoses are rare (usually <1 per mm2).

B

 FIGURE 27-18 Desmoplastic Spitz nevus. (A) The lesion is entirely intradermal and characterized by a nondescript appearance at this magnification. Nonetheless, the tumor exhibits symmetry and an orderly pattern. (B) Nests, cords, and individual melanocytes dispersed in sclerotic dermis.

639

Table 27-14 Desmoplastic Spitz Nevus vs. Desmoplastic Melanoma Preferred site

Preferred age group Melanocytic atypia Intraepidermal Dermal

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Mitoses Necrosis Maturation

640

DESMOPLASTIC SPITZ NEVUS Extremities

Early adulthood

DESMOPLASTIC MELANOMA Chronically sun-exposed skin such as the head and neck Late adulthood

Rare Not uncommon, but usually slight Rare Absent Common

Common Common, often more than slight Variable Occasional Uncommon

Pigmented Spindle Cell Nevus Synonyms: Pigmented spindle cell nevus of Reed, pigmented spindle cell tumor CLINICAL FEATURES The pigmented spindle cell nevus (PSCN) is a distinctive clinicopathologic entity that is important to recognize because of its frequent confusion with melanoma (Table 27-15). PSCN usually presents as a symmetric, sharply circumscribed, dark brown or black papule or nodule.19,20,134,162-165 It is typically a small lesion, often measuring less than 0.6 cm in diameter. PSCN is preferentially located on the extremities. It appears to affect women slightly more often than men.134,163-165 HISTOPATHOLOGIC FEATURES These lesions are usually relatively small, strikingly well circumscribed, and remarkable for a slightly elevated, flat-topped plaque-like appearance of the epidermis (see Table 27-15 and Fig. 27-19A).20,134,162—165 Although the PSCN may be junctional or compound, many are almost entirely intraepidermal. If papillary dermal involvement occurs, the base of PSCN is typically broad with pushing borders. The PSCN contains uniform, delicate spindle cells present in tightly packed fascicles. These fascicles tend to have a fairly uniform and symmetric spacing and size within the epidermis and are often vertically oriented. The fusiform cells are often slightly more slender than the spindle cells of “classic” Spitz nevus (Fig. 27-19B). Their nuclei are equal in size or smaller than the nuclei of adjacent keratinocytes.165 The nucleoli are usually inconspicuous. Some PSCN, particularly in children, may show florid upward migration of single melanocytes closely simulating melanoma in situ.23,165 Also in contrast to ordinary Spitz nevus, melanocytes of PSCN contain variable

amounts of granular melanin. Heavy pigmentation may also involve the adjacent keratinocytes, cornified layer, and papillary dermis.20 Table 27-15 Pigmented Spindle Cell Nevus

Clinical Features Peak incidence in third decade of life Most often located on extremities (especially thighs) Women ≥ men Small (usually <0.6 cm) Symmetry Pigmented (usually evenly, often heavily) Sharply circumscribed Papule or nodule History of recent onset Histopathologic Features Junctional or compound nevus Predominantly spindle cells, but occasionally epithelioid cells Spindle cells more slender and delicate than in Spitz nevi Uniform population of cells from side to side Symmetric configuration Predominance of junctional nests or fascicles Typically ovoid nests with fusiform cells oriented vertically Often confluence of nests leading to irregular shapes Sharp lateral borders, occasional lentiginous lateral spread Usually abundant coarse melanin Uniform nuclear features Decrease in cell size from top to bottom (“maturation”) Mitoses not uncommon in intraepidermal component Absent or rare dermal mitoses Differential Diagnosis Lentiginous melanoma Pagetoid melanoma Atypical (dysplastic) nevus

There is a histologic continuum of Spitz nevus and PSCN23 (see Table 27-15). One will encounter many nevi showing varying degrees of transition between these two poles of the spectrum. For example, some nevi may exhibit slender spindle cells typical of PSCN yet at the same time contain somewhat larger fusiform cells and epithelioid cells that are less heavily melaninized.

Pigmented Spindle Cell Nevus with Atypical Features The same discussion applies to the atypical variants of PSCN as for atypical forms of Spitz nevus20,134 (see Table 27-11). However, most atypical variants of PSCN are primarily intraepidermal. Some overlap may occur with conventional atypical (dysplastic) nevi. DIFFERENTIAL DIAGNOSIS PSCN and its atypical variants must be distinguished from in situ or microinvasive melanoma and from atypical nevus. PSCN (particularly atypical forms of PSCN) and lentiginous melanocytic proliferations of sun-exposed skin (SIMPs with atypia or lentigo maligna) may occasionally show considerable similarity.23 Both are typically composed of pigmented spindle cells that may be arranged in junctional nests and may involve skin appendages. Discrimination of the two is based on clinical features, the usual small size, sharp circumscription, predominantly nested pattern, and uniformity of cell type in PSCN. SIMPs with atypia, on the other hand, tend to be broader, poorly circumscribed, and usually typified by a mainly basilar single-cell proliferation of pleomorphic melanocytes. Rare lesions may show such overlap that distinction may not be possible. Such lesions should be completely excised with a cuff of normal tissue, and the patient carefully monitored. PSCN and atypical variants of PSCN are often confused with pagetoid variants of melanoma because of prominent pagetoid spread.20,134 One must again rely on clinical factors, including young age and anatomic site (eg, the extremities), as well as the overall morphologic appearance. PSCN are typically small, welldemarcated, symmetric, and orderly. Even with striking pagetoid spread in some lesions, the latter features argue strongly in favor of a benign process, especially if present in a young individual and on a site such as the thigh. However, atypical forms of PSCN are extremely challenging to diagnose, and all of the

reticular dermis and are absorbed by the melanin. However, the shorter wavelengths representing the bluish part of the color spectrum do not penetrate so deeply and are reflected back from the superficial dermis and epidermis. The dermal melanocytoses and blue nevi are thought to result from the dermal arrest of cells migrating from the neural crest. In contrast to ordinary nevi, it is believed that these migratory cells never reach the epidermis but instead give rise to melanocytic lesions with varying degrees of cellularity and melaninization.

A

The following six entities are related because they are all essentially bluish macular lesions that histologically demonstrate scattered dendritic melanocytes in the reticular dermis with little or no stromal alteration (see Table 27-16).20,168,170-179

Mongolian Spot B  FIGURE 27-19 Pigmented spindle cell nevus. (A) The lesion is small, symmetric, and well circumscribed. (B) Fascicles of spindle cells are both vertically and horizontally disposed and seem to be part of the thickened epidermis. Note the uniformity of the spindle cells.

clinical and histologic features must be carefully weighed. In many instances, a clear-cut diagnosis of melanoma cannot be made. Such lesions should be designated as PSCN (or melanocytic proliferation) with atypical features and appropriate surgery and careful follow-up of the patient arranged. Recurrence of such lesions appears to be extremely rare. The same features characteristic of PSCN, such as cytologic uniformity and nuclear regularity, as well as its tendency to contain vertically disposed melanocytes (“raining down”) to the epidermal surface, help distinguish PSCN from atypical (dysplastic) nevus, in which the melanocytes are oriented more parallel to the epidermal surface and show more cytologic variability and atypia.141 Atypical (dysplastic) nevi are generally less cellular and often display a pronounced lentiginous melanocytic proliferation with elongation of the rete ridges and associated papillary dermal fibrosis, which are not typical features of PSCN. However, some atypical forms of PSCN show substantial overlap with conventional atypical nevi. Discrimination

of the two lesions thus may not be reproducible. Such lesions may be designated as PSCN with atypical features or as atypical (dysplastic) nevus with features of PSCN.

DERMAL MELANOCYTOSES, BLUE NEVI, AND RELATED CONDITIONS The classification of blue nevi and related lesions is based on assessing a number of features, including clinical appearance; anatomic site of lesion; localization in the reticular dermis, subcutis, and the like; the extent to which the lesion is made up of dendritic, spindle-shaped, or epithelioid melanocytes; the degree of cellularity of the lesion; and the degree of fibrosis (sclerosis) (Table 27-16).166-184 The bluish appearance of these various lesions is primarily related to the depth of melanin in the dermis and the Tyndall phenomenon. The longer wavelengths of visible light penetrate the

CLINICAL AND HISTOPATHOLOGIC FEATURES Mongolian spots are oval or round, often poorly defined, macules (approximately 1 to 10 cm) varying in color from slight gray to blue-black or dark brown, most often affecting the lumbosacral region, but they may also be seen in other (ectopic or aberrant) locations. These lesions are present at birth but usually spontaneously regress by age 3 to 4 years. Mongolian spots are observed primarily in persons of color. The Mongolian spot is characterized by widely spaced dendritic melanocytes localized to the lower half or two-thirds of an unaltered reticular dermis (Fig. 27-20).168

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Dermal Melanocytoses

Nevus of Ota (Nevus Fuscoceruleus Ophthalmomaxillaris) CLINICAL FEATURES This hamartomatous or nevoid condition usually presents at birth or in childhood as a unilateral speckled bluish macule involving the periorbital region, forehead, temple, cheek, or nose, corresponding to the distribution of the first two branches of the trigeminal nerve.168,171-174 Examination may also disclose involvement of the sclera, conjunctiva, cornea, retina, or oral and nasal mucosa. Brownish lentigo-like lesions and bluish papules or nodules are occasionally associated with nevus of Ota.

Nevus Fuscoceruleus Zygomaticus Synonyms: Acquired nevus of Ota-like macules, sun nevus

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Table 27-16 Differential Features of Dermal Melanocytoses FEATURE

MONGOLIAN SPOT

NEVUS OF OTA

NEVUS OF ITO

Onset Size Color Surface Hair Distribution Number Site

Birth or soon after 5 cm Gray-tan, slate blue Macular Normal for site Midline Single, can be multiple Lumbosacral

Birth or soon after 5 cm Brown, slate blue Macular, rarely discrete papules Normal for site Unilateral Single Shoulder and upper arm

Racial incidence Familial incidence Gender Age of appearance Spontaneous fate

Asians and dark-skinned races Common No difference At birth Usually disappears during first few years of life Never reported

Birth or soon after 5 cm Brown, slate blue Macular, rarely discrete papules Normal for site Unilateral Single First and second division trigeminal nerve Asians and dark-skinned races Rare 80% in females 60% at birth Persist; rarely disappear Rare

Rare

Moderate number of dermal melanocytes in upper dermis

Moderate number of dermal melanocytes in upper dermis

Fully developed melanocytes with only mature melanosomes; virtually no premelanosomes

Fully developed melanocytes with only mature melanosomes; virtually no premelanosomes

Tendency to malignancy Histopathologic features Ultrastructure

Scattered dermal melanocytes in lower half of dermis in low concentrations Fully developed melanocytes with only mature melanosomes; virtually no premelanosomes

CLINICAL FEATURES The development of bilateral bluish macules in the zygomatic areas of the face has primarily been reported in Chinese and Japanese women.176,177

Acquired Dermal Melanocytosis of the Face and Extremities CLINICAL FEATURES This particular disorder is associated with bilateral bluish or brownish discoloration of the face of adults somewhat similar to nevus of Ota; it is also associated with involvement of the extensor surfaces of the upper extremities and possibly the palms.178

Nevus of Ito (Nevus Fuscoceruleus Acromiodeltoideus) CLINICAL FEATURES The nevus of Ito is closely related to nevus of Ota but is distinguished by its unilateral distribution involving the supraclavicular, scapular, or deltoid regions.171

Dermal Melanocyte Hamartoma

642

CLINICAL FEATURES The term dermal melanocyte hamartoma describes a small number of developmental abnormalities usually present at birth and exhibiting extensive involvement of the skin.20,179

HISTOPATHOLOGIC FEATURES Scattered dermal melanocytes with prominent dendritic processes are noted in the upper dermis without alteration of the dermal stroma. There may be aggregation of these cells about sebaceous glands, eccrine ducts, blood vessels, and cutaneous nerves. As in Mongolian spots, the cells contain prominent deposits of fine melanin granules. Melanophages, in general, are uncommon. The density of melanocytes is greater than in Mongolian spots. A new histopathologic classification of nevus of Ota based on the location of melanocytes in the dermis has been reported: (1) superficial type (ie, melanocytes present in the superficial dermis), (2) deep type, (3) diffuse type (melanocytes scattered throughout entire dermis), (4) superficial dominant type, and (5) deep dominant type.174 The brownish macules in any of these lesions demonstrate dermal melanocytes located very close to the epidermis or slight basilar melanocytic hyperplasia and basal layer hypermelanosis.8 The slightly raised or papular lesions demonstrate an even greater concentration of dendritic melanocytes, resembling blue nevus. DIFFERENTIAL DIAGNOSIS As a group, the dermal melanocytoses are distinguished from blue nevi by the lack of dermal

Asians and dark-skinned races Rare 80% in females 60% at birth Persist; rarely disappear

fibrosis, sparse cellularity, and a singlecell disposition of dendritic melanocytes. Mongolian spots are distinguished from other dermal dendritic lesions by their location (sacral area), disappearance in infancy, and sparse number of dermal melanocytes without melanophages or fibrosis. Persistent ectopic “Mongolian spots” may be difficult to discriminate from nevi of Ota and nevi of Ito. It is likely that some previously reported examples of ectopic Mongolian spots are in fact nevi of Ota or nevi of Ito.

Blue Nevus Historically, the classification of blue nevus has included two principal variants: 20,166-169the more prevalent common blue nevus and the relatively uncommon, larger variant, the CBN. However, examination of sufficient numbers of blue nevi reveals that there is indeed a morphologic spectrum rather than necessarily two well-defined subtypes. The morphologic features that account for the spectrum of blue nevi include the relative number and density of dendritic and spindled melanocytes, melanophages, the degree of fibrosis, the disposition and relationship of the latter components, and the overall size of the lesion. The spindle cells may be individually disposed or arranged in fascicles or in compact nests.

Epithelioid Blue Nevus

 FIGURE 27-20 Mongolian spot. A punch biopsy shows a largely unaffected dermis. There are pigmented dendritic cells in the mid-reticular dermis scattered among collagen bundles. Neither fascicles of cells nor fibrosis are present, as would be observed in blue nevus.

Finally, some blue nevi contain cellular elements observed in other nevi such as ordinary nevi or Spitz nevi and have been designated “melanocytic nevi with phenotypic heterogeneity” by the author (historically “combined” nevi).20 The clinical characteristics of some blue nevi, such as a plaquelike or agminated appearance, may also warrant attention.168,180-184 The following classification of blue nevi is based on the predominant histologic changes:

Common Blue Nevus Synonym: Blue nevus of JadassohnTieche CLINICAL FEATURES The most common form of blue nevus usually presents as a welldemarcated, slightly raised or dome-shaped bluish papule (see Table 27-16).166,168 The color is usually a uniform slate gray, blueblack, or black. The borders are generally regular, and these nevi usually measure less than 1 cm in diameter (Fig. 27-21A). They are primarily located on the dorsal aspects of the hands and feet or may involve the face and scalp. The onset is generally in childhood but may occur

later in life. Melanoma has only rarely been reported to originate from this type of blue nevus.185 HISTOPATHOLOGIC FEATURES This form of blue nevus shows an aggregation of dendritic melanocytes that alters the normal configuration of the dermis (see Figs. 27-21A and Table 27-16).20,166,168 The lesion may occur anywhere in the reticular dermis and even in the papillary dermis, but it most commonly involves the superficial dermis. In general, there are bundles of dendritic cells with frequent aggregation about appendages and neurovascular bundles. The cells are generally bipolar or stellate and characterized by lengthy dendritic processes (Fig. 27-21B). Most cells contain a dense accumulation of relatively fine melanin granules. The nuclei are ovoid with uniform chromatin patterns. Melanophages are usually present and may be the principal cell type in some cases. Variable degrees of fibrosis are also present. DIFFERENTIAL DIAGNOSIS This type of blue nevus shares the common dendritic cell type noted in the discussion of

CLINICAL AND HISTOPATHOLOGIC FEATURES This variant of blue nevus has been described in association with the Carney complex, which is a familial syndrome demonstrating lentigines; psammomatous melanotic schwannomas; myxomas involving the skin, heart, and breast; and endocrine tumors of the adrenal cortex, pituitary, testis, and thyroid.186,187 Nonetheless, such blue nevi occur outside the latter syndrome.188,189 In addition to features of an ordinary blue nevus, these lesions often show epidermal thinning and effacement or sometimes hyperplasia and epithelioid melanocytes of two types: (1) heavily pigmented polygonal cells with their nuclei largely obscured by melanin granules and (2) lightly pigmented polygonal cells often with large vesicular nuclei and prominent nucleoli (Fig. 27-22). Rare mitotic figures are observed in a significant proportion of cases. The presence of mitotic figures should prompt careful study for other atypical features and the possibility of melanoma.

CHAPTER 27 ■ TUMORS OF MELANOCYTES

dermal melanocytoses. The blue nevus differs from the above entities by a greater concentration of dendritic melanocytes and is usually accompanied by varying degrees of fibrosis and melanophage accumulation. However, the papular and nodular lesions within nevus of Ota or nevus of Ito are indistinguishable from this variant of blue nevus. The differential diagnosis might also include primary or metastatic melanoma, possibly with some degree of regression. In general, blue nevi can be distinguished from melanoma by their small size, overall symmetry, lack of cytologic atypia, and absence of mitotic activity and necrosis.

Pigmented Epithelioid Melanocytoma The recently reported entity “pigmented epithelioid melanocytoma” shares features with if not being identical to epithelioid blue nevus.190 Such lesions have demonstrated a significant frequency of sentinel lymph node involvement perhaps comparable to Spitz tumors. Although some proportion of both epithelioid blue nevi (and pigmented epithelioid melanocytomas) demonstrate atypical features, including cytologic atypia and increased mitotic rates, that raise concern as to their biologic potential, progression to overt malignancy has only rarely been documented and usually after one or more recurrences.

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A

C  FIGURE 27-21 Blue nevus, common type. (A) The lesion shows a small diameter, symmetry, well-defined borders, and uniform blue color with dermoscopy. (B) The nevus is composed of pigmented dendritic melanocytes disposed in fascicles. (C) The dendritic melanocytes have long cellular processes that are heavily melaninized. The dermis is slightly collagenized. (Figure 27-21A: Courtesy of P Guitera and SW Menzies, Sydney Melanoma Diagnostic Centre and Dermatology Department, Royal Prince Alfred Hospital, NSW, Australia.)

A

644

B

B

 FIGURE 27-22 Blue nevus, epithelioid cell variant. (A) The lesion is large, well-defined, and symmetrical. (B) Note the large epithelioid melanocytes, which define this variant. The melanocytes have large, round nuclei with dispersed chromatin and display nuclear pleomorphism and large nucleoli.

Sclerosing Blue Nevus

Cellular Blue Nevus

HISTOPATHOLOGIC FEATURES This variant is characterized by a symmetric and fairly well-circumscribed fibrous nodule in the dermis.20 The fibrous component is conspicuous relative to a sparse number of dendritic or spindled melanocytes and melanophages (or both).

CLINICAL FEATURES CBN are generally 1 to 3 cm in diameter with a blue, blue-black, or black coloration. Their surface is usually smooth but may be uneven. They most commonly involve the buttocks, sacral area, scalp and face, and dorsa of the feet and hands (Table 27-17).167,169,193,194 They are generally diagnosed between the ages of 10 and 40 years and in rare instances may be congenital. They are usually asymptomatic. Rarely, these

Hypopigmented Blue Nevus The lack of significant melanin pigment may result in a so-called hypopigmented or amelanotic variant of blue nevus.191 Many such lesions are also sclerosing forms of blue nevus and demonstrate sparse cellularity. However, overall cellularity may vary considerably, with some examples fulfilling criteria for cellular blue nevi (CBN).

“Compound” Blue Nevus These lesions exhibit basilar epidermal proliferation of heavily pigmented dendritic melanocytes.192 Junctional nests are not present. The papillary and upper reticular dermis contains a fairly well-circumscribed aggregate of spindle and dendritic melanocytes, usually heavily melanized with numerous melanophages.

Table 27-17 Cellular Blue Nevus

Clinical Features Onset: birth, childhood, adolescence Age: mean, 33 years (range: birth-85 years) Site: buttocks, sacrococcygeal area, forearm or wrist, leg, ankle, foot, scalp, face Gray-blue to blue-black papule, nodule Usually well circumscribed Regular borders Size: ≥ 0.3-3 cm Histopathologic Features Symmetry Localization to reticular dermis Often deep extension with bulging, nodular configuration, rounded, well-demarcated inferior margin Heterogeneity of patterns Biphasic pattern most common: (1) Melanin-laden dendritic melanocytes and fibrosis and (2) Bundles of amelanotic fusiform cells Alveolar pattern: Fascicles or nests of fusiform cells compartmentalized by fibrous trabeculae Fascicular pattern Fascicles of spindle cells often with clear cytoplasm and prominent schwannian differentiation Cellular blue nevus with atypical features (atypical cellular blue nevus) Large size ( 1-2 cm) Marked cytologic atypia Increased mitotic rate Necrosis Infiltration of surrounding tissue Lacunae-containing melanophages Cystic degeneration in central part of nevus with loose edematous stroma Few or no mitotic figures Necrosis absent or uncommon Differential Diagnosis Malignant blue nevus Metastatic melanoma Clear cell sarcoma

HISTOPATHOLOGIC FEATURES There is a continuum from ordinary blue nevi to “cellular” blue nevi, as discussed previously (Figs. 27-23).20,167,169,193,194 However, no criteria have been established as to what proportion of a blue nevus should consist of fusiform cells to qualify as a CBN. The following criteria are proposed for diagnosis of CBN: the lesion should occupy the reticular dermis, at least one-third to onehalf of the lesion should contain oval to fusiform cells, and the overall architecture should be multilobular or plexiform with deep involvement of the reticular dermis or subcutis (see Table 27-17). CBN may show a single lobular mass with a well-defined horizontal inferior margin that parallels or bulges into the subcutaneous fat, or alternatively, there may be two or more lobules or digitate bulbous projections that extend into the deep reticular dermis or subcutaneous fat (see Figs. 27-23).167,169,193,194 CBN are heterogeneous, and their morphologic limits have not been clearly defined.20 For example, the distinction from ordinary blue nevi, some pigmented peripheral nerve sheath tumors, and other unusual melanocytic nevi may be problematic. Essential for the diagnosis are cellular foci of round, oval, elongate, or fusiform cells that constitute at least one-third to one-half, if not most, of the tumor (see Fig. 27-23C). These cells are arranged in a number of patterns and vary considerably as to melanin content. As opposed to the frequent diffuse distribution of melanin-laden dendritic melanocytes in the ordinary type of blue nevus, the fusiform cells of CBN are usually disposed in variably organized nests or bundles. These bundles may or may not be encapsulated by fibrous tissue. In some instances, fascicles of fusiform cells are oriented randomly in all directions without evidence of compartmentalization. However, a common pattern is that of compact cellular nests or fascicles separated by fibrous trabeculae. There may be linear or concentric arrangements of cells within these nests. Pigmented dendritic melanocytes and melanophages are often present in the peripheral fibrous tissue surrounding the cellular fascicles. The sizes of fascicles or nests may vary considerably. There may be large lobules of fusiform cells constituting much of the tumor without intervening fibrous tissue. Well-defined, rounded nests of cells have been described as the “alveolar” pattern

CHAPTER 27 ■ TUMORS OF MELANOCYTES

DIFFERENTIAL DIAGNOSIS Entities to be distinguished from sclerosing blue nevus include dermatofibroma, particularly the hemosiderotic variant, sclerosing Spitz nevus, and DM. The type of dermatofibroma associated with prominent deposits of hemosiderin may closely mimic blue nevus. However, the typical epidermal changes resembling seborrheic keratosis are usually found with dermatofibroma as well as the typical infiltrating pattern of cells in dermatofibroma. Close inspection of the pigment granules in dermatofibroma usually reveal the golden refractile character of hemosiderin. If necessary, special stains for iron and melanin can be useful in distinguishing between these two entities. The desmoplastic or sclerosing form of Spitz nevus is usually easily separated from blue nevus because there is usually no pigment in the Spitz variant and the cell type is usually epithelioid. DM is distinguished from sclerosing blue nevus by clinical features, the presence of an atypical lentiginous melanocytic proliferation, fascicles of atypical spindle cells, and inflammatory infiltrates in DM. However, this distinction may occasionally be quite difficult. Diagnosis must be based on weighing the degree of cellularity, cytologic atypia, and mitotic activity.

lesions may undergo transformation to melanoma (MBN). Incomplete excision of CBN is rarely associated with recurrence.195

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A

C

B

D

 FIGURE 27-23 Blue nevus, cellular variant. (A) This lesion occupies the entire dermis. The superficial eosinophilic portion of the lesion corresponds to that of a common blue nevus whereas the deeper pale-staining areas correspond to densely cellular nests and fascicles of spindled melanocytes. (B) Characteristic bulbous configuration of cellular blue nevus extending into subcutis. (C) Discrete fascicles of ovoid and spindled melanocytes with clear cytoplasms partitioned by fibrous trabeculae. (D) The melanocytes display fairly uniform nuclei.

in CBN.169,194 Fascicles of spindle cells may have schwannian differentiation and may merge with and infiltrate cutaneous nerves.169 The cells comprising the “cellular” foci are most often fusiform or spindle shaped but may also be round or oval.23 These cells are usually somewhat enlarged but may be relatively small. The cells boundaries are often ill defined, and the cytoplasm is usually clear, vacuolated, slightly eosinophilic, or bluish (see Fig. 27-23D). The fusiform cells do not contain readily apparent melanin by conventional microscopy. Because of the paucity or absence of melanin, these cellular foci appear pale or clear on scanning magnifi-

cation, in contrast to the often heavily pigmented areas containing dendritic melanocytes, melanophages, and sclerosis. The latter pale areas are quite helpful in recognizing CBN. However, the degree of melaninization may vary from barely visible fine granular melanin to heavy pigmentation obscuring cytologic detail. Usually, the dendritic melanocytes and melanophages contain the heaviest deposition of melanin. However, the latter cells are usually located in peripheral fibrous trabeculae or in areas of sclerosis. The nuclei of these cells are usually round, oval, or fusiform and commonly somewhat enlarged. The chromatin tends to be evenly dispersed, and one or

more small nucleoli are often observed. Minimal or low-grade nuclear pleomorphism is noted in many CBN. However, this should not be pronounced. Similarly, occasional mitoses are noted in many CBN. As a general rule, if two or more mitoses are present per mm2, the lesion should be carefully evaluated for other corroborating evidence of malignancy. Multinucleate giant cells are occasionally noted in the cellular areas and may be numerous. Such giant cells may also occur in areas of cystic degeneration. Occasional CBN are composed of discrete nests of amelanotic round or oval cells analogous to the usual fusiform cells. Such nests are separated

Atypical Variants of Cellular Blue Nevus Atypical variants of CBN may be extremely difficult or impossible to distinguish from MBN.196-198 Morphologic criteria are not clearly established for such atypical variants, and their biologic potential often cannot be predicted. However, they are generally characterized by large size (>1 to 2 cm), deep extension, large expansile nests of spindle cells, prominent cellularity and cytologic atypia, necrosis, infiltration of adjacent tissue, and significant mitotic activity (usually > 2/mm2).196-198 DIFFERENTIAL DIAGNOSIS The differential diagnosis of CBN (and atypical CBN) includes MBN (malignant melanoma arising in association with CBN; see Table 27-18 and Fig. 27-24),194,196-198 metastatic melanoma, and clear cell sarcoma (CCS). The clinical history of a long-standing blue nevus with subsequent change or finding an associated benign blue nevus remnant (usually CBN) is extremely important for the diagnosis of MBN. Without such a clinical history or finding, MBN cannot be distinguished from conventional

Table 27-18 Comparison of Cellular Blue Nevus and Malignant Blue Nevus CELLULAR BLUE NEVUS

MALIGNANT BLUE NEVUS

Clinical Features Mean age, 32.6 (birth to 85) years Women > men Buttocks, sacrococcygeal area, extremities Size: 1.8 cm (1-2 cm) Blue, blue-gray, blue-black nodule

Extremely rare: mean age, 46.1 years Men > women Scalp most common site Size: 2.9 cm (1.3-4 cm) Blue, blue-black nodule

Lymph Node Involvement by Cellular Blue Nevus On occasion, foci of CBN may be detected in regional lymph nodes,167,203,204 such as the axillary or inguinal lymph nodes proximal to a CBN on an extremity. These nodal foci of CBN have most commonly involved the subcapsular peripheral sinuses and parenchyma of the lymph nodes, which are sites involved by metastatic cancer, but also the lymph node capsule. Explanations for such nodal involvement include benign metastases and aberrant histogenesis of CBN in lymph nodes.203,204 The latter phenomenon should be recognized, carefully assessed, and not misdiagnosed as metastatic melanoma or MBN. Similarly, a cutaneous lesion should not be misdiagnosed as MBN simply because of the lymph node involvement.

Patchlike Blue Nevus

Histopathologic Features Component of ordinary blue nevus in 60% Symmetry Lobular or multilobular Cytologic atypia, low grade or absent Mitoses <1 or 2/mm2 Usually no atypical mitoses Necrosis uncommon

melanoma, whether primary or metastatic. MBN is discriminated from CBN by greater degrees of cytologic atypia, greater mitotic activity with atypical forms, and necrosis. There may be considerable heterogeneity within MBN, and the diagnosis has been missed because of this histologic variation.199-202 The presence of a concomitant conventional blue nevus element favors a diagnosis of CBN. It cannot be overemphasized that although MBN is exceedingly rare, atypical CBN should be completely excised and the patient monitored very carefully for recurrence. Metastases from such lesions have been observed after the passage of several years (as long as 15 years). Thus, because of the unusual nature of these lesions, their rarity, and the lack of long-term follow-up, the biologic potential of atypical forms of CBN is largely unknown and requires further study.

CHAPTER 27 ■ TUMORS OF MELANOCYTES

in the typical fashion by fibrous trabeculae that usually contain some dendritic melanocytes and melanophages. Recognition of other features of CBN, such as the lobular, well-demarcated configuration and clinical features, are necessary for diagnosis as CBN. Perhaps two-thirds or so of CBN have a so-called “biphasic” pattern, that is, a component of common blue nevus, areas containing pigmented dendritic melanocytes, variable sclerosis, and melanophages, in addition to the cellular areas.169,194 These areas are often in the superficial dermis overlying or at the periphery of cellular lobules. A rather characteristic feature of CBN is cystic degeneration (“encystification”), which is often centrally located and probably indistinguishable from similar changes in ancient schwannoma. The latter may have an ischemic or traumatic basis. These degenerative changes are typified by edema, myxoid stromal alteration, diminished cellularity, and scattered melanophages. Alterations of blood vessels also tend to be a prominent feature and include ectatic vessels with hyalinization of their walls and thrombosis.

Blue nevus component, cellular in 92% Asymmetry Lobular or multilobular Substantial cytologic atypia in some Mitoses 1-2/mm2 Atypical mitoses may be present Necrosis in 33% Pronounced heterogeneity in most tumors (1) Frankly malignant component in some — severely atypical epithelioid or spindle cells with prominent nucleoli (2) Confluent sheets of spindle cells suggesting sarcoma (3) Presentation of “atypical cellular blue nevus”

CLINICAL AND HISTOPATHOLOGIC FEATURES A macular area of blue-gray pigmentation from 1 cm to several centimeters clinically resembles a Mongolian spot.205,206 However, in contrast to a Mongolian spot, the patchlike blue nevus contains a greater number of dendritic melanocytes in the dermis.

Plaque-Type Blue Nevus CLINICAL AND HISTOPATHOLOGIC FEATURES A palpable area of blue-gray pigmentation measures 1 cm to several centimeters or more in diameter.168,181-184 The plaque is either a single lesion or composed of

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discussed below. A number of closely related processes reported in the literature as “combined” nevus, deep penetrating nevus, plexiform spindle cell nevus, inverted type A nevus, and melanocytic nevus with focal dermal epithelioid cell components or dermal nodules are mentioned because of their unusual histologic features. The latter processes are often related because of depth, architecture, and the presence of pigmented cells that may be oval, elongate, epithelioid, spindled, or perhaps dendritic.20 Discriminating features include superficial or deep disposition, configuration (ie, plexiform, bulbous), cell type (ie, pigmented spindle cell, epithelioid cell, dendritic cell), and two or more populations of cells.20

Melanocytic Nevus with Phenotypic Heterogeneity (Combined Nevus)

 FIGURE 27-24 Cellular blue nevus with atypical features. Note the uniformly and highly cellular nodular nature of the lesion without typical zonation of superficial common and deep cellular blue nevus components.

multiple but distinct papules. Eruptive or agminated blue nevi, patchlike blue nevus, pilar neurocristic hamartoma, and plaque-type blue nevus are probably closely related.214 The histologic features are similar to ordinary blue nevi; there may be prominent periappendageal aggregation of dendritic melanocytes and compact bundles of spindle cells.

Pilar Neurocristic Hamartoma CLINICAL AND HISTOPATHOLOGIC FEATURES Multiple perifollicular papules occupy an area of skin measuring several centimeters in diameter.207 Individual papules vary in color from tan to blue or black. There is some similarity to patch and plaquelike blue nevi in humans and equine melanotic disease. Prominent perifollicular accumulation of dendritic melanocytes shows extension to nearby eccrine ducts. The intervening reticular dermis contains scattered pigmented dendritic cells resembling a Mongolian spot.

Target Blue Nevus

648

CLINICAL AND HISTOPATHOLOGIC FEATURES A central dark blue nodule is surrounded by a flesh-colored annulus and more peripheral blue-black macular annulus.

The lesion measures approximately 1 cm in greatest diameter and has been reported to occur on the dorsal aspect of the foot.208 The dark central nodule has the features of a typical blue nevus, that is, a fibrotic tumor containing pigmented dendritic cells and fusiform cells. The flesh-colored annulus shows dermal sclerosis and significantly reduced numbers of pigment-containing cells. However, in contrast, the most peripheral zone has prominent numbers of the pigmented dendritic cells.

MELANOCYTIC LESIONS WITH PHENOTYPIC HETEROGENEITY The developmental biology of melanocytic nevi is poorly understood and thus explanations for the variance in cell type, melanin content, stroma, and other characteristics currently do not exist. To better characterize the wide range of cellular and stromal variations that may occur in melanocytic lesions, the author has coined the overarching term melanocytic nevus (or tumor) with phenotypic heterogeneity (MNPH).20 Accordingly, the salient features of the most common melanocytic lesions with phenotypic heterogeneity the pathologist is likely to encounter are

The term combined nevus was used initially to describe the combination of ordinary nevus, blue nevus,20 and components of Spitz nevus and PSCN.209-211 However, the spectrum of combined nevus has been subsequently extended by the author as MNPH to include components of any type of nevus such as blue nevus (ordinary, cellular, congenital, epithelioid, and so on); congenital nevus; Spitz nevus; PSCN (deep-penetrating nevus [DPN] and plexiform PSCN); and nevi with pigmented dermal components that have been characterized under a number of terms, including inverted type A nevus, nevus with focal dermal epithelioid component, and nevi with dermal nodules.20,212-214 CLINICAL FEATURES The characteristics of MNPH are probably related to the predominant cellular population present, for example, whether blue nevus or Spitz nevus (Table 27-19).20,209-218 Most patients are young, and there is a predominance of women. MNPH may demonstrate a small, well-circumscribed blue or blue-black focus, often 1 to 3 mm in diameter, within an otherwise ordinary flesh-colored, tan, or brown nevus.213,214 HISTOPATHOLOGIC FEATURES A very common pattern is that of an ordinary nevus and blue nevus (see Table 27-19 and Fig. 27-25). The ordinary nevus component may be compound or dermal and often overlies or is adjacent to the blue nevus component. Another common pattern is an ordinary nevus in combination with discrete foci of pigmented spindle

Table 27-19 Melanocytic Nevus with Phenotypic Heterogeneity (Combined Nevus)

cells or pigmented epithelioid cells.212,214 The latter cells are often enlarged, contain abundant granular melanin, and are disposed in nests or fascicles in the deep portions of or beneath the ordinary nevus,

Melanocytic Nevus with Focal Atypical Epithelioid Cell Component Synonyms: Inverted type-A nevus, nevus with dermal nodules The morphologic pattern invoked by melanocytic nevus with focal atypical epithelioid cell component is one probably also encompassed by MNPH.20,211-214 The term describes discrete nests of epithelioid cells, usually pigmented, within the dermal component of an

 FIGURE 27-25 Melanocytic nevus with phenotypic heterogeneity (ordinary compound nevus overlying blue nevus component). Note the well-defined zone of small nevus cells in superficial dermal overlying the blue nevus.

ordinary nevus. These nests are often deep and may be multifocal. DIFFERENTIAL DIAGNOSIS The histologic change of most concern is an aberrant focus of cytologically altered or atypical cells in an otherwise ordinary nevus, suggesting transformation to melanoma. However, the development of melanoma in the dermal component of a nevus is highly unusual. Although occasional aggregates of epithelioid cells are large, many are small and well circumscribed. Cytologic atypia is usually low grade or insignificant compared with melanoma. The surrounding nevus, which commonly is of ordinary type, is generally unremarkable with reference to atypicality. An occasional mitosis may be observed in such a focus without undue concern; however, the presence of two or more mitoses per high-power field should prompt careful inspection for melanoma. Although combined nevi are heterogeneous, they tend to be present in fairly young individuals (younger than 40 years of age), measure less than 5 or 6 mm, and exhibit an overall symmetry and regular appearance.

Deep-Penetrating Nevus DPN describes a group of unusual nevi with disturbing morphologic features, 215,216 but that are nonetheless related to blue nevus, CBN, and Spitz nevus. CLINICAL AND HISTOPATHOLOGIC FEATURES Most patients range in age from 10 to 30 years (Table 27-20). DPN most commonly involves the face, upper trunk, and proximal extremities; measures less than 1 cm in greatest diameter; and is clinically diagnosed as blue nevus or CBN. Scanning magnification discloses a symmetric, well-circumscribed lesion with involvement of the deep reticular dermis and possibly subcutis (see Table 27-20).215,216 The overall architecture is usually that of a wedge extending into the deep dermis (Fig. 27-26). The superficial dermal portion is characterized by a diffuse proliferation of pigmented spindle cells that show progressive organization as discrete fascicles or nests with descent into the deep dermis. Junctional nests are noted in some lesions. The fascicles of spindle cells tend to be associated with neurovascular and adnexal structures of the lower reticular dermis. These cellular aggregates often exhibit bulbous contours and may bulge into the subcutis, as do CBN. Melanophages are usually intimately associated with the spindle cells. Some

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Clinical Features Any age (birth to old age) but usually <40 years of age Women > men Head and neck (especially for blue nevus variants), upper trunk, proximal extremities Often component of blue, blue-black May have small (1-5 mm) blue, blue-black focus in ordinary nevus Size <6-7 mm in most instances Histopathologic Features Symmetric Well circumscribed Orderly arrangements of cells Two or more of the following: (1) Ordinary nevus component (2) Pigmented dendritic melanocytes (3) Pigmented spindle or epithelioid cells (4) Amelanotic spindle cells (5) Spitz nevus cells Ordinary nevus component often overlies or is adjacent to other component Deep involvement occurs often Plexiform configuration on occasion Differential Diagnosis Cellular blue nevus Melanoma

sometimes in a plexiform arrangement. The sizes of the nests or fascicles may vary from minuscule to large lobular or digitate aggregates. The nuclei are usually slightly enlarged round, oval, or elongated and uniform, but on occasion show slight to moderate atypia. Melanophages are also frequently associated with these pigmented foci. This pattern may be morphologically identical to DPN and plexiform PSCN.215-218 Spitz nevi uncommonly are observed in association with ordinary nevus elements.209 The topographic relationships of these two components include the Spitz nevus component being adjacent to, beneath, or admixed with the common nevus elements. Almost any combination of cell types is possible. Thus, one may encounter nevi containing various admixtures of ordinary nevus cells, dendritic melanocytes, Spitz nevus cells, and perhaps other transitional cell types. Atypical features may also be observed, such as melanocytic atypia of the intraepidermal component.209-211

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Table 27-20 Deep-Penetrating Nevusa

650

Clinical Features Age range, 10-30 years, but any age may be affected Site: face, upper trunk, proximal extremities Size: <1 cm Raised lesions with bluish color Histopathologic Features Symmetric Well circumscribed Wedge configuration in dermis Extension of cellular fascicles into deep dermis or subcutis Pigmented spindle cells in fascicles associated with neurovascular bundles Occasional junctional nests Diffuse involvement of superficial dermis Occasional cytologic atypia Differential Diagnosis Spitz nevus Cellular blue nevus Melanoma

A

a

Plexiform spindle cell nevus is similar to deeppenetrating nevus but shows a striking plexiform configuration that is not always present in deeppenetrating nevus. Neither does the plexiform nevus always extend as deeply as deep-penetrating nevus. B

nevi may show sometimes disturbing cytologic atypia. Rare mitoses (1 to 2/mm2) may be encountered in some lesions.

 FIGURE 27-26 Plexiform pigmented spindle cell nevus. (A) Characteristic appearance on scanning magnification of fascicles of pigmented spindle cells in plexiform arrangement. The fascicles are associated with appendages, blood vessels, and nerves. There is normal collagen separating these cellular aggregates. (B) This field shows a bundle of uniform-appearing fusiform cells. The cells contain fine granular melanin and monotonous nuclei with dispersed chromatin.

Plexiform Spindle Cell Nevus CLINICAL AND HISTOPATHOLOGIC FEATURES Plexiform spindle cell nevus is closely related to superficial PSCN, Spitz nevus, blue nevus, and DPN.20,134,217,218 The lesions thus far reported have occurred in young adults (mean age, 22.5 years) and have involved the shoulders and back.223 Clinically, the lesions are raised and bluish or black, suggesting blue nevus, an atypical nevus, or melanoma. Most lesions are slightly raised, symmetric, and exhibit a wedge-shaped configuration in the reticular dermis.217 The most striking feature is the plexiform arrangement of fascicles of pigmented spindle cells that track along adnexal structures and neurovascular bundles (see Fig. 27-26A). Other common features include junctional nests, diffuse involvement of the superficial dermis, and infiltration of cutaneous nerves and arrector pili muscles. The spindle cells

contain abundant granular melanin and oval or elongate nuclei with delicate chromatin patterns and inconspicuous nuclei (see Fig. 27-26B). Occasional low-grade cytologic and rare mitotic figures (usually no more than 2/mm2) are observed. DIFFERENTIAL DIAGNOSIS Because of the presence of pigmented spindle cells and frequent deep involvement, plexiform spindle cell nevi are closely related to DPN. However, they are discriminated from DPN by their striking plexiform configuration (often lacking in DPN) and frequent absence of bulbous cellular aggregates and deep involvement. Because of the unusual nature of these nevi, the immediate concern is melanoma, whether primary or metastatic

(see Table 27-20). Particular features that aid in this differential diagnosis are the usual size being less than 6 or 7 mm (almost always <1 cm), overall symmetry, nondisruptive growth patterns, lack of high-grade atypia, and lack of significant mitotic activity in such nevi. Nonetheless, some of these nevi are quite challenging because of large size, confluent masses of cells without evidence of maturation, and cytologic atypia. As a result, the biologic potential of a small minority of such lesions may be difficult to predict. Rare instances of lymph node metastases have been observed.218 The most appropriate management is to communicate to the clinician the uncertain but possibly aggressive potential of such tumors.

CLINICALLY AND HISTOLOGICALLY ATYPICAL MELANOCYTIC NEVI; DYSPLASTIC NEVI; MELANOCYTIC NEVI WITH ARCHITECTURAL DISORDER AND CYTOLOGICAL ATYPIA

been termed simply “atypical nevi,” (2) nevi with abnormal histopathologic features, (3) nevi with both abnormal clinical and histopathologic features, and (4) nevi with histopathologic features that are equivocal or of unknown significance. The latter group of nevi may demonstrate findings that may be reactive or proliferative in nature rather than neoplastic.234 The immediate significance of such lesions is whether they are markers of increased melanoma risk; whether they are precursors of melanoma; and in practical terms, what their histologic distinction is from outright melanoma. Because of the controversy surrounding these nevi, a National Institutes of Health Consensus Conference recommended that the term dysplastic nevus be abandoned in favor of nevus with architectural disorder or cytologic atypia.248

The Significance of Atypical Melanocytic Nevi MARKERS OF INCREASED MELANOMA RISK Based on studies of hereditary melanoma kindreds,219,220,222,228,253,254 the presence of AMN on individuals in these kindreds confers a significantly increased risk for the development of melanoma. In fact, the presence of DMN in this setting confers a 48.9% cumulative risk for melanoma by age 50 years.254 In prospective follow-up, only family members with DMN developed melanoma; those without DMN did not develop melanoma. Individuals in the general population have DMN,265 which also serve as markers for increased melanoma risk, although not nearly so great as in familial melanoma.222,228 Estimates of the relative risk for melanoma in persons with sporadic DMN may be in the range of 7 to 20.263,265 The prevalence of individuals with sporadic DMN has been difficult to accurately gauge but may be in the range of 0.5% to 20%.223,229,244 One particular reason for the difficulty in estimating the prevalence of DMN is the lack of standardized clinical and histopathologic criteria for DMN and what constitutes the minimum essential criteria for the DMN phenotype (eg, 50 or 100 or more clinically atypical nevi) (Table 2721).240,255 Classifications have been devised for individuals with DMN and the extent to which they have a personal or family history of melanoma and DMN. Although much more information is needed on this subject, risk stratification protocols have been formulated to facilitate assessment of melanoma risk and the management of patients. Melanoma risk is probably a continuum,

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Synonyms: B-K mole, Clark nevi, melanocytic nevi with atypical features Since the description of atypical or “dysplastic” melanocytic nevi (DMN) in the setting of melanoma-prone families about 30 years ago and subsequently in individuals outside such kindreds, these lesions have remained highly controversial.219-271 This has largely resulted from the failure to reach consensus about the nature of these lesions, an inability to formulate precise criteria for recognition, and a lack of understanding about their biologic significance. Specifically, this relates to criteria for individual lesions and for the so-called “dysplastic nevus syndrome,” that is, how many clinically DMN are needed and what minimal essential gross morphologic criteria are needed for diagnosis of an individual lesion. One particular problem dating back to the original studies on DMN in hereditary kindreds has been the tendency to consider that histopathologic diagnosis of DMN is the gold standard; however, it has been shown that the histopathologic features ascribed to DMN lack specificity.234,239,257,269,270 To appreciate the nature of the problem, one must emphasize, as already discussed, the considerable clinical and histopathologic heterogeneity among benign melanocytic nevi. This is present to such a degree that there is substantial disagreement among many as to how to categorize a significant proportion of nevi with atypical, aberrant, or unusual features and their importance as risk markers for and precursors to melanoma. Furthermore, some authors consider “dysplastic” nevi to be distinctly different from other unusual nevi, such as small congenital-pattern nevi and nevi occurring on particular anatomic sites, such as acral skin, the vulva, scalp, and so on despite the frequent presence of histomorphologic features ascribed to “dysplastic” nevi in these other nevi. In principle, the author contends that all melanocytic nevi, even normal-appearing ones, may demonstrate atypical histologic features intermediate between banal nevi and melanoma. Until recently the biologic significance of such abnormal features had not been established.

However a recent case-control study involving the grading of histologic atypia (“dysplasia”) in a series of melanocytic nevi by 13 pathologists has shown that nevi with moderate to severe atypia versus nevi with lesser degrees of atypia are an independent risk factor for melanoma.271 Many pathologists are sufficiently well schooled to be able to reliably recognize a prototypic “dysplastic” nevus. However, significant problems arise when these pathologists encounter the upper and lower limits of this histopathologic spectrum. Many variations of nevi do not fit the textbook picture of a “dysplastic” nevus and the reproducible assessment of architecture and cytologic atypia in such nevi. Accordingly, much remains to be learned about the development and natural history of nevi; their variation with anatomic site, age, and so on; and how many external or intrinsic factors induce reactive versus neoplastic alterations in nevi, or both. As a result, there is currently no consensus about histopathologic definitions of atypical nevi. Consequently, it is difficult to estimate the prevalence or melanoma risk related to them, except in the instance of specific gross morphologic features and numbers of nevi. Thus, many studies have established that irrespective of histology, melanoma risk is directly related to numbers of ordinary nevi (>50 or 100 on the total skin surface), the presence and number of atypical nevi as defined by size (eg, >5, 6, or 8 mm), irregular or ill-defined borders, variation in color, macular component, and the like. On the other hand, it seems logical that histopathologically, atypical nevi should be associated with increased melanoma risk. However, this has not been convincingly demonstrated until recently and requires more detailed study. Furthermore, studies examining the relationship between clinical DMN and histopathologic DMN have shown a poor correlation. Therefore, the “dysplastic” nevus cannot be considered a distinct clinicopathologic entity because the histopathologic features ascribed to histopathologic DMN lack specificity, as already mentioned. Currently, melanoma risk assessment of patients is based solely on gross morphologic parameters of nevi—that is, total numbers of nevi on the skin surface and the presence and numbers of clinically DMN—along with other factors such as personal and family history of melanoma. Therefore, at present, DMN undoubtedly encompass a large and heterogeneous group of nevi, including (1) nevi with atypical clinical features that have

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Table 27-21 Atypical Melanocytic (Dysplastic) Nevi

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Clinical Features General Increased numbers of typical and atypical nevi (eg, >50) Variation in gross morphologic features among nevi Increased numbers of nevi on scalp, female breasts, buttocks Nevus characteristics Increased size (4-12 mm, but not always) Asymmetry Macular component Irregular border Ill-defined border Altered topography, pebbled or cobblestoned surface Haphazard, variegated, or greater complexity of coloration Histopathologic Features Architectural features Lentiginous melanocytic proliferationa Variation in size, shape, location of junctional nests with bridging or confluencea Lack of cellular cohesion of junctional nests Lateral extension (the “shoulder” phenomenon) of junctional component Cytologic features Spindled cell (with prominent retraction artifact of cytoplasm) pattern Epithelioid cell pattern Discontinuous nuclear atypia (not all nuclei atypical)a Nuclear enlargement Nuclear pleomorphism Nuclear hyperchromatism Prominent nucleoli Prominent pale or “dusty” cytoplasm Large melanin granules Host response Lymphocytic infiltrates Fibroplasia Concentric eosinophilic pattern Lamellar pattern Prominent vascularity Differential Diagnosis Banal melanocytic nevi Congenital nevi Melanoma, in situ or invasive a

Essential features needed for diagnosis. Either lentiginous melanocytic proliferation or variation in junctional nesting is acceptable.

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with risk directly related to family history of melanoma, especially for individuals with at least two first-degree blood relatives with melanoma; the total number

of nevi on the skin surface; the total number of clinically atypical nevi; and the patient’s personal history of melanoma.240,249 ATYPICAL MELANOCYTIC NEVI AS PRECURSORS TO MELANOMA AMN occasionally progress to melanoma and thus serve as precursors to melanoma. This progression has been observed through the use of serial photographs and the documentation histologically of focal melanoma developing in an otherwise stable DMN.227 Various authors have also reported remnants of DMN associated with melanoma with an average frequency of approximately 33%.239,233,256 A confounding problem in this situation is the inability in all instances to clearly distinguish the intraepidermal component of melanoma from DMN. CLINICAL FEATURES The numbers of clinically atypical nevi on an individual patient may vary from only one or two to in the hundreds or more.228 Although the majority of AMN occur on the trunk, these nevi show a peculiar propensity for the scalp, female breasts, buttocks, and dorsal surfaces of the feet (see Table 27-21). DMN tend to show considerable variation in size, shape, and coloration from nevus to nevus. DMN (Table 27-21)19,235 are usually larger than common nevi and smaller than melanoma (but not necessarily so) and generally measure 3 to 12 mm or larger (Fig. 27-27A). They often show asymmetry, often have irregular and illdefined borders, and have a relatively flat surface (at least part of the lesion is entirely flat). The surface may also be “pebbled” or have a cobblestoned appearance. DMN generally have a more complex color than do ordinary nevi. There are often more than two colors present (ie, tan, brown, dark brown), and the colors have an irregular or haphazard pattern. HISTOPATHOLOGIC FEATURES The histologic criteria include parameters of architectural disorder, cytologic atypia, and host response (Figs. 27-27 to 27-29; see Table 27-21).20,220,221,224,226,238,240,243,248,266-268 The majority of DMN, perhaps 80%, are compound; the remainder are junctional. Most are relatively flat with only slight expansion of the papillary dermis by limited dermal components. Many (but not all) DMN are lentiginous, that is, the epidermal rete ridges are elongated, are often club shaped, and are accompanied by melanocytic hyperpla-

sia, and the epidermis has an increased melanin content (see Figs. 27-26 to 27-29).238,240 Many heavily pigmented AMN also contain melanin macroglobules in the basilar epidermis, an entirely nonspecific finding.238 Many (perhaps the vast majority) compound AMN have lateral extension and poor circumscription of the intraepidermal components (see Fig. 27-27A). The latter features refer to the intraepidermal melanocytic component extending laterally or peripherally beyond the papillary dermal nevus elements (the “shoulder” phenomenon) and gradually diminishing in cellularity without clear-cut demarcation. Although not a fundamental component of dysplasia as outlined above, lateral extension is a useful feature in recognizing most compound AMN, particularly at scanning magnification, and correlates with the peripheral macular annulus observed clinically in many AMN. Junctional AMN by definition do not display lateral extension but tend to be poorly circumscribed. The essential architectural feature is disordered intraepidermal melanocytic proliferation,226,238 which includes two patterns: (1) lentiginous melanocytic proliferation (see Fig. 27-27B) and (2) disordered or irregular junctional nesting (see Fig. 27-27C and 27-27D). Both patterns are often present to varying degrees in many AMN, but either pattern may be present alone. The frequency of melanocytes in AMN is, as a rule greater than in a lentigo, often reaching confluence and replacing basilar keratinocytes. In its most extreme version, the proliferation of melanocytes may result in multilayered confluence of cells along the dermal-epidermal junction, often “bridging” between rete. The melanocytes present in this pattern commonly exhibit retraction of cytoplasm, resulting in a vacuolated appearance of the basal layer, almost suggesting basal layer vacuolopathy. The nuclei within these vacuolated cells are commonly pleomorphic with angulated contours (see Fig 27-27D).238,240 Compared with typical nevi, junctional nests in AMN tend to vary significantly in size, shape (ovoid, elongate, or confluent along the dermal-epidermal junction), and spacing (nests are not present at equidistant intervals). Instead of being located at the tips of rete, junctional nests are irregularly distributed on the sides and between rete, often with no regular pattern (“irregularly irregular”). Bridging of nests between rete is another feature of the abnormal nesting pattern. Often paralleling the variation

B

C

D

CHAPTER 27 ■ TUMORS OF MELANOCYTES

A

E  FIGURE 27-27 Compound nevus with architectural disorder and cytologic atypia (dysplastic nevus). (A) Clinically atypical compound melanocytic nevus. They measures about 1 cm in greatest diameter, exhibit slight asymmetry, and have some variation in color. (B) This field demonstrates the lateral extension of the intraepidermal component (to the left) beyond the dermal nevus component (right side of the field). (C) Disordered junctional nested pattern. There is variation in the size, shape, and placement of junctional nests. (D) Higher magnification shows irregular junctional nesting and horizontal confluence of melanocytes at the dermal-epidermal junction. Cytologic atypia of melanocytes is evident at this magnification. (E) Disordered lentiginous pattern. The basilar melanocytes reach confluence along the rete ridges. (Figure 27-27A: Courtesy of P Guitera and SW Menzies, Sydney Melanoma Diagnostic Centre and Dermatology Department, Royal Prince Alfred Hospital, NSW, Australia.)

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 FIGURE 27-28 Compound nevus with architectural disorder and cytologic atypia (dysplastic nevus). Higher magnification discloses variation in size, shape, and staining of nuclei of basilar melanocytes. Some melanocytes have nuclei larger than those in spinous layer keratinocytes.

 FIGURE 27-29 Junctional nevus with architectural disorder and cytologic atypia (dysplastic nevus). Note the severe cytologic atypia. Some nuclei are more than twice the size of adjacent keratinocytic nuclei.

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in nesting is the loss of cellular cohesion in junctional nests. The individual nevus cells literally appear to fall apart, with clear spaces forming between individual cells and aggregates of cells. Although upward migration of melanocytes throughout the epidermis is not a common feature of AMN, it is seen on occasion but is often limited, focal, or orderly in appearance.

CYTOLOGIC FEATURES A fundamental criteria for AMN is variable (or discontinuous) cytologic atypia of intraepidermal melanocytes (see Figs. 27-27 to 27-29).226,237,238,243,266 The latter refers to intraepidermal melanocytes that are not uniformly atypical but tend to vary from cell to cell as to the degree of nuclear atypia. In general, this nuclear atypia is a continuum and is characterized by gradual

nuclear enlargement, pleomorphism, variation in nuclear chromatin pattern, and the eventual development of prominent nucleoli. The beginnings of nuclear atypia may be almost imperceptible and may not be reproducible. Commonly with slight or low-grade cytologic atypia, the cells show retraction of cytoplasm, and the size of the melanocytic nuclei is increased and approximates that of or is slightly larger than the nuclei of spinous layer keratinocytes.266 With greater (moderate) atypia, the nuclei are somewhat larger than the nuclei of spinous layer keratinocytes, and the nucleoli are more commonly visible. With severe cytologic atypia, the melanocytes may contain abundant cytoplasm, which often has a granular eosinophilic appearance or may contain finely divided (“dusty”) melanin. The nuclei may be enlarged to twice the size of spinous layer keratinocyte nuclei or larger (see Fig. 27-29). Nucleoli are often enlarged and may be eosinophilic. The ultimate end point is a uniformly atypical population of cells, which marks the development of melanoma. The cell types that comprise AMN include basilar melanocytes with retracted cytoplasm; small, rounded nevus cells; spindle cells; sometimes pigmented cells; and epithelioid cells.20,266 Whereas the basilar melanocytes with retraction of cytoplasm are often observed in predominantly lentiginous forms of AMN, the epithelioid cell type is often present in a much less prevalent, predominantly nested form of AMN (so-called epithelioid cell dysplasia). HOST RESPONSE Among mononuclear cell infiltrates, fibroplasia, and prominent vascularity, the first two have received considerable attention as criteria for AMN.226,266 Lymphocytic infiltrates are present in the overriding majority of AMN. These infiltrates vary from sparse perivascular lymphoid infiltrates (see Fig. 27-27) to dense, bandlike infiltrates filling the papillary dermis. The more common form of fibroplasia is concentric eosinophilic fibrosis, which is hyalinized collagen that is compactly disposed about the epidermal rete ridges. Lamellar fibroplasia is less prevalent and notable for delicate stacking of horizontally disposed collagen, subjacent to the epidermal rete ridges (see Fig. 27-27). Mesenchymal spindle cells typically line these filamentous strands of collagen. Both patterns of fibroplasia may be present in the same lesion or occur separately.

Histologic Variants of Atypical Melanocytic Nevi If melanocytic nevi constitute a clinical and histologic continuum encompassing typical and atypical variants, one can envisage that there is theoretically an atypical histologic variant corresponding to every recognized conventional nevus entity. Thus, one can predict that many variants of AMN exist, taking into consideration the lack of universally accepted criteria for AMN, the inherent heterogeneity of nevi, and the influence of other factors such as age and anatomic site.

HALO NEVUS VARIANT These AMN display dense mononuclear cell infiltrates, filling the papillary dermis and obscuring any nests of nevus cells present.20 These nevi are distinguished from benign halo nevi by aberrant architectural features and cytologic atypia.

Specificity of Histologic Features of Atypical Melanocytic Nevus Disordered arrangements of melanocytes and cytologic atypia are encountered in a spectrum of lesions that are thought to be distinct from conventional AMN.20,265 As extensively discussed above, such dis-

DIFFERENTIAL DIAGNOSIS The AMN must be distinguished from in situ or invasive melanoma, solar atypical lentiginous melanocytic proliferations, and melanoma in situ of sun-damaged skin (historically termed lentigo maligna and Hutchinson melanotic freckle), lentiginous nevi, PSCN, Spitz nevus, halo nevus, congenital nevus, and recurrent nevus. One of the most difficult problems is the discrimination of severely atypical AMN from in situ or microinvasive melanoma. This differential diagnosis is discussed below, and Table 27-22 summarizes the most salient points. In one sense, this distinction is somewhat arbitrary and subjective because no consensus has been reached regarding criteria for separating the two entities. However, in another sense, the central issue is whether a particular lesion retains some degree of growth control, an orderly nevic appearance, and variable or discontinuous nuclear atypia versus loss of growth control, loss of an orderly nevic appearance, and continuous nuclear atypia. AMN, lentiginous melanocytic proliferations (SIMP), and melanoma in situ of sun-damaged skin show histologic similarities on occasion and may be difficult to separate. SIMP is distinguished from AMN in most instances because SIMP is an atypical melanocytic proliferation secondary to cumulative sun exposure and consequently develops on markedly sun-exposed skin of elderly individuals

(average age, 60 years). The most common locations are the cheek and nose, which are unusual sites for conventional AMN. SIMP is usually a de novo atypical melanocytic proliferation because whereas dermal nevus components are uncommon, approximately 80% of AMN contain dermal nevus cells.237 SIMP developing on the central face most commonly shows a basilar proliferation of variably atypical melanocytes that often involve the appendageal epithelium. The epidermis is usually effaced (ie, has no rete ridge pattern), and prominent solar elastosis is present in the dermis. In contrast, the AMN generally has elongated rete ridges with concentration of basilar melanocytes and many junctional nests along the rete ridges, and solar elastosis is usually minimal. Solar melanoma in situ may also have junctional nests, but they are often discohesive elongate nests composed of pigmented spindled cells. On occasion, the latter nests show striking involvement of hair follicles and eccrine ducts, a finding not typically observed in AMN. SIMP and solar melanoma in situ may show a rete-ridge pattern and thus present an even greater problem in the differential diagnosis. Discriminating features favoring SIMP include a mainly lentiginous pattern of melanocytic proliferation, prominent involvement of appendages, presence of pigmented spindle cells, and solar elastosis. Overlap with AMN may occasionally be so great that separation may be difficult, often arbitrary, and unnecessary. The various clinical and histologic features present must be assessed. If discrimination is not possible, a reasonable approach is a descriptive diagnosis—for example,

CHAPTER 27 ■ TUMORS OF MELANOCYTES

EPITHELIOID CELL VARIANT The “epithelioid” cells resemble the cell type in pagetoid melanoma except that they tend to be less cytologically atypical.226 The cells are round or polygonal and contain abundant pink or “dusty” (finely divided melanin) cytoplasm. Relatively small, round nuclei are usually present in the centers of the cells. The cells tend to have an almost exclusively nested distribution, often without an associated lentiginous element.

tinctions in general terms may be meaningless for many nevi; however, without more definitive data, the possibility exists that such a distinction may be legitimate for some lesions or for a spectrum of atypia.271

Table 27-22 Comparison of Severely Atypical Melanocytic Nevus and Melanoma

a

SEVERELY ATYPICAL MELANOCYTIC NEVUSa

IN SITU OR MICROINVASIVE MELANOMAa

Some asymmetry Poorly circumscribed Rete ridges preserved Some maintenance of nevus nesting pattern and order Some diminished cohesion of nests Lentiginous melanocytic proliferation concentrated on rete ridges Pagetoid spread absent, miminal, or not prominent Discontinous cytologic atypia Often some maturation of dermal component Usually no mitoses in dermal component Usually perivascular lymphocytic infiltrates

Prominent asymmetry Poorly circumscribed Tendency to loss or effacement of rete ridges Loss of orderly nesting pattern Diminished cohesion of nests may be prominent Loss of rete-oriented melanocytic proliferation Pagetoid spread prominent Fairly uniform (continuous) cytologic atypia Often no maturation of dermal component Uncommon mitoses in dermal component (microinvasive melanoma) Tendency to bandlike lymphocytic infiltrates

The histologic guidelines listed in this table represent the most common presentation. However, there is considerable variation among these features.

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“intraepidermal melanocytic proliferation with features of both SIMP and AMN and cytologic atypia.” Another conundrum is the distinction of AMN from lentiginous nevi, particularly those from acral skin. Here, the main problem is one of threshold: is there sufficient disordered architecture and cytologic atypia for the diagnosis of AMN? Such lesions should be evaluated for poor circumscription, asymmetry, substantially increased frequency of basilar melanocytes, irregularity of junctional nesting with elongated confluent nests, bridging of nests between rete ridges, and finally cytologic atypia of intraepidermal melanocytes. Lesions having equivocal changes should not be diagnosed as AMN. It is reasonable to designate the latter lesions as showing some architectural disorder or, alternatively, as having atypical or unusual features. As discussed below, a number of types of melanocytic nevi such as PSCN, Spitz nevus, and congenital nevus may on occasion demonstrate disordered architectural patterns and cytologic atypia. Yet at the same time, these various nevi retain many of the histologic features that make them distinctive—for example, fascicles of slender pigmented spindle cells in PSCN, large epithelioid cells in Spitz nevus, and extensive involvement of the reticular dermis in congenital nevus. Recurrent melanocytic nevi may occasionally enter into the differential diagnosis of AMN.

distinction from lentiginous nevi with architectural disorder and no cytologic atypia may not be possible. In general, slightly atypical AMN do not exhibit DNA aneuploidy.258

Histopathologic Reporting of Atypical (Dysplastic) Nevi The pathologist should communicate directly to the clinician in clear and unambiguous language the nature of the lesion and its significance, regardless of terminology used. In one sense, the significance of the individual lesion is related to the degree of histologic atypia in that lesion and its risk for progression to melanoma. The immediate concern is to ensure proper management of the individual lesion (ie, degree of histologic atypia is properly assessed) and the need for additional therapy (ie, surgery), if any, is communicated to the clinician (Table 27-23). In another sense, the significance of an AMN must be viewed from the perspective of global melanoma risk in the patient. Thus, the significance of the individual AMN can be viewed in quantitative terms and is directly related to the degree of histologic atypia (eg, moderate to severe versus slight or no atypia), family history of melanoma, family history of AMN, personal history of melanoma, the patient’s nevus phenotype (total number of typical and atypical nevi on the skin surface), the degree of atypia of previously removed nevi, and other risk factors for melanoma.

MALIGNANT MELANOMA

Classification of Cutaneous Melanoma The morphologic spectrum of cutaneous melanoma (Table 27-24) may be described according to number of phenotypic characteristics: (1) the location of melanoma cells in the skin, whether intraepidermal, dermal, subcutaneous, or soft tissue; (2) the disposition and frequency or density of melanocytes in these domains, for example, pagetoid (dispersion of single and small groups of melanocytes throughout epidermis), lentiginous (a basilar epidermal single-cell proliferation of melanocytes), or nested arrangements of cells in the epidermis, single-cell infiltrating, or aggregative (nodular) patterns in the dermis and subcutis; (3) unusual histologic features or stromal alterations, such as verrucous, papillomatous, or polypoid epidermal surface configurations; desmoplasia, myxoid stroma, neurotropism, neurogenic or neural differentiation; and resemblance to melanomas developing in animals, experimentally or spontaneous; and (4) cytologic features such as epithelioid, spindled, dendritic, nevuslike, small, clear, balloon, Spitz nevus-like and other cell types.20,272-277 Because nearly all melanomas are initiated in and localized to the epidermis (or epithelium) for some period of time, a classification of melanoma based on the presence or absence and patterns of intraepidermal involvement was developed and

Grading of Atypical (Dysplastic) Nevi The following guidelines are suggested: (1) severely atypical or high-grade AMN should be recognized because of their overlap with melanoma in situ. Such lesions should be completely excised with margins of at least 5 mm. (2) AMN with moderate atypia (see earlier discussion) should be completely removed with clear margins. Because DNA aneuploidy has been documented in such lesions, they may have a greater potential for progression to melanoma than less atypical lesions.258 In addition, nevi with moderate to severe atypia appear to be risk markers for melanoma,271 and the author has observed such nevi with positive margins to recur as melanoma (RL Barnhill, unpublished observations, 2009). (3) AMN with slight or minimal atypia need not have reexcision if the bulk of the lesion has been removed, even if the margins are involved. Such lesions are common, and reproducible

Table 27-23 Histopathologic Reporting of Atypical Melanocytic (Dysplastic) Nevi (Melanocytic Nevi with Architectural Disorder and Cytologic Atypia) GRADE OF LESIONa Low-grade lesions Junctional or compound nevus with architectural disorder (no cytologic atypia) Junctional or compound nevus with architectural disorder and slight cytologic atypia High-grade lesions Junctional or compound nevus with architectural disorder and moderate cytologic atypia Junctional or compound nevus with architectural disorder and severe cytologic atypia a

REEXCISION IF MARGINS INVOLVED No No, if bulk of lesion removed

Yesb Yes, with about 5-mm margins

See text for criteria for grades of cytologic atypia. This recommendation is based on the presence of nuclear aneuploidy in such lesions. However, the grading of atypia in nevi has not been standardized and is controversial; many histopathologists would not agree with these guidelines. b

Table 27-24 Classification of Melanoma According to Tissue Localization, Organizational Attributes (Disposition) of Melanocytes, Other Morphologic Features, and Cytology

has been used for some time.272-277 One idea behind such a classification was that particular intraepidermal patterns (also termed radial or horizontal growth phases) might correlate with differences in etiology and possibly prognosis.278 Four clinicopathologic subtypes of melanoma have been proposed (Table 27-25).19,272-277 Melanoma with an adjacent lentiginous intraepidermal component of sun-

Presence of radial growth phase Superficial spreading Lentigo maligna Acral lentiginous Unclassified Absence of radial growth phase Nodular melanoma

exposed skin (so-called lentigo maligna melanoma) may be distinct from other forms of melanomas with intraepithelial components (the pagetoid and acral forms of melanoma) because of its strong correlation with cumulative sunlight exposure, onset in older persons, and uncommon association with melanocytic nevi.272-284 Furthermore, this group of melanomas seems to have significantly fewer chromosomal aberrations compared with acral and mucosal melanomas, an absence of BRAF mutations, frequent gains in CCND1 and regions of chromosome 22, and losses of chromosome 4q.278 Melanomas with adjacent pagetoid intraepidermal components have been reported to correlate with intermittent sunlight exposure, develop in relative young individuals, have a frequent association with atypical nevi, and are associated with a high frequency of BRAF mutations.272-278 Acral (and mucosal) melanomas develop in relatively sun-protected sites, have a high frequency of chromosomal aberrations, and generally lack BRAF mutations.275-278,285,286 “Nodular” melanoma (NM) is described as having no adjacent intraepithelial component and is thought by many to be a final common pathway of rapid tumor progression irrespective of the intraepithelial pattern or location.20,272-278,287 Although no correlation between intraepidermal pattern (so-called radial growth phase) and prognosis has been established,288,289 some evidence shows that etiologic factors might still explain some of the morphologic patterns of melanoma, as discussed above.278 Nevertheless, an objective assessment of the classification of melanoma according to intraepidermal pattern or growth phase has not been clearly validated.290,291 The reasons for this view are (1) the tremendous morphologic heterogeneity of melanoma; (2) morphologic patterns may correlate with anatomic site; (3) the intraepithelial components of many

melanoma are not easily classified (because of overlapping features), and classification is not reproducible;290 (4) some intraepithelial components are difficult to recognize as either clearly benign, that is, a potential precursor such as atypical nevus, or malignant; and (5) the idea that nodular melanomas develop as de novo invasive tumors without any initial intraepithelial melanocytic proliferation272,273 is theoretically possible but has not been proved.287,290 Despite the drawbacks in the current classification of melanoma outlined above, melanoma nonetheless still seems to have distinct developmental pathways that are related to genetic and other host factors interacting with the environment. The schema outlined in Table 27-24 provides the framework for a working classification. An (adjacent) intraepithelial component, if present, should be recorded and, if possible, described according to its pattern as predominantly pagetoid, lentiginous, or nested, or any combination of these features, rather than necessarily applying a term such as superficial spreading or lentigo maligna melanoma. An invasive component should be recorded if present and measured in millimeters, and certain features should be recorded, such as anatomic level of invasion (Table 27-26), stromal alterations (eg, desmoplasia), invasion of nerves (neurotropism), cell type, and presence of a nevus remnant. CLINICAL FEATURES In general, cutaneous melanoma is a disease of adult whites and is rarely observed before puberty.292 Men and women are equally affected, although some European studies suggest a higher incidence in women. Patients are most commonly diagnosed with melanoma in the fourth through seventh decades of life. The most common sites include the trunk (back) followed by the upper extremities and head and neck for men and the lower extremities followed by the back, upper extremities, and head and neck for women. Gross morphologic features of melanoma include size often larger than 1 cm (range, 2 mm to >15 cm); irregular or notched borders; asymmetry; complexity of color, including a variable admixture of tan, brown, blue, black, red, pink, gray, and white; and ulceration and bleeding (Fig.27-30A).19,292 Early melanomas, especially those involving sun-exposed (Fig. 27-30B) and acral sites (Fig. 27-30C), may be completely flat, but with progression, usually developing a papular or nodular component (Fig. 27-30D). Melanomas lacking pigment (amelanotic melanoma)

CHAPTER 27 ■ TUMORS OF MELANOCYTES

1. Location in the skin Intraepidermal Dermal Subcutaneous Soft tissue 2. Disposition and frequency Intraepidermal component Pagetoid Lentiginous Nested Two or more patterns Not melanoma Dermal component Single cell infiltration Nests of cells Aggregative (nodule formation) 3. Specific morphologic features Epidermal surface configuration Verrucous Papillomatous Polypoid Stromal alterations Desmoplasia Myxoid alteration Other alterations Neurotropism Neural differentiation (neurogenic, neural transforming) Angiotropism Alveolar or glandular 4. Cell type Epithelioid Spindle Dendritic Nevus-1ike Small cell Balloon cell Clear cell Anaplastic giant cell Plasmacytoid Rhabdoid Signet ring 5. Precursor lesion Nevus remnant of any kind Other precursor

Table 27-25 Historical Classification of Malignant Melanoma

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A

B

C

D

E

F

 FIGURE 27-30 (A) Pagetoid melanoma. The lesion is relatively large, asymmetrical, and shows scalloped irregular borders. The color varies from a reddishbrown hue in the peripheral surrounding component to blue-black centrally. (B) Melanoma of chronically sun-exposed skin. Relatively thin lesion demonstrating asymmetry, irregular borders, and a tan to dark brown color. (C) Lentiginous melanoma of acral skin. The lesion exhibits a large diameter, asymmetry, irregular borders, and a striking variation in color. (D) Nodular melanoma. Small reddish-brown, blue-black nodule without visible surrounding component. (E) Pagetoid melanocytosis of epithelioid cells throughout epidermis. (F) Higher magnification shows the striking density of epithelioid melanoma cells within the epidermis and the degree of involvement of the superficial epidermis. (Figure 27-30A-D: Courtesy of P Guitera and SW Menzies, Sydney Melanoma Diagnostic Centre and Dermatology Department, Royal Prince Alfred Hospital, NSW, Australia.)

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Table 27-26 Anatomic Levels of Invasion Level I: Entirely intraepidermal; melanoma in situ Level II: Microinvasive into papillary dermis Level III: Expansion of papillary dermis by cohesive cellular nodule or plaque (but confined to papillary dermis) Level IV: Invasion of reticular dermis Level V: Invasion of subcutaneous fat

HISTOPATHOLOGIC FEATURES The Intraepithelial Component Almost all melanomas begin as a proliferation of melanocytes initially confined to the epidermis (Figs. 27-30 to 27-33).290 The latter proliferation may develop with or without a detectable melanocytic nevus. Estimates of the frequency of melanomas developing in continuity with a nevus of any kind vary widely; approximately one-third of melanomas have nevus remnants. The duration of this intraepidermal phase ranges from months to many years, during which these proliferative lesions show progressive degrees of architectural and cytologic atypicality. Increasing cytologic atypia of melanocytes accompanies the aberrant architectural appearance. The melanocytes vary in degree of atypia and the proportion of cells with nuclear atypia. However, atypical melanocytes usually have enlarged nuclei that exhibit variation in nuclear shapes and chromatin patterns and may have large nucleoli. Thickening of nuclear membranes and irregular nuclear contours is

Clinical Features In general, onset after puberty, but all ages affected Most frequent ages 30-70 years Whites >> Africans, Asians Women ≥ men Most common sites: lower extremities and trunk of women and trunk (back) of men Pain, pruritus Size often >1 cm (range: 2 mm - >15 cm) Initially macular; later stages may be papular and nodular Asymmetry Irregular and often notched borders Complexity and variation in color often with admixtures of tan, brown, black, blue, gray, white, red May be entirely skin-colored (amelanotic) or black Ulceration and bleeding may be present Histopathologic Features Architecture Asymmetry Heterogeneity of lesion Large size (>6 mm) but many exceptions Poor circumscription of proliferation Melanin not uniformly distributed Organizational abnormalities of intraepidermal component (1) Pagetoid spread Upward migration of melanocytes in random pattern, single cells predominate over nests Cells often reach granular and cornified layers (2) Lentiginous melanocytic proliferation Melanocytes reach confluence Nesting of melanocytes (sun-damaged skin) Melanocytes not equidistant Proliferation of melanocytes along adnexal epithelium (3) Nesting pattern Variation in size, shape, placement of nests Nests replace large portions of squamous epithelium Diminished cohesiveness of cells in nests Confluence of nests Loss of epidermal rete pattern (effacement) Mononuclear cell infiltrates, often bandlike Fibroplasia of papillary dermis Regression frequently present Cytology (1) Nuclear changes Majority of melanocytes uniformly atypical Nuclear enlargement Nuclear pleomorphism (variation in sizes and shapes) Nuclear hyperchromasia with coarse chromatin One or more prominent nucleoli (2) Cytoplasmic changes Abundant granular eosinophilic cytoplasm in epithelioid cells Finely divided (“dusty”) melanin Variation in size of melanin granules High nuclear to cytoplasmic ratios in spindle cells Retraction of cytoplasm Mitoses (in dermal component) Atypical mitoses Necrotic cells

CHAPTER 27 ■ TUMORS OF MELANOCYTES

and those resembling keratoses are particularly difficult to diagnose without a high index of suspicion. Acral melanoma, although accounting for 5% or less of melanomas among whites, is the most frequent form of melanoma among Asians, Africans, and other ethnic groups of color (Tables 27-27 to 27-30).20,276,277,285,286 However, approximately the same incidence of acral melanoma occurs in all ethnic groups.276 Subungual melanoma is a distinctive variant of acral melanoma293-297 that most often involves the nail bed of the great toe or thumb where it commonly presents as an ulcerated tumor.19 However, the initial manifestations may include a longitudinal pigmented band of the nail plate (frequently <9 mm in width) or a mass under the nail plate.297 A useful clinical sign is pigmentation extending from the nail onto the surrounding periungual skin (Hutchinson sign).19

Table 27-27 Conventional Melanoma with Particular Reference to Those of Intermittently Sun-Exposed Skin

(Continued)

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Table 27-27 Conventional Melanoma with Particular Reference to Those of Intermittently Sun-Exposed Skin (Continued)

660

Invasive component usually in dermis Architecture Tumefactive cellular aggregates Pushing, expanding pattern without regard for stroma Hypercellularity Less host response Cytology As above Increased nuclear to cytoplasmic ratios Mitoses in dermal component Atypical mitoses Necrotic cells Differential Diagnosis Melanocytic tumors Atypical (dysplastic) melanocytic nevus Halo nevus with atypia Spitz nevus or tumor Pigmented spindle cell nevus Recurrent melanocytic nevus Other melanocytic nevi with prominent pagetoid spread Nonmelanocytic tumors Squamous cell carcinoma Paget disease, mammary or extramammary Sebaceous carcinoma Cutaneous T-cell lymphoma Epidermotropic eccrine carcinoma Metastatic carcinoma, other Angiosarcoma Kaposi sarcoma Leiomyosarcoma Atypical fibroxanthoma Malignant fibrous histiocytoma

also characteristic. The cytoplasms of such melanocytes may be abundant with a pink granular quality; may contain granular or finely divided (“dusty”) melanin; or may show retraction, resulting in a clear space around the nuclei. Melanocytes with scant cytoplasms typically have high nuclear-tocytoplasmic ratios. Such proliferations have been variously labeled atypical melanocytic hyperplasia, premalignant melanosis, melanocytic dysplasia, and (recently) “pagetoid melanocytic proliferation,” as well as melanoma in situ.298,299

Invasive Melanoma After the period of intraepidermal proliferation, invasion of the papillary dermis often occurs,11,273,276 primarily as single cells and small aggregates of cells (Table 27-26).276 Microinvasive melanoma (generally considered Clark level II) is also remarkable for a striking host response in the papillary dermis, typically a dense cellular infiltrate of lymphocytes and monocytes or macrophages. Presumably,

because of this host reaction, regression, often focal, is common in up to 50% of microinvasive melanomas.300 The term vertical growth phase has been used by some to describe the proliferation of invasive melanoma cells as cohesive aggregates (Fig. 27-34).11,301 It has been postulated that the so-called vertical growth phase may signify the onset of the metastatic phenotype because it may be indistinguishable from metastatic melanoma.301,302 Melanomas with prominent invasive components may display polypoid morphologies such that more than half (sessile forms) or virtually all (pedunculated forms) of the tumor is above the epidermal surface. Amelanotic variants may also develop in any type of melanoma.20

Melanoma with Adjacent Predominately Pagetoid Intraepidermal Component Synonym: superficial spreading melanoma Pagetoid spread or melanocytosis (transepidermal migration of cells in a manner analogous to Paget disease of the

breast)11,20,272-278,303 refers to single cells and small groups of cells are randomly scattered throughout the epidermis reaching the granular layer and stratum corneum (see Table 27-27). The melanoma cells often have an epithelioid cell appearance; that is, they resemble epithelial cells because of abundant cytoplasm, which is usually granular and eosinophilic or contains finely divided (“dusty”) melanin (see Figs. 27-30B and 27-30C). The cells are usually larger (sometimes two or three times larger) than the surrounding keratinocytes. The epidermis may be hyperplastic, the epidermal rete pattern is often lost (effaced), and the surface of the epidermis abutting the intraepidermal tumor may exhibit a characteristically scalloped contour. Melanoma cells often proliferate as variably sized nests and horizontally disposed aggregates immediately underneath this scalloped epidermis. These aggregates are frequently large in size and have diminished cohesion of cells. In some instances, the latter proliferative pattern may predominate with little or no pagetoid spread. The most common cell in the invasive component is epithelioid (see Fig. 27-34C). Less frequently, spindle cells, small cells, or large bizarre mononuclear or multinucleate cells may predominate or are admixed with the other cell types. Many melanomas show considerable heterogeneity of cell type, such that the cells vary in nuclear size and shape and amount of cytoplasm from one focus to another.

Solar Melanoma with Adjacent Predominately Lentiginous Intraepidermal Component of Sun-Exposed Skin Synonyms: Lentigo maligna melanoma, Hutchinson melanotic freckle Lentigo maligna is a confusing term because it has been used to describe a histologic spectrum from slightly increased numbers of basilar melanocytes with variable, low-grade cytologic atypia20,272284 that is not clearly melanoma in situ to a contiguous and often nested intraepidermal proliferation of highly pleomorphic melanocytic cells that is melanoma in situ (see Table 27-28).283-284 Furthermore, some pathologists consider all lentigo maligna to be melanoma in situ,281,290 but others do not,20,283 hence the confusion. Irrespective of the terminology used, the pathologist must clearly communicate to the clinician the meaning of the pathologic terms used to describe these lesions. For clarity, the author recommends the term solar intraepidermal melanocytic proliferation with atypia (SIMP) (atypia may be graded as slight, moderate, or severe according to guidelines proposed for

Table 27-28 Solar Melanoma

atypical nevi) for lesions judged to fall short of melanoma in situ; otherwise, solar melanoma in situ should be used for lesions showing sufficiently disordered melanocytic proliferation and

cellular atypia, that is, contiguous proliferation of uniformly markedly atypical melanocytes. In addition to a mainly basilar proliferation of melanocytes (see Figs. 27-31 and

Melanomas with Adjacent Predominately Lentiginous Intraepithelial Component of Acral Skin, the Nail Apparatus, and Mucosal Surfaces These tumors are usually advanced, often ulcerated, and characterized by a tumor nodule frequently extending deeply into the stroma (see Table 27-29).20,275-277,285,286,293-296 Scanning magnification usually reveals a

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Clinical Features Age 60-70 years Men = women Sun-exposed surfaces: cheek (most common), nose, forehead, ears, neck, dorsal surfaces of hands 0.2-20 cm Initial tan macule suggesting a varnish-like stain Tan, brown, black macule or patch (black flecks characteristic) (early lesions) Pink, gray, white with progression and areas of regression Papule or nodule, pigmented or amelanotic (advanced) Ulceration, bleeding Asymmetry Irregular, notched borders Histopathologic Features Effacement and thinning of epidermis common Prominent solar elastosis Solar intraepidermal melanocytic neoplasia (lentigo maligna): (1) Solar intraepidermal melanocytic proliferation (insufficient for melanoma in situ) Lentiginous melanocytic proliferation Pleomorphic melanocytes (variable cytological atypia) Extension of melanocytic proliferation downward along appendages Usual absence of nesting and pagetoid spread (2) Melanoma in situ Contiguous or near contiguous lentiginous melanocytic proliferation Intraepidermal nesting of melanocytes Pagetoid spread Promient extension of melanocytic proliferation downward along appendages, often with nesting Significant cytologic atypia Melanocytes somewhat spindled to increasingly epithelioid Pigmented spindle cell variant (often on ears) Prominent intraepidermal discohesive nesting of atypical spindle cells Spindle cells often comprise invasive component but polygonal, small cells common Appendage-associated nesting of atypical melanocytes suggests invasion and may be florid (not true invasion) Partial regression relatively common Precursor nevus present ∼3% of cases Desmoplasia, neurotropism, angiotropism common Differential Diagnosis Solar lentigo Solar melanocytic hyperplasia (photoactivation) De novo Occurrence with nevi, fibrous papule, basal cell carcinoma, actinic keratosis, etc. Atypical intraepidermal melanocytic proliferation, not otherwise specified Solar lentiginous junctional or compound melanocytic nevi with or without atypia (may overlap atypical [dysplastic] nevi) Pigmented spindle cell nevus Pigmented actinic keratosis Squamous cell carcinoma, spindle cell type Atypical fibroxanthoma Cellular neurothekeoma Malignant peripheral nerve sheath tumor Angiosarcoma Kaposi sarcoma Leiomyosarcoma

27-31), this form of melanoma is also characterized by atrophy and effacement of the epidermis (see Fig. 27-31), involvement of appendageal structures (see Fig. 27-31), and marked solar elastosis.20,272-284 However, the presence of the latter changes may simply be related to the anatomic site; the skin of the cheeks in older individuals usually exhibits a flattened epidermis and prominent solar elastosis. There may be prominent involvement of appendageal epithelium with large cellular nests (see Figs. 27-32A and 27-32B). Recognition of prominent appendageal involvement by melanoma is of critical importance so that the lesion is not misdiagnosed as invasive rather than simply as intraepithelial or in situ. The most typical cell type has retracted cytoplasm and often an elongate, stellate, or spindled configuration279 and a high nuclear-to-cytoplasmic ratio. The nuclei are commonly pleomorphic and hyperchromatic. With progression, the cells become more epithelioid in appearance and exhibit nuclear enlargement and prominent nucleoli. Another characteristic feature is the presence of prominent spindle cell differentiation with formation of confluent fascicles of spindle cells along the dermal-epidermal junction and appendages.20,279 One particular variant may closely simulate PSCN. Extension of melanoma into the dermis may be difficult to recognize because of prominent cellularity of the stroma and activation of mesenchymal cells. The invasive dermal component is frequently composed of spindle cells occurring either singly or in bundles with varying stromal desmoplasia and invasion of nerve twigs (see Desmoplastic Melanoma). However, the invasive component may contain any cell type. Invasion of the dermis may originate from appendageal-associated melanoma cells or nests. In the latter instances, the depth of invasion (Breslow thickness) should not be measured from the granular layer of the epidermis because this value would overestimate tumor depth. The measurement of tumor thickness instead should ideally be taken from the granular layer of the hair follicle or sweat gland.

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Table 27-29 Acral Melanoma

662

Clinical Features Age 60-70 years Men women Equal incidence in all racial groups Most prevalent form of melanoma in Africans, Asians, Native Americans, other peoples of color Glabrous (volar) skin and nail unit Palms, soles, digits, 85% of AM Nail unit, 15% Feet, 90% of cases Soles, 68% to 71% Toes, 11% Nail units, 16% to 20% Palms, 4% to 10% Fingers, 2% 0.3-12 cm Often ≥ 0.7 cm <0.7 cm with irregular borders, color, or “parallel ridge” pattern on epiluminescence microscopy Often jet-black macule early, but also tan, brown, gray, blue, pink, white Pigmented or amelanotic papule or nodule (advanced) with ulceration, bleeding, eschar Irregular borders, notching Histopathologic Features Prominent acanthosis with elongated epidermal rete common Thickened stratum corneum Contiguous or near contiguous lentiginous melanocytic proliferation in almost all lesions Intraepidermal melanocytes appear to lie in lacunae (clear spaces) Variable cytologic atypia with minimal atypia in early lesions Pagetoid spread (particularly in more advanced lesions) Intraepidermal nesting (particularly in more advanced lesions) Proliferation of melanocytes downward along eccrine ducts (even into deep dermis and subcutis) Pronounced pagetoid spread, large intraepidermal nests, significant numbers of melanocytes in stratum corneum in advanced lesions Polygonal to spindled melanocytes often with prominent dendrites Nuclear enlargement, hyperchromatism, pleomorphism prominent Invasive component Cohesive nests, sheets of cells, or loosely aggregated files of cells Spindle cells common but also polygonal, small, and highly pleomorphic cells are noted Nevoid and sarcomatoid variants occur Desmoplasia, neurotropism, angiotropism common Differential Diagnosis Melanotic macule Lentigo Atypical intraepidermal melanocytic proliferation, not otherwise specified Acral melanocytic nevus with or without atypia (may overlap atypical [dysplastic] nevus) Pigmented spindle cell nevus Squamous cell carcinoma, spindle cell type Atypical fibroxanthoma Cellular neurothekeoma Malignant peripheral nerve sheath tumor Angiosarcoma Kaposi sarcoma Leiomyosarcoma

hyperplastic epidermis and lentiginous proliferation of atypical melanocytic cells (see Figs. 27-33A and 27-33B). These cells are commonly contiguous with occasional clustering, appear to lie within

lacunae, and display prominent dendrites that extend through the epidermis. Pagetoid patterns are also observed frequently, either alone or associated with lentiginous proliferation. The nuclei are

enlarged, hyperchromatic, and often highly pleomorphic (see Fig. 27-33B). With tumor progression, there is a tendency for upward migration and dermal invasion. Variable degrees of melanization are present. The dermal component is most often composed of spindle cells, but epithelioid cells, small nevus-like cells, and highly pleomorphic cell types are occasionally noted.277 A small proportion exhibits desmoplasia and neurotropism.

Melanoma with Little or No Adjacent Intraepithelial Component (“Nodular” Melanoma) Scanning magnification discloses a raised, dome-shaped, or polypoid tumor often (but not always) exhibiting some asymmetry (see Fig. 27-34A and Table 27-30).20,272-278 The epidermis over the tumor is usually thin and effaced and may be ulcerated. Variable upward migration of melanoma cells in the epidermis may be present, but intraepidermal spread should not extend beyond the margins of the tumor. The dermal component is typified by a cohesive nodule or smaller nests of tumor cells that have a pushing or expansile pattern of growth (see Fig. 27-34B).11,276,301 The tumor cells most frequently are epithelioid, but other cell types, including spindle cells and small epithelioid cells resembling nevus cells, may predominate or be admixed with other cell types.276 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes various melanocytic proliferations (see Tables 27-27 to 27-30), including markedly atypical nevi, halo nevi, Spitz nevi, pigmented spindle cell nevi, recurrent or persistent melanocytic nevi, and congenital nevi (particularly in the first year of life). Nevi associated with prominent pagetoid spread are commonly confused with melanoma. AMN with pronounced atypia may be misdiagnosed as melanoma because of appearances suggestive of early pagetoid spread, confluence of cellular aggregates along the dermal-epidermal junction, prominent variation in nesting pattern, significant cytologic atypia, entrapment of nests of dermal nevus cells in the papillary dermis, and dense mononuclear cell infiltrates. On occasion, the distinction of AMN from melanoma is exceedingly difficult. Nonetheless, discrimination of melanoma from AMN is usually possible because of the greater asymmetry and disorder encountered in melanoma. AMN usually maintains an overall symmetry; a nevic appearance, as exemplified by fairly organized

Table 27-30 Conventional Melanoma with Little or No Adjacent Intraepidermal Component (“Nodular” Melanoma)

junctional nesting; and a basilar proliferation of melanocytes that is still concentrated along the epidermal rete and with greater density toward the lower poles of the rete. Thus, the intervening epidermis between rete contains a lesser density of melanocytes compared with that on the epidermal rete. If pagetoid spread is present, this architectural pattern is often more prominent about the epidermal rete and confined to the lowermost

epidermis. Occasional AMN exhibit effacement of the epidermal rete pattern and confluence of melanocytic cells along the dermal-epidermal junction in this zone. The latter changes are commonly associated with dense mononuclear cell infiltrates and may strongly suggest melanoma; the findings must be carefully interpreted in the overall context of the lesion. AMN are generally characterized by variable or discontinuous

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Clinical Features Age 30-70 years (often 40–50 but any age) Men = women Any site, especially trunk dorsal surfaces of hands 0.4-5 cm Often rapid evolution, eg, 4 months to 2 years Papule or nodule, pigmented or amelanotic (advanced) Often protuberant, polypoid Black, blue-black, pink Ulceration, bleeding Asymmetry but symmetry may be present Often well-defined borders Histopathologic Features Dome-shaped polypoid or sessile tumor often May be pedunculated Asymmetry with exceptions Epidermis commonly thinned, effaced, ulcerated Overlying intraepidermal component may or may not be present and usually does not extend peripherally beyond dermal invasive tumor Pagetoid spread, lentiginous melanocytic proliferation, intraepithelial nesting may be present Cohesive aggregate or aggregates of tumor cells fill subjacent dermis, subcutis Usually no maturation Host response at base or tumor-infiltrating lymphocytes common Epithelioid cells often comprise invasive component but spindle cells, small cuboidal cells common and often heterogeneity is present Partial regression relatively uncommon Precursor nevus present ~6% of cases Differential Diagnosis Spitz tumor Pigmented spindle cell nevus Atypical halo-like nevus Metastatic melanoma Cellular blue nevus with atypia Squamous cell carcinoma Adnexal carcinomas Atypical fibroxanthoma Fibrous histiocytoma Adult xanthogranuloma Lymphoma, particularly large cell anaplastic variants Cellular neurothekeoma Malignant peripheral nerve sheath tumor Capillary hemangioma Malignant glomus tumor or with atypia Angiosarcoma Kaposi sarcoma Leiomyosarcoma

cytologic atypia, that is, the degree of nuclear enlargement, pleomorphism, and hyperchromatism varies from cell to cell.23 This cytologic feature is very helpful in discriminating AMN from the more uniform or contiguous cytologic atypia of melanoma. A finding that raises the possibility of melanoma is entrapment of atypical nevus cells in a fibrotic papillary dermis of an AMN. Such findings may even suggest partial regression of melanoma. A distinction from melanoma should be based on an assessment of all the cytologic and architectural characteristics of the lesion. Importantly, the dermal nevus cells in question usually lack the marked and uniform cytologic atypia, especially manifested as hyperchromasia, of melanoma cells. In general, halo nevi have dense mononuclear cell infiltrates, histologic regression in some instances, and varying degrees of architectural and cytologic atypia that may suggest melanoma. The typical halo nevus in children and adolescents is characterized by overall symmetry, orderly appearance, and little or no cytologic atypia.20 The lymphoid cells that permeate the dermal nevus have a uniform density and regular horizontal contour. The nevus cells of halo nevi may demonstrate cellular enlargement with prominent eosinophilic cytoplasm, but their nuclear details are usually little altered. In contrast, a variant of halo nevus has prominent pattern and cellular atypia and is perhaps best categorized as an AMN. The discussion of AMN is relevant to this form of (atypical) halo nevus. The misdiagnosis of other melanocytic nevi, including acral nevi, Spitz nevi, pigmented spindle cell nevi, congenital nevi, recurrent melanocytic nevi, and nevi in children as melanoma, is primarily related to misinterpretation of patterns of minor pagetoid spread. Overall symmetry, sharp circumscription, and a well-organized appearance, as well as little or no cytologic atypia, favor a benign melanocytic proliferation. Pagetoid spread in benign melanocytic nevi is generally characterized by an orderly pattern and is generally limited to the lower epidermis and aggregates of cells predominate over single cells. Spitz nevi pose particular diagnostic problems (see Spitz Nevus above). Solar melanocytic proliferations with atypia and lentiginous melanomas from markedly sun-damaged skin must be distinguished from solar lentigo, AMN, and PSCN. The former lesions may actually develop from some varieties of solar lentigo. Well-differentiated forms of SIMP

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 FIGURE 27-31 Solar melanoma in situ. There is a striking basilar proliferation of atypical melanocytes in both the epidermis and the follicular epithelium.

and solar melanoma in situ with spindle cells may cause confusion with PSCN. Whereas typical PSCN usually involves covered skin and commonly occurs in children and young adults, SIMP and solar melanoma in situ invariably develop in sun-exposed skin and usually in old persons. An effaced epidermis,

A

664

cellular nests with diminished cohesion, and a prominent basilar single cell proliferation of markedly atypical spindle cells argue in favor of SIMP and solar melanoma in situ. Pigmented spindle cell nevi are usually well circumscribed with well-formed, orderly, and regular fascicles of pigmented spindle cells. Epidermal

hyperplasia usually encountered in PSCN contrasts with the atrophy of SIMP and solar melanoma in situ. Cytologically, PSCN is usually composed of monotonous fusiform cells with nuclei containing delicate chromatin. The differential diagnosis for acral melanoma primarily includes lentigines and lentiginous melanocytic nevi of acral skin. Lentigines of acral skin usually do not exhibit the frequency of melanocytic proliferation or cytologic atypia that is typical of acral melanoma.285 Occasional acral nevi may have alarming features such as upward migration of cells throughout the epidermis, prominent lentiginous melanocytic proliferation, and some degree of cytologic atypia. Although upward migration may be noted in acral nevi, particularly in children, the constituent cells seldom reveal more than low-grade cytologic atypia, and the pattern of pagetoid spread is usually orderly and confined to the lowermost epidermis. Other characteristics of acral nevi include regular size and spacing and cohesive qualities of the junctional nesting. One particular note of caution is that well-differentiated acral melanoma may exhibit dermal components with little or no inflammatory response. In such cases, careful evaluation for cytologic atypia, necrotic cells, and mitotic activity are helpful in recognizing melanoma. NM may be confused with metastatic melanoma, Spitz nevus, atypical varieties of CBN, squamous cell carcinoma, atypical fibroxanthoma, fibrous histiocytoma, leiomyosarcoma, myoid fibroma, cellular capillary hemangioma, and Kaposi

B

 FIGURE 27-32 Melanoma of chronically sun-exposed skin. (A) This lesion shows not only lentiginous melanocytic proliferation but also significant nesting of melanoma cells involving the epidermis and particularly the follicular epithelium. (B) Higher magnification demonstrating florid nesting of melanoma cells and pagetoid melanocytosis.

B

 FIGURE 27-33 Lentiginous melanoma of acral skin. (A) The epidermal is hyperplastic and exhibits characteristic lentiginous proliferation of pleomorphic melanoma cells. (B) Note the confluence of severely atypical melanocytes along the dermal-epidermal junction.

sarcoma (see Table 27-30). Epidermotropic metastatic melanoma involving the papillary dermis may prove difficult to distinguish from NM.20,304 Whereas metastatic melanoma is often fairly monomorphous with little stromal response, NM are often polymorphous and exhibit greater stromal response. However, distinction may be impossible in certain cases, and discrimination must rely on clinical information and the patient’s clinical course. Spitz nevi, particularly those with atypia, enter into the differential diagnosis of NM. Clinical information is pertinent to the diagnosis because melanoma is uncommon in young people, but atypical lesions are more suspicious for melanoma in adults. On occasion, nonmelanocytic lesions are considered in the differential diagnosis

A

of melanoma. The principal conditions include Paget disease, either mammary or extramammary; squamous cell carcinoma in situ; sebaceous carcinoma; epidermotropic eccrine carcinoma; cutaneous T-cell lymphoma; and other epidermotropic carcinomas. In most instances, the dilemma can be resolved simply by careful attention to histologic details in routinely stained sections.305

UNUSUAL VARIANTS OF THE INVASIVE COMPONENT OF MELANOMA

Desmoplastic Melanoma DM is a rare variant of cutaneous melanoma first reported by Conley et al

in 1971.306-325 In one population-based study, the general prevalence of DM was estimated as 1% of all cutaneous melanomas.289 The essential histologic criteria for DM are (1) a predominant spindle cell phenotype and (2) an associated densely collagenized (or “desmoplastic”) stroma of the invasive or dermal component. The spectrum of DM was subsequently expanded by the delineation of neurotropic melanoma by Reed and Leonard in 1979.314 These authors pointed out that many DM (anywhere from 16.7% to 77.8% in a recent comprehensive review of DM) manifested neurotropism or neural differentiation.323 As a result, the terms DM with neurotropism, DM without neurotropism, and desmoplasticneurotropic melanoma have been introduced to accommodate these additional

CHAPTER 27 ■ TUMORS OF MELANOCYTES

A

B

 FIGURE 27-34 Nodular melanoma. (A) Nodular melanoma. The tumor has a dome-shaped configuration. (B) Dermal component demonstrating large anaplastic epithelioid melanoma cells.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 666

phenotypic variants of DM. Unfortunately, since the initial description of DM, many authors in their published series have often failed to use the term DM and its descriptors with precision. Thus, in many instances, no rigorous histologic definitions of DM have been offered, such as what proportion of the neoplasm should show a sclerosing spindle cell phenotype (ie, any part of the neoplasm versus virtually all of the tumor, or <50%, >50%, or >80%-90%?) versus a melanoma with pure spindle cell, neurotropic, neural, or even myxoid phenotype. Thus, a heterogeneous spectrum of melanomas have commonly been reported under the overarching term of DM, and the published work on DM should be interpreted with this in mind.322,324 Suffice to say that the majority of DM reported thus have probably met the essential histologic criteria for DM. With the description of probably more than 1000 cases of DM in the world literature, one can more precisely delineate the gross morphologic, histopathologic, immunophenotypic, and molecular properties of DM and its variants and its natural history in patients. It has become increasing evident that DM is a distinctive clinicopathologic variant of melanoma with unique biologic characteristics. Of course, one must bear in mind that DMs exhibit a continuum of histologic features in common with other melanomas, and their properties are directly related to the criteria used to define DM and how rigidly they are applied. The phenotype of the tumor corresponds to the neuroectodermal origin of the melanocyte306-325 and thus may include any combination of conventional melanoma; desmoplasia; neurotropism (perineurial invasion)—invasion of nerve structures by tumor cells; neural differentiation (both schwannian and perineurial)—formation of nervelike structures recapitulating perineurium and endoneurium or delicate sheets of spindle cells reminiscent of neurofibroma; and less commonly, neuroendocrine, myofibroblastic, and diverse forms of mesenchymal differentiation. Although DM most frequently arises in association with lentiginous melanomas,20,276 de novo variants of DM also occur.312 The pathogenesis of desmoplasia and the true nature of the spindle cells in DM remain a subject of controversy.306-325 Some authors maintain that the fibroplasia results from the induction of collagen synthesis by benign fibroblasts, but others believe that melanoma cells function as adaptive fibroblasts to promote collagenization in these tumors.307,311,312

The latter conclusion is based on ultrastructural and immunohistochemical studies and the fact that melanocytes are capable of collagen production, as well as melanin synthesis and schwannian differentiation.311-313 CLINICAL FEATURES In general, DM presents in older white individuals (mean age, ~65 years); presents more frequently in men than women; involves predominately sun-exposed skin of the head and neck region, often presenting clinically as a nondescript raised, firm nodule or sometimes depressed indurated plaque that is amelanotic or associated with variable pigmentation (Table 27-31)20,306-325; and usually not recognized until late compared with conventional melanomas. DMs may also involve acral and mucosal sites less frequently and ultimately any cutaneous site. The irregular and variegated features of an associated intraepithelial component, such as SIMP or melanoma in situ, may be the most visible feature of DM. Difficulty in recognizing DM, clinically and histologically, usually causes a delay in recognition and appropriate surgery. HISTOPATHOLOGIC FEATURES The essential histologic criteria for DM are (1) individual spindle cells and variably sized fascicles of spindle cells interspersed among dense collagenous fibers (Fig. 27-35) (2) involving a significant proportion of the melanoma.306-325 The mere presence of spindled melanoma cells alone is thus not sufficient for the diagnosis of DM. The proportion of such melanomas showing a sclerosing spindle cell component may range from less than 10% to more than 80% or 90% (ie, virtually all of the neoplasm). Thus, some proportion of DMs are biphasic (ie, they show a desmoplastic component associated with another distinct melanoma component, often of the conventional type). How much of a melanoma must be “desmoplastic” to qualify as “DM,” and does this differential composition of desmoplastic versus conventional components have potential biologic and prognostic significance? Although most authors have not directly specified their threshold definitions for DM, one can infer that a large proportion—perhaps well over 50% of the lesion—should have the desmoplastic phenotype. To more precisely address this issue of composition of DM and its biologic and prognostic implications, Hawkins et al324 have recently proposed subclassifying DM as pure DM (>80%-90% of the lesion being DM) and mixed DM

Table 27-31 Desmoplastic Neurotropic Melanoma

Clinical Features Age 60-65 years Men ≥ women Sun-exposed skin, head and neck, but also acral, mucosal sites Firm nodule Flesh-colored or with pigmented lesion (29% to 43%) 1-3 cm Occasional dysesthesias, nerve palsies Histopathologic Features Intraepidermal melanocytic proliferation in >75% Solar melanoma in situ, most common Fibrous nodule in dermis and possibly subcutis Often absence of pigment Fascicles of atypical spindle cells Schwannian, perineurial differentiation Neurotropism common (perineurial and endoneurial invasion) Patchy lymphoid infiltrates common Variable myxoid stroma Occasional mitoses in dermis Differential Diagnosis Sclerosing blue nevi including variants with hypercellularity Desmoplastic (sclerosing) Spitz nevus Neurothekeoma, particularly cellular variants Malignant peripheral nerve sheath tumors Myxoma Dermatofibroma Dermatofibrosarcoma protuberans Atypical fibroxanthoma Malignant fibrous histiocytoma Scar Fibromatosis Spindle cell squamous cell carcinoma Leiomyosarcoma Immunohistochemistry S-100 protein + Vimentin + p75 neurotrophin receptor + HMB45, MART-1, MIFT, tyrosinase often − Leu 7 − Keratin −

(10%-<50% desmoplasia). The preliminary results from the latter study suggest that this subclassification may have practical utility in terms of being reproducible and potentially delineating biologic and prognostic differences between these subgroups of DM. More detailed studies will be needed to verify the latter findings given the inherent heterogeneity of melanoma and DM

B

C

D

CHAPTER 27 ■ TUMORS OF MELANOCYTES

A

 FIGURE 27-35 Desmoplastic melanoma. (A) Fibrotic nodule occupies dermis. (B) Fascicles of atypical spindled melanocytes with dense fibrous stroma. (C) Note nuclear enlargement and pleomorphism of spindle cells. (D) A cutaneous nerve shows prominent endoneurial infiltration by melanoma cells (neurotropism).

and interobserver reproducibility. It is certain that it is desirable to arrive at a consensus as to how DMs are defined and perhaps subclassified based on tumor phenotypic properties. Examination of a typical DM at scanning magnification usually discloses a fibrous nodule suggesting a scar or fibroma that displaces the normal dermal collagen or lamina propria and often extends into subcutaneous fat (see Table 27-31 and Fig. 27-35).311-313 In many instances, relatively dense perivascular or nodular lymphocytic infiltrates are present. An intraepidermal melanocytic proliferation is observed in a range from less than 50% to about 75% of cases.312 The most common pattern is lentiginous melanocytic proliferation, but the intraepidermal component may be highly heterogeneous and show one or more of the following: junctional nesting, pagetoid melanocytosis, or extensive proliferation

along adnexal structures. Likewise, the frequency and degree of cytologic atypia of melanocytes may vary enormously from paucicellular, minimally atypical proliferations to florid intraepidermal melanoma (melanoma in situ). Recurrent, misdiagnosed late-stage and de novo variants of DM therefore may not exhibit an intraepidermal melanocytic proliferation. The histologic appearance of the invasive or dermal/subcutaneous component of DM varies along a continuum.311-313 The spectrum of the desmoplastic component itself varies in terms of overall cellularity and degree of cytologic atypia. The nuclei may show little, no, or considerable pleomorphism and wavy or serpiginous nuclear morphology, although most nuclei are enlarged and exhibit tapering contours (see Fig. 27-35B). However, some nuclei are plump, and occasionally bizarre, multinucleate giant cell forms are noted. Most

DMs lack pigment, but occasional cells may contain fine melanin granules within cellular processes. The tumor stroma is usually fibrous, but myxoid alteration is occasionally encountered and uncommonly may be prominent.312 A finding typical of DM and useful in its recognition is the presence of variably dense perivascular lymphocytic infiltrates that are usually scattered throughout the tumor.312 The tumor cells in DM are also notable for angiotropism on occasion. Mitotic figures can usually be found even in the most paucicellular forms of this tumor.311-313 DMs are usually diagnosed at an advanced stage because they are usually at least 4 or 5 mm in thickness and level IV or V (see Table 27-31).306-325 Because of misdiagnosis, they are commonly first recognized as recurrent or metastatic tumors. DMs frequently recur locally (27.2% among 707 patients; range,

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6.7%-56.%).310,312 Based on a series of 45 cases, local recurrence was associated with the following factors: failure to correctly diagnose the tumor, inadequate surgery (resection margins <1 cm), location on the head and neck, anatomic level V, and thickness greater than 4 mm.310 Failure to completely extirpate DM is related to the difficulty of assessing the margins, nerve infiltration, and the fact that they are usually amelanotic. It is held that distant spread is less common despite the advanced tumor thickness that is characteristic of DM.320 One study involving 129 patients and a mean tumor thickness of 4.2 mm reported recurrence in 51% of the cases.325 A review of the literature, encompassing a total of 703 patients, documented a recurrence rate of 26.2%, a nodal metastatic rate of 7.1%, and a rate of systemic metastasis of 19.8%.323 A more recent study addressing the issue of nodal metastasis in DM reported one nodal metastasis in their cohort of 18 cases that underwent lymph node biopsy.323 The prognosis of DM is generally regarded as being more favorable than conventional melanomas for a given tumor thickness. One study of 129 patients with a mean tumor thickness of 4.2 mm reported 5- and 10-year rates of survival of 76% and 64% respectively.325 In addition, a study performed at the Sydney Melanoma Unit that evaluated 280 patients with a mean tumor thickness of 2.5 mm reported a 5-year survival of 75%. Ninety of these 280 patients represented cases of the neurotropic variety of DM. The researchers failed to demonstrate that perineural invasion affected rates of survival in patients with DM. Furthermore, they reported fewer lymph node metastasis in DM compared with those associated with conventional melanomas.320 It has further been reported that DM lesions greater than 4 mm in thickness demonstrate a 60% 5-year survival compared with 40% in non-DMs.9 These findings contrast with those of a study involving 89 patients in which investigators reported rates of survival that were similar to those of non-DMs of similar thickness.10 A recent study engaged in a nuanced examination of the histologic features insofar as their prognostic contribution. They subdivided cases of DM into “pure” and “mixed” subtypes, being respectively representative of lesions with prominent stromal desmoplasia and those in which the desmoplastic component was simply an element of what was otherwise a more conventional melanoma. They reported that

patients classified as having pure DM showed a significantly lower incidence of lymph node metastasis and a lower 5-year melanoma-specific mortality compared with the patients with mixed DM. Furthermore, they discovered that the melanoma-specific mortality rate was equal among the pure DM and conventional melanoma patients despite a threefold higher median tumor depth in the former. Interestingly, they also reported that the lymph node metastases in the patients with mixed DM were characterized by the nondesmoplastic component of the primary mixed DM lesions.11 It may, therefore, be reasonable, as Hawkins et al suggest, to subclassify these lesions and designate the pure forms of DM as spindle cell melanomas.

Neurotropic Melanoma The term neurotropism refers to the involvement of perineurium or endoneurium of cutaneous nerves by melanoma cells (see Fig. 27-35C).314 There may be considerable thickening of the perineurium and expansion of the endoneurial space by the tumor involvement.310,314,315 Extension of tumor along the cutaneous nerves may, however, be extensive and subtle. Histologic clues to nerve involvement include the presence of hyperchromatic spindle cells in the perineurium or endoneurium and mucinous alteration of the nerve. Careful examination of cutaneous nerves at the surgical margins is mandatory to assess adequate excision. Melanoma spindle cells involving cutaneous nerves usually show nuclear enlargement, hyperchromatism, and pleomorphism. The term neurotropic (or neurogenic) melanoma also describes neural or schwannian differentiation in a pattern resembling peripheral nerve sheath tumors such as neurofibromas or neuromas and the recapitulation of perineurium and endoneurium.310,314,315 The tumor cells in such areas are characterized by serpiginous or wavy nuclear configurations and filamentous cytoplasmic processes. The cells are embedded in a variably mucinous and fibrous stroma. In some instances, the stromal may be so sufficiently myxoid to suggest a myxoma. However, the tumor cells demonstrate loose fascicular arrangements, cytologic atypia, and occasional mitotic figures. DIFFERENTIAL DIAGNOSIS The spectrum of tumors potentially confused with desmoplastic and neurotropic melanoma is varied and includes spindle cell

proliferations and tumors with a fibrous appearance (see Table 27-31).306-325 The principal lesions to be considered include sclerosing blue nevus,311 desmoplastic Spitz nevus,153 neurothekeoma,326 malignant peripheral nerve sheath tumor, dermatofibroma, atypical fibroxanthoma, malignant fibrous histiocytoma, scar, fibromatosis, myxoma, spindle cell squamous cell carcinoma, and leiomyosarcoma.312 The epidermal lentiginous melanocytic proliferation commonly found in DM is usually absent in the other conditions. Sclerosing blue nevus and desmoplastic Spitz nevus311,153 are both characterized by an orderly infiltration of the fibrotic stroma and an overall benign cytologic appearance. Mitotic figures, usually encountered in DM, are exceedingly rare or absent in sclerosing blue nevus, but early forms of DM may be exceedingly difficult to distinguish from sclerosing blue nevus,311,312 and it is vital to weigh all clinical and histologic features. For example, DM in a young individual on an anatomic site other than the head and neck or acral areas is highly unusual, and such circumstances argue against a diagnosis of DM. The desmoplastic Spitz nevus is characterized by symmetry, a wedge-shaped configuration, and infiltration of the dermis by relatively monotonous epithelioid or spindle cells,153 allowing its distinction from DM in most instances. DM may also show a fascicular arrangement of cells that is generally lacking in desmoplastic Spitz nevus. Relatively cellular variants of neurothekeoma (nerve sheath myxoma) may suggest DM.326 Neurothekeoma commonly arises in the head and neck region, as does DM. Neurothekeoma generally occurs in young individuals (average age, 20 years), does not demonstrate an intraepidermal melanocytic proliferation, and is typified by a lobular architecture in the dermis. Concentric and fascicular arrangements of cells are often noted in neurothekeoma, the constituent cells may be epithelioid or bipolar, and stellate and multinucleate forms are seen. Low-grade nuclear pleomorphism and occasional mitotic figures are occasionally encountered. Distinction from DM is based on a regular, organized appearance; orderly infiltration of the dermis; and a lesser degree of cytologic atypia. Because of prominent schwannian differentiation, discrimination of desmoplastic–neurotropic melanoma from peripheral nerve sheath tumors may be difficult or impossible. All clinical and histologic

A

Squamous cell carcinoma may show keratinization, dyskeratosis, and intercellular bridges. Leiomyosarcoma may exhibit the cytologic characteristics of smooth muscle cells, but immunohistochemistry may be essential to finalize the diagnosis. Because of the serious consequences of this tumor, immunohistochemistry is needed in most DMs to confirm the diagnosis. Almost 100% of desmoplasticneurotropic melanomas demonstrate immunoreactivity with antibodies against vimentin, S-100 protein, and p75 neurotrophin receptor, 312,313,316,318,320,321,323,327,328 but uniquely, almost all are negative for HMB45, MART-1 (Melan-A), MITF (microphthalmia transcription factor), and tyrosinase. If there is positive immunostaining for HMB45 and the latter markers in DM, it involves nondesmoplastic foci only, that is, an intraepidermal component or superficial dermal focus of conventional melanoma cells.312 A battery of markers must be used to evaluate such tumors. Other antibodies with variable reactivity with DM are neuron-specific enolase and NK1/C3. Antibodies against keratin, desmin, actin, and Leu-7 (specific for peripheral nerve sheath differentiation but negative in melanocytic tumors), in general, are negative in DM.312

Angiotropic Melanoma Angiotropism of melanoma cells as a biologic phenomenon and prognostic factor in melanoma and correlate of extravascular migratory metastasis (EVMM) has recently been delineated in some detail in the literature.329-337 Angiotropic melanoma

is defined as the ensheathing of (the close opposition to) the external surfaces of either blood or lymphatic channels (in a pericyte-like location), or both by melanoma cells (Fig. 27-36A). By definition, no tumor is present within the vascular lumina. Angiotropic foci must be located either at the advancing front of the tumor or at some distance (usually within 1 to 2 mm) from the main tumoral mass. Although angiotropism is likely to be present within the mass of an invasive melanoma, there is no specific means at present of differentiating simple entrapment of microvessels by tumor from angiotropism. Immunohistochemistry with markers such as S-100 protein or MART-1 (Fig. 27-36B) may aid in the identification or confirmation of angiotropism. Angiotropism is observed with greater frequency in melanomas also demonstrating desmoplasia and neurotropism, suggesting closely related mechanisms. Angiotropism is observed with much greater frequency than vascular or lymphatic invasion; for example, in a series of 650 consecutive invasive melanomas, the frequency of vascular or lymphatic invasion was 1.4%. Lugassy and Barnhill have proposed that an important mechanism of melanoma metastasis may be the migration of tumor cells along the external surfaces of vessels or EVMM, a mechanism by which some cells spread to nearby or more distant sites.330,331 This hypothesized mechanism of tumor spread has been based on ultrastructural and immunopathologic studies; in the latter, melanoma cells are closely apposed to the external surfaces of the endothelial

CHAPTER 27 ■ TUMORS OF MELANOCYTES

characteristics must be considered. Tumors of the head and neck of elderly patients associated with lentiginous melanomas are usually not a diagnostic problem. Tumors in other anatomic sites without an intraepidermal component cause difficulty, and immunohistochemistry may be of particular value in them.312,313,316,318,320,321,323,327,328 Lesions demonstrating fibrous or fibrohistiocytic differentiation figure prominently in the differential diagnosis of DM and include dermatofibroma (fibrous histiocytoma), juvenile xanthogranuloma, dermatofibrosarcoma protuberans, atypical fibroxanthoma, superficial forms of malignant fibrous histiocytoma, scar, and fibromatosis. These lesions generally lack intraepidermal melanocytic proliferation, melanin pigment, and neurotropism. Atypical fibroxanthoma and malignant fibrous histiocytoma enter the differential diagnosis and often require immunohistochemical evaluation, although they may contain xanthoma cells, not usually seen in DM. Fibrohistiocytic tumors as a general rule do not display neurotropism. DMs with extensive mucin may raise problems of differential diagnosis, suggesting, for example, a myxoma.312 However, myxomas generally lack the cytologic atypia and neurotropism of desmoplastic–neurotropic melanoma, and the myxomatous variants of DM usually have zones of prominent cellularity. Spindle cell squamous carcinoma and cutaneous leiomyosarcoma may be confused with DM, but each fails to demonstrate intraepidermal melanocytic proliferation and melanin synthesis.312

B

 FIGURE 27-36 Angiotropic melanoma. (A) Melanoma cells cuff microvessels in a pericytic location in the superficial dermis. (B) Striking immunostaining of angiotropic melanoma cells with melan-A.

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cells of blood vessels in a pericyte-like location without evidence of intravasation.330,331 Ultrastructurally, the melanoma cells are linked to endothelium by an amorphous matrix containing laminin (not organized in basement membranes) as confirmed by immunohistochemistry.330-332 The latter morphologic structure has been termed the angiotumoral complex. According to this proposed mechanism, tumors cells begin the process of local spread by competing with pericytes for the periendothelial position or pericyte-like location for migration along the external surfaces of vessels.330

670

CLINICAL AND HISTOPATHOLOGIC FEATURES The clinical and histologic features of primary angiotropic melanoma have been described in a series of 36 cases.332 The clinical findings did not differ significantly from those in a large populationbased study of melanoma. All conventional types of cutaneous melanoma were observed with pagetoid, lentiginous, and nested intraepidermal components or “nodular” morphologies. The 35 cutaneous tumors ranged in Breslow thickness from 0.46 to 8.25 mm with a mean of 1.64 mm. One patient had a mucosal melanoma involving the uterine cervix with lentiginous intraepithelial melanoma component and an extensive invasive component measuring 35 mm in thickness. All cutaneous melanomas (31 of 35) were level IV, with the exception of two that were level II and two that were level V. Six (17%) of the tumors also showed neurotropism.29 The prognostic significance of angiotropism as a qualitative variable (ie, one that is simply recorded as present or absent) has recently been reported.333 A series of patients with primary cutaneous melanoma and documented metastasis were matched for Breslow thickness, age, gender, and site with a similar group of patients with nonmetastasizing primary melanoma and long-term follow-up. Angiotropism as defined above was found exclusively in patients with metastasizing melanoma, and vascular and lymphatic invasion was absent. These preliminary results strongly suggest that angiotropism is an important prognostic factor correlating with metastasis, even beyond that of tumor thickness. The prevalence of angiotropism and EVMM in melanoma metastases has been investigated in 26 patients with metastatic melanoma. Among the 26 melanoma metastases studied, angiotropism of melanoma cells was observed in some portion of the metastasis in

23 cases.336)Thirteen of 16 in-transit metastases, all seven epidermotropic metastases, and two of three satellite metastases showed angiotropism. In general, the in-transit metastases were small, and some were epidermotropic; others involved solely the reticular dermis and possibly the subcutaneous fat. Melanoma cells cuffed the external surfaces of microvessels within the metastasis at the peritumoral interface of the metastasis or in immediate proximity to the main portion of the metastasis in a pattern analogous to the angiotumoral complex. The melanoma cells were present in one or more layers and occasionally in small aggregates juxtaposed to the external vascular wall. There was no evidence of intravascular involvement (intravascular invasion) in any of the 26 human melanoma metastases. Simultaneous (double) immunostaining of five specimens with S-100 protein and CD31 highlighted melanoma cell angiotropism (ie, melanomas cells expressing S-100 were observed along the external surfaces of microvessels labeling with CD31).35

Minimal Deviation Melanoma The term minimal deviation melanoma (MDM) connotes a subset of melanomas presumably characterized by lesser cytologic atypia and a better prognosis compared with conventional melanomas.338 Thus, central to the concept of MDM is the presence of a cohesive nodule of dermal tumor cells. The growth pattern of such a nodule potentially indicates aggressive properties, such as recurrence or metastasis. Also implicit is the presence of a cell type lacking the characteristics of “fully evolved” melanoma cells. The cell types presumed to occur in MDM resemble ordinary nevus cells, spindled melanocytes, and epithelioid cells as from Spitz nevi. 338 Because of the lack of specific histologic criteria and objective markers, data are not available that confirm or refute MDM as an entity. The diagnosis of MDM has probably been applied to a heterogeneous collection of tumors of widely varying biologic potential from atypical nevi to conventional melanomas. Until sufficient numbers of MDM have been identified using standardized histologic criteria and patients have been followed for adequate periods, the legitimacy of MDM remains in question.

Nevoid Melanoma It is well established that melanoma may show differentiation along the lines

of almost every variant of benign melanocytic nevus or tumor. Thus, a priori, a subset of melanomas, closely resembles melanocytic nevi. Hence, the rubric “nevoid” melanoma has appeared in the literature as a direct result of this fundamental diagnostic problem of differentiating melanoma from nevus.339-342 In this chapter “nevoid” melanoma (NM) is defined as a tentative group of melanomas that more or less recapitulate the architectural configuration and cytomorphology of melanocytic nevi yet concomitantly demonstrate histologic criteria for, and the biologic behavior of, melanoma. However, one can make the case that until a series of “NMs” has been characterized at the clinical, histologic, and molecular levels with long-term follow-up, there is no scientific basis that NMs exist as a legitimate entity. Because many such lesions are not diagnosed initially and are detected only in retrospect, the histologic diagnosis of NM remains highly controversial, and consensus criteria have not been established. Suffice to say that nevoid melanoma remains a subject of ongoing research. In any case, this problem of the distinction of melanoma from nevus is among the most treacherous diagnostic problems in all of dermatopathology, and as such, carries significant medicolegal implications. In very broad terms, the term nevoid melanoma could encompass any form of melanoma having some resemblance to or mimicking any type of melanocytic nevus. An objection to this term is that a large number of melanomas may more or less resemble banal nevi and that the application of the term may be rather subjective. A variety of other terms has been used to describe this general group of melanomas, depending on how stringent are the criteria for inclusion, for example, MDM, verrucous and pseudonevoid melanoma and closely related terms, spitzoid melanoma (SM), smalldiameter melanoma, and small cell melanoma. Some nevoid melanomas might also be characterized as having a small diameter and also being comprised of small melanoma cells (ie, small cell melanoma). However, this chapter uses the term rather restrictively, as have most authors, to describe melanomas that closely resemble ordinary compound or dermal nevi; nevoid melanomas generally fall into four groups: (1) those with a raised, dome-shaped, or polypoid (nodular nonverrucous) configuration that resemble a predominately dermal nevus; (2) those with a distinctly papillomatous or verrucous surface; (3) those resembling

a lentiginous melanocytic nevus arising in sun-exposed skin of older individuals; and (4) those with a predominately or exclusively intraepidermal nested appearance mimicking a junctional or compound nevus. CLINICAL FEATURES Nevoid melanomas have no distinctive clinical features compared with conventional melanomas (Table 27-32); however, verrucous or papillomatous variants may suggest a verruca, seborrheic keratosis, or warty nevus. Most tumors reported have been in adults.

Table 27-32 Nevoid Melanoma

Clinical Features Women = men All ages, but commonly fifth decade of life Occurs anywhere, but trunk and lower extremities most common No distinctive features, but may have verrucous appearance Any size, often relatively small diameter but ≥ 2 cm Histopathologic Features Striking resemblance to banal compound or dermal nevus at scanning magnification Symmetry common Well-circumscribed lateral margins Pagetoid spread not common Often limited intraepidermal component Relatively small nevus-like cells, monomorphous appearance Some maturation may be present but often incomplete or absent Single-cell infiltration at base Cytologic atypia Nuclear pleomorphism Angulated nuclei Hyperchromatism Prominent nucleoli may be present Mitoses in dermal component, particularly deep Infiltration of adnexal structures Little or no inflammation Differential Diagnosis Melanocytic nevus, especially papillomatous dermal nevus Metastatic melanoma

heterogeneity of the lesion is another feature consonant with melanoma. Although the lateral margins are commonly well demarcated, the base of the melanoma is often poorly defined and characterized by the presence of single cells infiltrating collagen. In most instances, there is no host inflammatory response. The melanocytes comprising NM, at least in the superficial part of the lesion and perhaps throughout, are generally polygonal or epithelioid cells (mimicking the so-called type A or epithelioid nevus cells), sufficiently small to suggest nevus cells. They nonetheless demonstrate definite, but sometimes subtle, nuclear enlargement, pleomorphism, and often hyperchromatism; rather prominent nucleoli may be present (Fig. 27-37C). Many NM may suggest maturation, that is, diminished cytoplasmic and nuclear diameters with depth and a transition to smaller “type B” or lymphocyte-like cells, and perhaps “type C” or Schwann-like cells. At the same time, the latter transition may be accompanied by diminished cellularity with depth and loss of pigment synthesis. Nonetheless, major clues to diagnosis of NM are the presence of definite nuclear pleomorphism, particularly irregular nuclear contours, hyperchromatism, and nucleoli and continued pigment synthesis in the deepest parts of the dermal component. Commonly, one observes well-defined nests of relatively small cuboidal cells in the deepest portions of NM with the latter characteristics. One of the most important, and sometimes the single most important, criterion for diagnosis is the presence of mitoses in the dermal component (see Fig. 27-37C).357 This finding is often the first clue to considering melanoma in the differential diagnosis. The presence of one or a small number of dermal mitoses does not constitute sufficient evidence for diagnosis of melanoma, but it should prompt the histopathologist to search for additional criteria for melanoma and to either confirm or exclude the diagnosis (if possible). Mitoses are present in virtually all cases, and their absence should provoke skepticism about melanoma. The mitotic rate is commonly relatively low, often less than 6/mm.2.Increasing mitotic rate, deeply situated mitoses, and atypical forms also provide progressively more support for NM. The author has found that the presence or absence of mitotic figures in the deepest portion of a lesion can be a decisive factor in confirming or ruling out NM.

CHAPTER 27 ■ TUMORS OF MELANOCYTES

HISTOPATHOLOGIC FEATURES The essential histopathologic criteria for diagnosis are as follows: (1) at scanning magnification, the lesion has a striking resemblance to an ordinary compound or dermal nevus (see Table 27-32 and Fig. 27-37A); (2) an overall symmetry (some asymmetry may be present); (3) a rather sharp

circumscription at the peripheries of the lesion; (4) the absence of or often only a limited intraepidermal component, commonly with little or no pagetoid spread; (5) a monomorphous population of nevus-like cells in the dermis usually characterized by a confluent or sheetlike growth pattern in some portion of the lesion; and (6) dermal mitotic figures.20,339-342 Other features commonly, but not invariably, present that may suggest a banal nevus include diameter under 5 to 6 mm and changes suggesting maturation. There are four general morphologic variants: (1) the nonverrucous papular or nodular forms that present with only limited or no epidermal hyperplasia and (2) the verrucous or papillomatous variants that have the configuration suggesting a common verruca, seborrheic keratosis, or papillomatous nevus343,344; (3) the lentiginous variants arising in sunexposed skin of older individuals345,346; and (4) the striking intraepidermal nested variants mimicking a junctional nevus. There may be no intraepidermal melanocytic component in a large proportion of cases. The intraepidermal component, if present, may be subtle or limited in nature. One may observe melanocytes arranged as single cells, as junctional nests, or as both along the dermal-epidermal junction. The latter nesting may result in confluence of nested aggregates of melanocytes replacing the basilar portion of the epidermis. The epidermis is frequently effaced, thinned, and associated with dermal-epidermal separation. Pagetoid spread may be present in a proportion of cases and is an important finding in confirming a diagnosis of melanoma; however, it is often not a conspicuous feature. The principal finding in the dermis includes a sheetlike or confluent arrangement of relatively small cuboidal or polygonal melanocytes closely mimicking nevus cells (Fig. 27-37B). Often the dermal melanocytic population fills the papillary dermis and is closely opposed to the epidermis, resulting in a strikingly crowded or hypercellular appearance. In many cases, the melanocytes extend into the reticular dermis, with some diminished cellular density as well as some reduction in cellular and nuclear sizes, suggesting some maturation. In some lesions, one may observe fairly discrete nesting of melanocytes in some areas, suggesting a nevus; however, other parts of the lesion usually demonstrate the confluence and hypercellularity that favors melanoma. Furthermore, the

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B

A

C  FIGURE 27-37 Nevoid melanoma. (A) The lesion resembles a dermal nevus at scanning magnification and displays a striking symmetry. (B) High magnification shows confluent ovoid to spindled cells in the dermis without maturation. (C) The nuclei are enlarged with pleomorphism and prominent nucleoli. Uncommon mitoses are present throughout. This lesion underscores the need to examine such “borderline” tumors at high magnification for additional features that are crucial for histopathologic interpretation.

DIFFERENTIAL DIAGNOSIS The principal dilemma is discrimination of such melanomas from melanocytic nevi, especially papillomatous dermal nevi, and metastatic melanoma. One’s confidence in rendering a diagnosis of nevoid melanoma directly correlates with the number of abnormal features present. The following attributes are of critical importance in distinguishing NM from a nevus: (1) dermal mitoses, usually multiple and scattered throughout the lesion, are probably mandatory for the diagnosis. The higher the absolute mitotic rate and the more deeply located the mitoses, the more certain the diagnosis. However, the presence of rare mitoses, particularly in nevi in young or pregnant individuals and in nevi without atypia, must be interpreted with caution and are not proof of NM. (2) Dermal aggregates or fascicles of melanocytes

showing high density and confluence, having a sheetlike appearance throughout, or showing both features. The dermal population often demonstrates a monotonous appearance. (3) Cytologic atypia of melanocytes is mandatory for the diagnosis (Table 27-33). By definition, there are lesser degrees of atypia than in conventional melanomas. Careful scrutiny at higher magnifications is necessary to establish the presence of cytologic atypia. In general, the melanocytes may be relatively small compared with the usual enlarged epithelioid melanoma cells and thus the resemblance to a nevus.

Verrucous Melanoma Although verrucous melanoma was initially described in his classification of melanoma in 1967,272 Clark subsequently

discarded the term because he believed that its features could be present in any type of melanoma.273 Recent reports emphasize the prominent clinical and histologic verrucous features of such melanomas and the difficulty in classifying many of these lesions.343,344 Some of these melanomas might also be described as nevoid melanoma (see Nevoid Melanoma above). CLINICAL AND HISTOPATHOLOGIC FEATURES Most lesions are well circumscribed; are 1 to 2 cm in diameter; and are characterized by a dark brown, black, or grayish appearance and hyperkeratotic verrucous surface and diagnosed clinically as seborrheic keratosis or papillomatous nevi.343,344 The most striking feature at scanning magnification is a fairly symmetric lesion with prominent papillomatous or

Table 27-33 Comparison of Nevoid Melanoma and Melanocytic Nevus NEVOID MELANOMA

MELANOCYTIC NEVUS

Clinical Features Older age Larger size (1-2 cm) Some variation in color Greater asymmetry

Younger age Smaller size (<6 mm) More homogenous color Less asymmetry

Histopathologic Features

verrucoid epidermal hyperplasia, suggesting a seborrheic keratosis, epidermal nevus, verruca, or papillomatous melanocytic nevus (see Fig. 27-14). The intraepidermal melanocytic component may vary from minimal or absent or show prominent pagetoid spread. Also common is the frequent presence of a laterally extending intraepidermal component. Some of these tumors may show a contiguous basilar and suprabasilar proliferation of atypical melanocytes, often involving adnexal epithelium.343,344 In common with nevoid melanoma, the dermal component in some melanomas may show a startling resemblance to dermal nevus.20,343,344 The cell type in the latter tumors resembles a small nevus cell, but careful inspection should disclose prominent cellular pleomorphism, little or no maturation, and cells dispersed in confluent nests and sheets without orderly infiltration of stroma. The presence of mitotic figures (eg,
Symmetry Well circumscribed Little or no pagetoid spread Basilar proliferation less common No infiltration of adnexae Maturation Usually no dermal mitoses No atypical mitoses No deep infiltration

Small Cell Melanoma The term small cell melanoma has been introduced into the literature to describe a heterogeneous assortment of melanomas from several settings, perhaps linked only by the common thread of a population of small melanoma cells. This term has been used to refer to (1) rare melanomas developing in children and adolescents on the scalp118,122; (2) melanomas developing in CMN of children and adolescents,20,108,118,122; (3) melanomas developing in any setting, but particularly in adults, that resemble small round cell malignancies such as Merkel cell carcinoma347; (4) melanomas developing in sun-damaged skin of older individuals in the setting of solar melanocytic neoplasia or atypical lentiginous nevi345,346,348; and (5) melanomas in adults that have the characteristics of nevoid melanoma, as described above. Because there is considerable overlap of small cell melanomas and nevoid melanomas in adults (see Nevoid Melanoma above), the following sections discuss only two entities (Table 27-34): (1) exceptionally rare melanomas that mimic high-grade, small, round cell malignancies and (2) small cell melanomas arising predominately in the sun-damaged skin of elderly individuals. SMALL CELL MELANOMA MIMICKING MERKEL CELL (NEUROENDOCRINE CARCINOMA) These variants of melanoma are so rare that one can only make anecdotal remarks about them.347 Perhaps they

SMALL CELL MELANOMAS ARISING PREDOMINATELY IN THE SUN-DAMAGED SKIN OF ELDERLY INDIVIDUALS Another variant of small cell melanoma that also might be subsumed under the general category of “nevoid melanoma,” occurring in the sun-damaged skin of individuals generally older than age 50 years, has been proposed by Kossard and Wilkinson.345,346,348 Although undoubtedly some proportion of these lesions may in fact be melanoma, the banal appearance of and resemblance of such lesions to lentiginous nevi, a negligible mitotic rate, and the lack of follow-up call into question the diagnosis of melanoma. Thus, the latter group of 131 cases may possibly include an admixture of atypical nevi, biologically indeterminate lesions, and melanomas. Although the author is confident that this entity exists, it is certain that these lesions as a group require further study. CLINICAL AND HISTOPATHOLOGIC FEATURES Such lesions generally develop in the sunexposed skin of older individuals, with about 80% of patients being age 50 years or older (range, 18-91 years).346 Men outnumber women by a ratio of approximately two to one. These tumors are most common on the backs of men and the lower extremities of women. Histologically, the lesions described by Kossard and colleagues suggest a lentiginous junctional or compound nevus at scanning magnification. Features favoring melanoma include a large diameter

CHAPTER 27 ■ TUMORS OF MELANOCYTES

Greater asymmetry Less well circumscribed Greater likelihood of pagetoid spread Intraepidermal basilar melanocytic proliferation common Infiltration of adnexae Reduced or no maturation Mitoses in dermis Atypical mitoses Deep infiltration of dermis

have been most commonly recognized as metastases, presumably indicating progression or de-differentiation to highgrade blastlike tumors. Nonetheless, primary tumors occur in adults. The lesions are primarily defined by a small, round cell population arranged in nests, cords, and sheets. Melanin and intraepidermal involvement may or may not be present. These tumors feature cells with scant cytoplasm, round to oval nuclei, high mitotic rates, and scattered necrotic cells. Amelanotic tumors resemble primary or metastatic neuroendocrine carcinoma, lymphoma, other small cell carcinomas, and metastatic small cell carcinoma of the lung. Immunohistochemistry is of fundamental importance for confirming a melanocytic origin versus the other entities mentioned above. In particular, neuroendocrine carcinoma, metastatic small cell carcinoma of the lung, and other small cell carcinomas may show intraepidermal involvement, including nesting and pagetoid spread.

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Table 27-34 Small Cell Melanoma

Clinical Features High-grade small cell melanoma mimicking Merkel cell carcinoma Extremely rare Adults (any age) Any site Often 0.4-2 cm Often amelanotic papule or nodule Small cell melanoma arising in predominately sun-damaged skin Often >50 years of age (range, l8–9l) Men > women (2:l) Backs of men, legs of women Usually >1 cm Variegated color Often tan, brown, black, gray Histopathologic Features High-grade small cell melanoma mimicking Merkel cell carcinoma Melanin and intraepidermal involvement may or may not be present Often cohesive nests, cords, sheets of small round cells Cells with scant cytoplasm Round to oval nuclei Prominent mitotic rate and necrosis Small cell melanoma arising in predominately sun-damaged skin Intraepidermal component often extensive, lentiginous and nested Usually some pagetoid spread Elongated epidermal rete ridges common Effacement and thinning of epidermis also common Small cuboidal melanocytes with scant cytoplasm Melanocytes larger than those in nevi Nuclear pleomorphism Irregular nuclear contours Dense chromatin Prominent nucleoli Dermal nests often large, nodular, cohesive, anastomosing Often absence of maturation Continued pigment synthesis with depth Mitotic figures rare Solar elastosis Host response with fibroplasia, partial regression common Differential Diagnosis High-grade, small cell melanoma mimicking Merkel cell carcinoma Metastatic melanoma Primary and metastatic neuroendocrine carcinoma Metastatic small cell carcinoma Lymphoma Other small, round cell malignancies Small cell melanoma arising in predominately sun-damaged skin Atypical lentiginous nevi of sun-exposed skin

(ie, ≥1 cm); asymmetry; poorly defined margins; effacement and atrophy of the epidermis; host response, including partial regression; large junctional and dermal nests of melanocytes that tend to confluence; some pagetoid spread, which is often subtle; and a lack of maturation.

674

DIFFERENTIAL DIAGNOSIS Distinguishing such lesions from atypical lentiginous

compound nevi is the major challenge; some lesions prove so difficult that they can only be categorized as biologically indeterminate. Unfortunately, because dermal mitoses are generally rare or absent, a major aid to diagnosis is lacking. Of particular utility is the recognition of melanoma in situ and contiguity of the latter with the dermal component. Effacement and thinning of the epidermis,

confluent nesting of melanocytes along the dermal-epidermal junction, some pagetoid spread, and sufficient atypia of the melanocytes allow for a diagnosis of intraepidermal melanoma.

Spitzoid Melanoma As with “nevoid” melanoma, the term SM has surfaced in the medical literature as a direct result of the difficulty or impossibility in some cases of distinguishing melanoma from Spitz nevi or tumors. The basis for the specific term SM has come about from the retrospective diagnoses of melanocytic lesions (as malignant melanoma) that have been initially interpreted as “Spitz nevus” and have subsequently shown clearly documented adverse events such as lymph node metastases, more distant metastases, or death. Thus, although the term SM would seem to have merit, the term has actually been used with such imprecision in the literature that the term itself has become almost meaningless in the author’s view. The essential problem is the indiscriminate application of this term to a heterogeneous group of spitzoid-appearing lesions that differ considerably in terms of many phenotypic and genotypic characteristics and biologic potential.118,133,135,349

Melanoma Arising in Association with Dermal Nevi The development of melanoma in the dermal component of an acquired nevus is an uncommon or rare event.350-352 Some of these melanomas may originate from adnexal-associated nevus elements. CLINICAL AND HISTOPATHOLOGIC FEATURES Most patients are approximately 40 to 60 years of age, and the most common site is the head and neck area.352 The lesions are often larger than ordinary dermal nevi (eg, 1-2 cm), and there is usually a history of recent change or enlargement. Within an otherwise ordinary dermal nevus, one usually encounters a distinct nodule of cytologically atypical melanocytes.352 There is usually an abrupt transition from the ordinary dermal nevus component to the nodular aggregate of atypical cells. Conventional maturation is usually absent, although some degree of “pseudo-maturation” is observed in some melanomas. The latter cells are most commonly enlarged with abundant cytoplasm and pleomorphic nuclei. Mitotic figures are usually easily found within the cellular nodule and should number more that 2 to 3/mm2.

of the patients are men, and the commonest site is the scalp. MBN most frequently present as blue or blue-black plaques or nodules ranging from 1 to 4 cm (mean, 2.9 cm)199-202 that are often multinodular. There is usually a history of recent enlargement or change in a previously stable blue nevus. MBN usually are highly aggressive with metastasis to lymph nodes and a variety of visceral sites. HISTOPATHOLOGIC FEATURES MBN usually presents in one of three patterns: (1) a lesion with an overtly malignant component juxtaposed to a benign blue nevus component, usually a CBN; (2) a more subtle sarcoma-like presentation (without florid benign and malignant components) initially suggesting CBN but exhibiting large densely cellular fascicles or nodules of spindle cells that on closer inspection have sufficient atypicality for malignancy and are distinctly more abnormal than the usual small fascicular or alveolar patterns in CBN; or (3) a lesion suggesting a benign CBN with additional atypical features such as a large diameter, asymmetry, prominent cellular density, nuclear pleomorphism, and some mitotic activity at least focally, but not obviously malignant, that subsequently results in malignant behavior (the author terms such lesions biologically indeterminate). In the most

common presentation, MBN are characterized by nodular or multinodular aggregations of spindle cells in tightly packed fascicles in the dermis and often the subcutis (Fig. 27-38).194,198-202 By definition, there is sparing of the epidermis. Occasional epithelioid cells and multinucleate giant cells are encountered. Melanin pigment and cytoplasmic vacuolization are noted in approximately two-thirds of cases.200 Necrosis, a feature previously thought characteristic of MBN, is observed in only about one-third of cases.200 In general, there is striking cytologic atypia, prominent nuclear pleomorphism, infrequent mitotic figures (~1-2 mitoses/mm2) and uncommonly atypical mitoses. Most MBN have a component of CBN, but elements of common blue nevus (pigmented dendritic melanocytes, fibrosis, and melanophages) and rarely nevus of Ota or nevus of Ito may be observed. DIFFERENTIAL DIAGNOSIS MBN must be distinguished from CBN and its atypical variants,20,169,198-202 primary or metastatic melanoma, and CCS. Because no histologic features are specific for MBN, a contiguous remnant of blue nevus should be identified or a history of an antecedent blue nevus documented to distinguish MBN from either nodular or metastatic melanoma.

CHAPTER 27 ■ TUMORS OF MELANOCYTES

DIFFERENTIAL DIAGNOSIS The most obvious dilemma is the differentiation of a focus of melanoma from dermal nevus, especially a nevus with cytologically bizarre nevus cells as in ancient schwannoma or a distinct focus of epithelioid or fusiform cells, that is, MNPH or socalled combined nevus, “inverted type A” nevus, or melanocytic nevus with focal dermal epithelioid cell component or dermal nodules.38,213,214 The nodular area in question should demonstrate a cohesive or expansile aggregate of cells with unequivocal cytologic atypia. Although these melanocytic cells usually have a monomorphous or clonal appearance, inspection of individual cells should disclose substantial nuclear pleomorphism and often prominent nucleoli and hyperchromatism. Mitotic figures should also be present in this focus. A dermal nevus with bizarre or ancient cytologic features usually does not show mitoses. One should also consider clinical factors such as the patient’s age (melanoma usually develops in persons older than 40 years of age), size (such lesions are often >1 cm in diameter), and history of recent change or enlargement. On the other hand, MNPH are often present in younger individuals; are characterized by a small, dark nodule or papule in a relatively small symmetric nevus; and usually show lowgrade or no cytologic atypia of the epithelioid or fusiform cells. The latter cells often display prominent melaninization of melanocytes and are accompanied by melanophages.

 FIGURE 27-38 Malignant blue nevus (melanoma arising in association with blue nevus). Fascicular arrangements of atypical spindle cells, many of which contain melanin, can be observed in this field.

675

Malignant Melanoma Arising in or Resembling a Blue Nevus (Malignant Blue Nevus) Malignant melanoma originating from or associated with a preexisting blue nevus, commonly a CBN, or closely resembling a blue nevus was first delineated by Allen and Spitz under the term malignant blue nevus.167 The term has been controversial, and many have called for its abandonment. Nonetheless, this appellation continues to be used in the literature because this variant of melanoma has a unique developmental basis (ie, origin from a BN, a rather distinctive clinicopathologic phenotype, and possibly prognostic differences from conventional melanoma, although this has not been definitively proven). So-called MBN are extremely rare, with fewer than 100 cases thus far being reported.94,167, 198-203 CLINICAL FEATURES The average age at diagnosis is about 46 years, two-thirds

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Clear Cell Sarcoma (Malignant Melanoma of Soft Parts)

676

CCS has been a perplexing tumor because of its origin in soft tissue, classification in the past as synovial sarcoma or fibrosarcoma,353-361 and a pattern of biologic behavior that is consistent with a sarcoma.355 However, CCS has also been considered an unusual variant of melanoma. At present, CCS is recognized as a distinct clinicopathologic entity, particularly because of an apparently tumor-specific translocation involving chromosomes 12 and 22 in 60% to 75% of cases.356 The latter translocation is characterized by the fusion of a portion of the activating transcription factor gene (ATF-1) on the long arm of chromosome 12 (12q13.1-13.2) and the Ewing sarcoma oncogene (EWS) on chromosome 22 (22q13). This translocation has not been identified in conventional melanoma when studied by reverse transcriptase polymerase chain reaction and fluorescent in situ hybridization.360 CCS develops in young adults between the ages of 20 and 40 years and most commonly involves the distal extremities (the foot being the most common site) (Table 27-35). The tumor typically presents as a slowly enlarging, deep-seated mass because of its association with tendons and aponeuroses, and there may be occasional tenderness or pain. CCS is slightly more prevalent in women. HISTOPATHOLOGIC FEATURES The tumor is characterized by a well-circumscribed, multilobulated appearance.353-361 Oval or fusiform cells with clear or eosinophilic granular cytoplasm are arranged in welldefined nests and fascicles (Fig. 27-39). Tumor aggregates are generally compartmentalized by fibrous tissue of variable thickness that merges with aponeurotic or tendinous structures. There is variation in nuclear size and shape, and the nuclei are notable for vesicular qualities and prominent nucleoli. Distinctive multinucleate giant cells occur in about two-thirds of cases. Melanin may be detected in approximately half of these tumors. Special stains yield more tumors containing melanin. Most tumors react with antibodies to vimentin, S-100 protein, HMB45, MART-1, tyrosinase, and neuron-specific enolase.357 Cytokeratin, epithelial membrane antigen, or leukocyte common antigen are not expressed. Melanosomes and premelanosomes are noted on electron microscopy. Local recurrences are frequent, with 70% of patients in one series experiencing

Table 27-35 Clear Cell Sarcoma

Clinical Features Ages 20-40 years Women ≥ men Distal extremities, the foot most commonly involved Deep location—tendons and aponeuroses Slowly enlarging mass Tenderness, pain Histopathologic Features Multilobulated tumor Oval or fusiform cells in nests and fascicles Fibrous trabeculae separate cellular aggregates Clear or eosinophilic cytoplasm Multinucleate giant cells Melanin in over half of cases Immunohistochemistry S-100 protein + HMB45 + MART-1 + Electron Microscopy Premelanosomes Melanosomes Differential Diagnosis Metastatic melanoma Cellular blue nevus Malignant blue nevus Malignant peripheral nerve sheath tumor Epithelioid sarcoma Synovial sarcoma Fibrosarcoma

at least one recurrence during a mean period of 4.2 years.354 The recurrences are often multiple and followed by lessfrequent regional node and lung metastases. In the series above, 43% of the individuals died of metastases.354 DIFFERENTIAL DIAGNOSIS CCS may be confused with CBN, MBN, metastatic melanoma, malignant peripheral nerve sheath tumor, epithelioid sarcoma, synovial sarcoma, and fibrosarcoma. The tumor probably most closely resembles CBN with atypia and MBN, but the latter do not usually occur in soft tissue. CCS is distinguished by the typical clinical presentation in young adults, involvement of distal extremities, typical histology, immunohistochemistry, and (if necessary) the ATF-1-EWS fusion gene. Epithelioid sarcoma and synovial sarcoma immunostain with cytokeratin and epithelial membrane antigen but not with S-100 protein, with some exceptions for synovial sarcoma and HMB45.

Balloon Cell Melanoma BCM exhibits ballooning in at least 50% of the melanoma cells.362 The individual “balloon cells” have abundant vacuolated cytoplasms that impart a clear cell appearance. Knowledge of BCM is

 FIGURE 27-39 Clear cell sarcoma. The tumor is remarkable for intersecting fascicles of spindle cells, compartmentalized by fibrous tissue focally.

patients, to lack “maturation” of melanoma cells, and to have cellular atypia and mitotic activity.362

CLINICAL AND HISTOPATHOLOGIC FEATURES There are no distinctive clinical features of BCM. The balloon cells are large, round, or polygonal cells with clear or eosinophilic, slightly granular cytoplasm.362 The nuclei are irregularly placed and exhibit only slight to moderate atypia. Mitotic activity is also generally low. Melanin has been noted in about 25% of cases. Metastases from BCM often show balloon cell change but maybe difficult to diagnosis because they are amelanotic and fail to exhibit nesting. Virtually all BCM studied thus far show positive immunostaining with S-100 protein and HMB45. A small number may be positive for carcinoembryonic antigen.

Table 27-36 lists other rare and unusual presentations of melanoma.363-366

DIFFERENTIAL DIAGNOSIS BCM may be confused with balloon cell nevus, xanthoma, hibernoma, granular cell tumor, metastatic clear cell carcinomas such as renal cell or adenocarcinoma, liposarcoma, and clear cell appendage tumors.362 Perhaps the greatest problem is distinction of BCM from balloon cell nevus. In general, balloon cell nevi occur in young individuals (younger than age 30 years) and show “maturation” of nevus cells (decreased size of cells and nuclei with depth) and the presence of multinucleate giant cells, in contrast to BCM, which tends to develop in older

OTHER RARE AND UNUSUAL VARIANTS OF MELANOMA

Regression Melanoma is notable for its frequency of spontaneous regression.20,300 The prevalence of histologic regression varies according to the definition of regression used and the thickness range of the melanomas reported.300,367,368 In a study of 563 cases of primary melanoma, histologic regression was noted in 46% of thin (<1.5 mm), 32% of intermediate (1.5 to 3.0 mm), and 9% of thick (>3.0 mm) melanomas.368 McGovern has also recorded regression in 58% of melanomas 0.70 mm or smaller in thickness.367-369 Complete regression of melanoma is uncommon and has been reported to occur with a frequency of 2.4% to 8.7% (Fig. 27-40).370,371 Many cases of metastatic melanoma with unknown primary are thought to be explained by spontaneous regression of the primary melanoma.371,372 Spontaneous regression is thought to be immunologically mediated because of mononuclear cell infiltrates containing T lymphocytes, and monocytes or macrophages at the site of regression.373 Regression is seen most often in microinvasive or thin melanoma and is present as focal, partial, and rarely complete regression of the tumor.300,374

Table 27-36 Unusual or Rare Presentations of Primary Melanoma Myxoid melanoma381–383 Melanoma resembling experimentally induced and spontaneous melanomas in animals (“animal type” melanoma)384

Plasmacytoid melanoma381,382

Rhabdoid melanoma381,382 Signet-ring cell melanoma381,382

Prominent myxoid stroma suggesting mucinous carcinoma or peripheral nerve sheath tumors Raised dermal tumor composed of heavily melaninized epithelioid cells, fusiform cells often with dendrites, and histiocytes. The striking melanin content tends to obscure cytologic detail and bleaching is often needed. Melanoma cells with eccentric nuclei suggesting plasma cells but lacking characteristic “clock face” nuclear chromatin patterns Cytologic alteration in melanoma suggesting rhabdoid tumor Cytoplasmic accumulation of vimentin-positive material suggesting adenocarcinoma

The changes of regression form a continuum but may be arbitrarily categorized into three stages (Table 27-37).372,374

METASTATIC MELANOMA Melanoma may spread through lymphatic channels, by direct extravascular migratory spread, or hematogenously and thus may occur in any site of the body. Much remains to be learned about the mechanisms of melanoma (and solid tumor) metastasis. Metastases are more frequent to lymph nodes, skin, and subcutaneous tissue (nonvisceral sites) than to visceral organs.20,304,375-377 Lymph nodes are the most common site of metastases, and 60% to 80% of patients with metastatic melanoma develop lymph node metastases.294,377 The lymph node groups most commonly involved are ilioinguinal, axillary, intraparotid, and cervical lymph nodes.378 The metastatic tumor may be clinically apparent (macroscopic metastasis) or detected only by histologic examination (microscopic metastasis). Nearly 50% of patients with metastatic melanoma develop skin metastases,376,377 which may occur in the area of locoregional lymphatic drainage or at a remote location. Two subtypes of regional cutaneous metastases are arbitrarily distinguished by their distance from the primary melanoma.379 Whereas cutaneous satellites are discontinuous tumor cell aggregates that are located in the dermis or subcutis within 5 cm of the primary tumor, intransit metastases are located more than 5 cm away from the primary melanoma. The finding of the latter metastases has poor prognostic implications because the majority of patients with such lesions develop disseminated metastatic disease.379 Although virtually any organ may be involved, the most common first sites of visceral metastases reported in clinical studies are the lung (14%-20%), liver (14%-20%), brain (12%-20%), bone (11%-17%), and intestine (1%7%); first metastases at other sites are very rare (<1%).375 Metastatic melanoma tends to grow in nests, sheets, or fascicles, often with an infiltrative border, pleomorphism, mitoses, and necrosis.20,304 Cytologically, epithelioid or spindle cells are commonly found in metastatic melanoma.23,322 Melanin, which greatly facilitates the recognition of metastatic melanoma, may be apparent, subtle, or absent (amelanotic melanoma).

CHAPTER 27 ■ TUMORS OF MELANOCYTES

important so that it is distinguished from the much more common balloon cell nevus and from other clear cell tumors of the skin. BCM is reported to have a particular propensity for multiple skin and subcutaneous metastases.362

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 FIGURE 27-40 Tumoral melanosis. There is complete regression of melanoma with a residual nodular aggregate of melanophages. (Courtesy of Drs. Walter LaMar and Neil Crowson.)

Diagnostic Problems Concerning Metastatic Melanoma Several situations may arise in which the diagnosis of metastatic melanoma is not straightforward. The problem may lie in the identification of a metastaticappearing lesion as melanocytic or in the distinction between a primary and secondary melanoma.20,304

others.363,364 The differential diagnosis is particularly difficult in patients with amelanotic melanoma. Often, additional studies are needed, such as melanin stains, immunohistochemistry using a panel of antibodies, and electron microscopy, to conclusively identify a metastatic tumor as melanocytic.

Melanoma Simulating Other Neoplasms

Primary Cutaneous versus Cutaneous Metastatic Melanoma

Metastatic melanoma may assume a great variety of morphologic appearances and may mimic a number of nonmelanocytic tumors, such as lymphoma, undifferentiated carcinoma, adenocarcinoma, a variety of sarcomas, and many

A common problem is distinguishing an epidermotropic metastasis from a primary melanoma (or possibly a nevus in some instances) (Table 27-38). Cutaneous metastases usually lie within the reticular dermis or subcutis and only rarely involve

the overlying epidermis, but primary cutaneous melanomas typically have an intraepidermal component.20,379 Also, metastases tend to be smaller (often <4 mm) than primary tumors (usually >4 or 5 mm). In cases of metastatic melanoma showing epidermotropism,380 the epidermal component is usually relatively limited compared with the dermal component (Fig. 27-41). If the dermal metastasis is superficial, the overlying epidermis may be thinned, and the lateral borders may show hyperplastic elongated rete ridges turned inward, forming a collarette. Angiotropic melanoma cells are more likely to be found in and around a metastatic lesion than near a primary tumor.380 Primary tumors generally display more pleomorphism than metastatic lesions, which often appear as an atypical but rather monomorphous population of cells.381 Primary tumors tend to show more variation in the overall composition of the lesion. There is often more fibrosis and more of an inflammatory host response.382 When deciding whether a melanocytic tumor is a metastasis or a primary lesion, one must weigh the histologic appearance against a detailed clinical history to arrive at the correct diagnosis.383 The importance of having precise clinical information is mandatory because there are exceptions to all of the guidelines for diagnosis mentioned above.383

Melanocytic Aggregates (Including Nodal Melanocytic Nevi) versus Micrometastases Collections of small melanocytes are occasionally seen within lymph nodes (sentinel or other) draining the skin.384-387 These aggregates are usually small and

Table 27-37 Stages of Histologic Regression of Malignant Melanoma

678

Early (or active) Zone of papillary dermis and epidermis within a recognizable melanoma, characterized by dense infiltrates of lymphocytes disrupting or replacing nests of melanoma cells within the papillary dermis and possibly the epidermis as compared with adjoining zones of tumor; degenerating melanoma cells should be recognizable. There is no obvious fibrosis. Intermediate Zone of papillary dermis and epidermis within a recognizable melanoma, characterized by reduction (loss) in the amount of tumor (a disruption in the continuity of the tumor) or absence of tumor in papillary dermis and possibly within the epidermis, when compared with adjacent zones of tumor, and replaced by varying admixtures of lymphoid cells and increased fibrous tissue (compared with normal papillary dermis) in this zone. Variable telangiectasia (and new blood vessel formation) and melanophages may also be present. Late Zone of papillary dermis and epidermis within a recognizable melanoma, characterized by marked reduction in the amount of tumor, when compared to adjacent areas of tumor, or absence of tumor in this zone, and replacement and expansion of the papillary dermis in this zone by extensive fibrosis (usually dense fibrous tissue, horizontally disposed) and variable telangiectasia (and new blood vessel formation), melanophages, sparse or no lymphoid infiltrates, and effacement of the epidermis (other than fibrosis; the latter features are frequently present but not essential for recognizing regression).

Table 27-38 Primary Cutaneous Melanoma Versus Cutaneous Metastasis

Location of tumor If epidermal involvement

Size Epidermal collarette Cytology Reactive fibrosis Angiotropism

PRIMARY MELANOMA

CUTANEOUS METASTASIS

Usually both dermis and epidermis Usually prominent; pagetoid horizontal and vertical spread commonly present; usually epidermal component extends laterally beyond dermal component Nearly always >0.4 cm and usually >1.0 cm Usually less common Usually pleomorphic May be marked Perhaps less commonly seen

Dermis and/or subcutis Usually dermal component extends laterally beyond epidermal component; pagetoid spread less common

Metastatic Melanoma with Unknown Primary Site Approximately 4% to 12% of patients with melanoma develop metastases without a clinically detectable primary tumor.388,389 Although it is possible that some melanomas may arise de novo within a lymph node, dermal, subcutaneous, or visceral site, it is generally believed that many of these cases are related to complete regression of a primary cutaneous melanoma.389,390 Metastatic melanomas with an unknown primary site are twice as common in men than in women, which is in agreement with the observation that tumor regression is more commonly observed in men than in women.390 The most common site of presentation is in lymph nodes (64%),391 and 21% of the cases present with visceral metastases.375,389,391

 FIGURE 27-41 Epidermotropic metastatic melanoma. There is focal involvement of epidermis. The metastasis resembles a compound nevus; however, the lesion exhibits angiotropism, which is an important finding supporting a metastasis.

Melanosis in Metastatic Melanoma Cutaneous or generalized melanosis is a rare complication of metastatic melanoma.375,393-394 Hyperpigmentation may be focal or diffuse, limited to the skin or generalized, and involving internal organs.

THE HISTOLOGIC DIAGNOSIS OF MALIGNANT MELANOMA The histologic diagnosis of malignant melanoma remains rather imprecise and usually depends on the recognition of a constellation of histologic features, no single feature in and of itself being diagnostic of melanoma.20 It must be emphasized that because there are so many exceptions to the conventional criteria for melanoma, the histopathologist must always use as much information as possible and common sense at all times. On the other hand, a large percentage of melanomas are diagnosed correctly by a majority of knowledgeable histopathologists. It is also true that a small percentage of melanocytic tumors are histologically challenging and produce no consensus even among expert histopathologists. In general, whereas melanomas are characterized by an overall asymmetry and disorder, benign melanocytic lesions tend to have symmetry and orderliness. Although there is no absolute size criterion, the larger the lesion in breadth (generally >4 to 5 mm and especially >10 mm), the greater the likelihood that the lesion is melanoma. Melanomas are also often characterized by poor circumscription of the peripherally extending intraepidermal component and heterogeneity. Other architectural attributes suggesting melanoma include a

CHAPTER 27 ■ TUMORS OF MELANOCYTES

inconspicuous but may occupy as much as one-third of a lymph node.402-405 They are usually located in the fibrous capsule or trabeculae of the node rather than the marginal sinus,385 but they can rarely be found in the parenchyma of the lymph node. Their bland appearance, their frequent resemblance to nevus cells, and their location in the fibrous capsule of the lymph node help to distinguish them from micrometastases and suggest that many are nodal nevi. However, especially in frozen sections or in the rare situation of intranodal location, such aggregates in lymph nodes may lead to diagnostic confusion. There has been considerable debate as to whether these nodal melanocytic lesions derive from aberrant migration of melanoblasts from the neural crest during embryogenesis or represent lymphatic spread from a benign cutaneous nevus.

Often small; may be <1.0 cm and occasionally <0.3 cm More likely present Usually monotonous Usually mild Usually present

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contiguous proliferation of single (often basilar) melanocytes, considerable variation in the sizes and shapes of intraepidermal cellular nests, and diminished cohesiveness of the nests of cells. There may be a confluence of melanoma cells along the dermal-epidermal junction. The epidermis is frequently significantly altered (eg, thinning, effacement, “consumption,” ulceration, hyperplasia, lack of uniformity from side to side, hyperkeratosis, parakeratosis) and replaced by melanoma compared with that in benign melanocytic lesions. One of the features most characteristic of melanoma, yet one that is not specific to melanoma, is upward migration or pagetoid spread (pagetoid infiltration or melanocytosis) of melanocytes with involvement of the superficial epidermis. A predominance of single cells over small aggregates or nests typifies this pattern in melanoma. Melanoma cells are usually present at all levels of the epidermis, including the granular and cornified layers. Characteristics of the dermal component suggesting melanoma include asymmetry, confluent or sheetlike patterns of melanocytes without maturation, heterogeneity, hypercellularity, mitoses particularly in significant numbers, deeply located, and atypical, necrosis, prominent host response, and angiotropism. Cytologic atypia is mandatory for a diagnosis of melanoma. There is a uniformity or monomorphous quality of the atypia in melanoma rather than the discontinuous pattern of atypia often found in atypical nevi. Melanoma is also notable for cellular and nuclear enlargement, nuclear pleomorphism, hyperchromatic nuclei, high nuclear to cytoplasmic ratios of melanoma cells, and often prominent nucleoli. Large polygonal melanoma cells often have abundant pink granular cytoplasms or may contain finely divided (“dusty”) melanin granules. The melanin granules may vary considerably in size and shape.

Application of Other Ancillary Techniques to the Diagnosis of Melanoma

680

For many years, a wide variety of techniques, including electron microscopy, DNA ploidy, immunohistochemistry, and (more recently) molecular biology, have been used in the diagnostic assessment of melanoma and its discrimination from other melanocytic (and nonmelanocytic) lesions. Suffice to say that histopathology

remains and will remain the gold standard for the foreseeable future. However, particular immunohistochemical markers such as S-100 protein, Melan-A (MART-1), gp100 (HMB45), tyrosinase, and MITF have greatly facilitated more specific diagnosis of melanoma versus nonmelanocytic neoplasms.20 Furthermore, the pattern of expression of various markers such as HMB45 may aide in discriminating melanoma from an atypical or benign melanocytic lesion. For example, melanoma may show diffuse expression of HMB45 in contrast to no expression or loss of expression with depth corresponding to maturation in a benign melanocytic lesion. Proliferation markers such as Ki-67 may provide additional information as, for example, labeling indices below 5% favoring benign lesions versus those above 15% to 25% favoring melanomas. The use other biomarkers such as loss of expression of p16 and cyclin-dependent kinase 4 and increased expression of cyclin D1 favor melanoma versus benign or atypical melanocytic lesions. 395 Finally, comparative genomic hybridization (CGH) has demonstrated that increased numbers and types of chromosomal aberrations (both losses and gains of DNA copy number) in melanocytic lesions may facilitate the diagnosis of melanoma and its distinction from other melanocytic neoplasms. CGH may help define the developmental pathways of melanoma.

Diagnosis of the Borderline or Controversial Lesion Suggesting Melanoma As has been emphasized throughout this chapter, the histopathologist must recognize his or her limitations; not all melanocytic lesions at present can be classified as benign or malignant. Thus, the histopathologist should marshal all resources available to interpret as precisely as possible a difficult melanocytic lesion and to place it into one of three categories—benign, biologically indeterminate, or malignant—for the optimal communication to and management of the patient. A biologically indeterminate lesion is defined as one that has some potential (uncertain) risk for local recurrence and metastasis but cannot be interpreted as malignant after applying all of the currently available criteria. The diagnostic exercise should be comprehensive and include collecting information such as age, gender, site, clinical characteristics, presence or absence of ulceration, diameter, thickness in millimeters, mitotic rate per millimeters squared,

possibly immunostaining for proliferative rate (eg, Ki-67, other biomarkers, and CGH) to quantify as much as possible the abnormalities present that favor or argue against melanoma.395 The diagnostic evaluation of such a difficult lesion should probably include obtaining the opinion of a recognized authority in the field.

PROGNOSTIC FACTORS IN MELANOMA Over the past 20 to 30 years, there has been extensive investigation of prognostic factors in melanoma using large databases and multivariate techniques.20,288,289,301,396 The most powerful predictors of survival from many such studies have been the thickness of the primary melanoma (measured in millimeters from the granular layer of the epidermis vertically to the greatest depth of tumor invasion) and the stage or extent of disease, that is, localized tumor, nodal metastases, distant metastases. Although a number of studies have described “breakpoints” for tumor thickness and prognosis—for example, patients with melanomas smaller than 0.76 mm have an almost 100% 5-year survival rate396,397—good evidence now suggests that this inverse relationship between thickness and survival is essentially linear.397,398 Although thickness is the best prognostic factor available for localized melanoma, occasional melanomas defy this relationship,288 that is, thin melanomas that metastasize and thick ones that do not. A number of other factors have also been reported to influence outcome in patients with localized melanoma (Table 27-39), particularly surface ulceration, mitotic rate, and microscopic satellites (localized metastases). However, these various factors largely derive their effect from a correlation with melanoma thickness and generally fail to remain significant after multivariate analysis.300,301 The presence or absence of melanoma involving regional lymph nodes has now been established as the most significant prognostic factor for survival in melanoma.398 After regional lymph node metastases have developed, 5-year survival decreases to the range of approximately 10% to 50% and is largely related to the number and extent of lymph nodes involved.398 The median survival for patients with distant metastases is approximately 6 months.396 The only factors influencing the time to death include the number of metastatic

Table 27-39 PROGNOSTIC FACTORS FOR LOCALIZED MELANOMA PROGNOSTIC FACTOR

7.

EFFECT ON PROGNOSIS 2

Tumor thickness (mm ) Levels of invasion Ulceration Mitotic rate Tumor-infiltrating lymphocytes (TILs) Regression

8. 9. 10. 11.

12. 13.

14.

sites, surgical resectability of the metastases, duration of remission, and location of metastases—that is, nonvisceral (skin, subcutaneous tissue, distant lymph nodes) versus visceral sites (lung, liver, brain, bone).396

HISTOPATHOLOGIC REPORTING OF MELANOMA The pathology report should include the following minimum information: diagnosis (ie, malignant melanoma, in situ or invasive), depth of tumor invasion in millimeters measured vertically from the granular layer of the epidermis or

Table 27-40 Histopathologic Reporting of Melanoma Essential information 1. Diagnosis: Malignant melanoma, in situ or invasive 2. Measured depth (in mm) 3. Presence of histologic ulceration 4. Mitotic rate (per mm2) 5. Presence of microscopic satellites 6. Adequacy of surgical margins Other prognostic information reported to be significant in some databases Clark level: I, II, III, IV, V Tumor-infiltrating lymphocytes Angiotropism Vascular or lymphatic invasion Desmoplasia-neurotropism Degree of regression, particularly >50% of lesion Radial or vertical growth phase Histologic subtype

from the surface of an ulcer with an ocular micrometer, and the adequacy of surgical margins (Table 27-40).20 The following histologic changes should also be mentioned if present: ulceration, mitotic rate per millimeter squared, and microscopic satellites because of new staging guidelines. Other prognostic factors such as angiotropism, true vascular or lymphatic invasion, marked or virtually complete regression, desmoplasia, neurotropism, histologic type of melanoma, and radial or vertical growth phase; tumor-infiltrating lymphocytes may be reported as well. However, some of the latter factors are highly correlated with tumor thickness and thus may not add significant information beyond thickness alone.

15. 16.

17. 18. 19.

20.

21.

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Microscopic satellites Angiotropism Vascular or lymphatic invasion Tumor cell type Age Gender Anatomic site

Worse with increasing thickness Worse with deeper levels Worse with ulceration Worse with increasing mitotic rate Better with TILs Unsettled; some studies have shown an adverse outcome with pronounced regression, but others show no effect or a favorable outcome Worse prognosis Worse prognosis Worse prognosis but rare Better prognosis with spindle cells vs. other cell types Worse prognosis with increasing age Women have better prognosis than men Extremity lesions have better prognosis than axial lesions (trunk, head and neck, palms and soles)

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326. Barnhill RL, Mihm MC: Cellular neurothekeoma: a distinctive variant of neurothekeoma mimicking nevomelanocytic tumors. Am J Surg Pathol. 1990; 14:113-120. 327. Iwamoto S, Burrows RC, Agoff SN, et al: The p75 neurotrophin receptor, relative to other Schwann cell and melanoma markers, is abundantly expressed in spindled melanomas. Am J Dermatopathol. 2001;23:288-294. 328. Xu X, Chu AY, Pasha TL, et al: Immunoprofile of MITF, tyrosinase, melan-a, and MAGE-1 in HMB45-negative melanomas. Am J Surg Pathol. 2002; 26(1):82-87. 329. Lugassy C, Eyden BP, Christensen L, Escande JP: Angio-tumoral complex in human malignant melanoma characterised by free laminin: ultrastructural and immuno-histochemical observations. J Submicrosc Cytol Pathol. 1997; 29:19-28. 330. Lugassy C, Dickersin GR, Christensen L, et al: Ultrastructural and immunohistochemical studies of the periendothelial matrix in malignant melanoma: evidence for an amorphous matrix containing laminin. J Cutan Pathol. 1999;26:78-83. 331. Lugassy C, Shahsafaei A, Bonitz P, et al: Tumor microvessels in melanoma express the beta-2 chain of laminin. Implications for melanoma metastasis. J Cutan Pathol. 1999;26:222-226. 332. Barnhill RL, Lugassy C: Angiotropic malignant melanoma and extravascular migratory metastasis: description of 36 cases with emphasis on a new mechanism of tumour spread. Pathology. 2004;36:485-490. 333. Barnhill R, Dy K, Lugassy C: Angiotropism in cutaneous melanoma: a prognostic factor strongly predicting risk for metastasis. J Invest Dermatol. 2002;119:705-706. 334. Lugassy C, Haroun RI, Brem H, et al: Pericytic-like angiotropism of glioma and melanoma cells. Am J Dermatopathol. 2002;24:473-478. 335. Lugassy C, Kleinman HK, Fernandez PM, et al: Human melanoma cell migration along capillary-like structures in vitro: a new dynamic model for studying extravascular migratory metastasis. J Invest Dermatol. 2002;119:703-704. 336. Lugassy C, Vernon SE, Busam, K, et al: Angiotropism of human melanoma: studies involving in transit and other cutaneous metastases and the chicken chorioallantoic membrane: implications for extravascular melanoma invasion and metastasis. Am J Dermatopathol. 2006;28:187-193. 337. Lugassy C, Kleinman HK, Vernon SE, et al: C16 laminin peptide increases angiotropic extravascular migration of human melanoma cells in a shell-less chick cam assay. Br J Dermatol. 2007; 157(4):780-782. 338. Phillips ME, Margolis RJ, Merot Y, et al: The spectrum of minimal deviation melanoma: a clinicopathologic study of 21 cases. Hum Pathol. 1986;17:796-806. 339. Schmoeckel C, Castro CE, Braun-Falco O: Nevoid malignant melanoma. Arch Dermatol Res. 1985;277:362-369. 340. Wong TY, Suster S, Duncan LM, Mihm M Jr: Nevoid melanoma: a clinicopathological study of seven cases of malignant

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melanoma mimicking spindle and epithelioid cell nevus and verrucous dermal nevus. Hum Pathol. 1995;26:171179. McNutt NS, Urmacher C, Hakimian, et al: Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity. J Cutan Pathol. 1995;22:502-517. Zembowicz A, McCusker M, Chiarelli C, et al: Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature. Am J Dermatopathol. 2001;23:167-175. Steiner A, Konrad K, Pehamberger H, Wolff K: Verrucous malignant melanoma. Arch Dermatol. 1988;124:1534-1537. Blessing K, Evans AT, Al-Nafussi A: Verrucous naevoid and keratotic malignant melanoma: a clinico-pathological study of 20 cases. Histopathology. 1993; 23:453-458. Kossard S, Wilkinson B: Nucleolar organizer regions and image analyis nuclear morphometry of small cell (nevoid) melanoma. J Cutan Pathol. 1995;22:132136. Kossard S, Wilkinson B: Small cell (naevoid) melanoma: a clinicopathologic study of 131 cases. Australas J Dermatol. 1997;38 (suppl):S54-S58. House N, Fedok F, Maloney ME, Helm KF: Malignant melanoma with clinical and histologic features of Merkel cell carcinoma. J Am Acad Dermatol. 1994; 31:839-842. Blessing K, Grant JJH, Sanders SDA, et al: Small cell malignant melanoma: a variant of naevoid melanoma. Clinicopathological features and histological differential diagnosis. J Clin Pathol. 2000;53:591-595. Okun MR: Melanoma resembling spindle and epithelioid cell nevus. Arch Dermatol. 1979;115:1416-1420. Okun M, Bauman L: Malignant melanoma arising from an intradermal nevus. Arch Dermatol. 1965;92:69-72. Okun MR, Di Mattia A, Thompson J, Pearson SH: Malignant melanoma developing from intradermal nevi. Arch Dermatol. 1974;110:599-601. Benisch B, Peison B, Kannerstein M, Spivack J: Malignant melanoma originating from intradermal nevi. A clinicopathologic entity. Arch Dermatol. 1980; 116:696-698. Enzinger FM: Clear-cell sarcoma of tendons and aponeuroses: an analysis of 21 cases. Cancer. 1965;18:1163-1174. Chung EB, Enzinger FM: Malignant melanoma of soft parts: a reassessment of clear-cell sarcoma. Am J Surg Pathol. 1983;7:405-413. Sara AS, Evans HL, Benjamin RS: Malignant melanoma of soft parts (clear cell sarcoma): a study of 17 cases, with emphasis on prognostic factors. Cancer. 1990;65:367-374. Zucman J, Delattre O, Cesmaze C, et al: EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993;4:341-345. Van Roggen JFG, Mooi WJ, Hogendoorn PCS: Clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts) and cutaneous melanoma: exploring the histogenetic relationship

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malignant melanoma. Hum Pathol. 1983; 14:1072-1080. Egbert B, Kempson R, Sagebiel R: Desmoplastic malignant melanoma. A clinico-histopathologic study of 25 cases. Cancer. 1988;62:2033-2041. Jain S, Allen PW: Desmoplastic malignant melanoma and its variants. A study of 45 cases. Am J Surg Pathol. 1989;13: 358-373. Smithers BM, McLeod GR, Little JH: Desmoplastic, neural transforming and neurotropic melanoma: a review of 45 cases. Aust N Z J Surg. 1990;60:967-972. Bruijn JA, Mihm MC Jr, Barnhill RL: Desmoplastic melanoma. Histopathology. 1992;20:197-205. Carlson JA, Dickersin GR, Sober AJ, Barnhill RL: Desmoplastic neurotropic malignant melanoma: a clinicopathologic analysis of 28 cases. Cancer. 1994;75:478-494. Skelton HG, Smith KJ, Laskin WB, et al: Desmoplastic malignant melanoma. J Am Acad Dermatol. 1995;32:717-725. Reed RJ, Leonard DD: Neurotropic melanoma: A variant of desmoplastic melanoma. Am J Surg Pathol. 1979;3: 301-311. Barnhill RL, Bolognia JL: Neurotropic melanoma with prominent melaninization. J Cutan Pathol. 1995;22:450-459. Anstey A, Cerio R, Ramnarain N, et al: Desmoplastic malignant melanoma: an immunocytochemical study of 25 cases. Am J Dermatopathol. 1994;16:14-22. Baer SC, Schultz D, Synnestvedt M, Elder DE: Desmoplasia and neurotropism: prognostic variables in patients with stage I melanoma. Cancer. 1995; 76:2242-2247. Longacre TA, Egbert BM, Rouse RV: Desmoplastic and spindle cell malignant melanoma. An immunohistochemical study. Am J Surg Pathol. 1996; 20:1489-1500. Kilpatrick SC, White WL, Browne JD: Desmoplastic malignant melanoma of the oral mucosal: an underrecognized diagnostic pitfall. Cancer. 1996;78:383-389. Quinn MJ, Crotty KA, Thompson JF, et al: Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer. 1999;83:1128-1135. Winnepenninckx V, De Vos R, Stas M, van den Oord JJ: New phenotypical and ultrastructural findings in spindle cell (desmoplastic/neurotropic) melanoma. Appl Immunohistochem Mol Morphol. 2003;11(4): 319-325. Busam KJ, Mujumdar U, Hummer AJ, et al: Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors. Am J Surg Pathol. 2004;28(11):1518-1525. Lens MB, Newton-Bishop JA, Boon AP: Desmoplastic malignant melanoma: a systematic review. Br J Dermatol. 2005;152(4):673-678. Hawkins WG, Busam KJ, Ben-Porat L, et al: Desmoplastic melanoma: a pathologically and clinically distinct form of cutaneous melanoma. Ann Surg Oncol. 2005;12(3):207-213. Posther KE, Selim MA, Mosca PJ, et al: Histopathologic characteristics, recurrence patterns, and survival of 129 patients with desmoplastic melanoma. Ann Surg Oncol. 2006;13(5):728-739.

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between these two clinicopathological entities. J Pathol. 1998;186:3-7. Deenik W, Mooi WJ, Rutgers EJ, et al: Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 30 cases. Cancer. 1999; 86:969-975. Langezaal SM, van Roggen JFG, CletonJansen AM, et al: Malignant melanoma in genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts). Br J Cancer. 2001;84:538-585. Panagopoulos I, Mertens F, DebiecRychter M, et al: Molecular genetic characterization of the EWS/AFT1 fusion gene in clear cell sarcoma of tendons and aponeuroses. Int J Cancer. 2002;99:560-567. Ferrari A, Casanova M, Bisogno G, et al: Clear cell carcinoma of tendons and aponeurosis in pediatric patients: a report from the Italian and German soft tissue sarcoma cooperative group. Cancer. 2002;94:3269-3276. Kao GF, Helwig EB, Graham JH: Balloon cell malignant melanoma of the skin: a clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations. Cancer. 1992;69:2942-2952. Nakhleh RE, Wick MR, Rocamora A, et al: Morphologic diversity in malignant melanomas. Am J Clin Pathol. 1990; 93:731-740. Banerjee SS, Harris M: Morphological and immunophenotypic variations in malignant melanoma. Histopathology. 2000;36:387-402. Prieto VG, Kanik A, Salob S, McNutt NS: Primary cutaneous myxoid melanoma: Immunohistologic clues to a difficult diagnosis. J Am Acad Dermatol. 1994; 30:335-339. Clark WH Jr, Elder DE, Guerry D IV: Dysplastic nevi and malignant melanoma, in Farmer ER, Hood AF (eds). Pathology of the Skin. Norwalk, CT: Appleton and Lange; 1990:684-756. McGovern VJ: Melanoma—growth patterns, multiplicity and regression, in Melanoma and Skin Cancer. Proceedings of the International Cancer Conference, Sydney. VCN Blight, Government Printer; 1972:95-106. Blessing K, McLaren KM: Histological regression in primary cutaneous melanoma: recognition, prevalence, and significance. Histopathology. 1992;20:315-322. McGovern VJ, Shaw HM, Milton GW: Prognosis in patients with thin malignant melanoma: Influence of regression. Histopathology. 1983;7:673-680.

370. Pack GT, Miller TR: Metastatic melanomas with indeterminate primary site. JAMA 1961;176:55-56. 371. Smith JL Jr, Stehlin JS Jr: Spontaneous regression of primary malignant melanomas with regional metastases. Cancer. 1965;18:1399-1415. 372. Barr RJ: The many faces of completely regressed malignant melanoma. Pathology (Phila). 1994;2:359-370. 373. Tefany FJ, Barnetson RS, Halliday GM, et al: Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma. J Invest Dermatol. 1991;97:197-202. 374. Kang S, Barnhill RL, Mihm MC, Sober AJ: Regression in malignant melanoma: an interobserver concordance study. J Cutan Pathol. 1993;20:126-129. 375. Balch C, Milton G: Diagnosis of metastatic melanoma at distant sites, in Balch CN, Milton GW, Shaw HM, Soong S-J (eds). Cutaneous Melanoma. Clinical Management and Treatment Results Worldwide. Philadelphia: JB Lippincott; 1985:221-250. 376. McNeer G, Das Gupta T: Life history of melanoma. AJR. 1956;93:686-694. 377. Peterson N, Bodenham D, Lloyd O: Malignant melanoma of the skin: a study of the origin, development, etiology, spread, treatment and prognosis. Br J Plast Surg. 1962;15:49-116. 378. Balch CM, Urist MM, Maddox WA, et al: Management of regional metastatic melanoma, in Balch CM, Milton GW, Shaw HM, Soon S-J (eds). Cutaneous Melanoma. Clinical Management and Treatment Results Worldwide. Philadelphia: JB Lippincott; 1985:93-130. 379. Elder DE, Murphy G: Metastatic malignant melanoma, in Elder DE, Murphy G (eds). Melanocytic Tumors of the Skin. Washington, DC: American Registry of Pathology, Armed Forces Institute of Pathology; 1991;191-205. 380. Kornberg R, Harris M, Ackerman A: Epidermotropically metastatic malignant melanoma. Arch Dermatol. 1978; 114:67-69. 381. Elder DE, Ainsworth A, Clark W: The surgical pathology of cutaneous malignant melanoma, in Clark W (ed). Human Malignant Melanoma. New York: Grune and Stratton; 1979;55-108. 382. Bengoechea-Beeby M, Velasco-Oses A, Fernandez F, et al: Epidermotropic metastatic melanoma. Cancer. 1993;72: 1909-1913. 383. White WL, Hitchcock MG: Dying dogma: the pathological diagnosis of epidermotropic metastatic malignant melanoma. Semin Diagn Pathol. 1998;15: 176-188.

384. McCarthy S, Palmer A, Bale P, Hist E: Nevus cells in lymph nodes. Pathology. 1974;6:351-358. 385. Johnson W, Helwig E: Benign nevus cells in the capsule of lymph nodes. Cancer. 1969;23:747-753. 386. Ridolfi R, Rosen P, Thaler H: Nevus cell aggregates associated with lymph nodes: estimated frequency and clinical significance. Cancer. 1977;39:164-171. 387. Andreola S, Clemente C: Nevus cells in axillary lymph nodes from radical mastectomy specimens. Pathol Res Pract. 1985;179:616-618. 388. Das Gupta T, Bowden L, Berg J: Malignant melanoma of unknown primary origin. Surg Gynecol Obstet, 1963; 117:341-345. 389. Giuliano A, Cochran AJ, Morton D: Melanoma from unknown primary site and amelanotic melanoma. Semin Oncol. 1982;9:442-447. 390. Chang P, Knapper W: Metastatic melanoma of unknown primary. Cancer. 1982;49:1106-1111. 391. Reintgen D, McCarty K, Woodard B, et al: Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet. 1983;156:335-340. 392. Silberberg I, Kopf A, Gumport S: Diffuse melanosis in malignant melanoma. Arch Dermatol. 1968;97:671-677. 393. Eide J: Pathogenesis of generalized melanosis with melanuria and melanoptysis secondary to malignant melanoma. Histopathology. 1981;5:285-294. 394. Rowden G, Sulicca V, Butler T, Manz H: Malignant melanoma with melanosis. Ultrastructural and histological studies. J Cutan Pathol. 1980;7:125-139. 395. Bauer J, Bastian BC: Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool. Dermatol Ther. 2006;19:40-49 396. Balch CM, Soong S-J, Shaw HM, et al: An analysis of prognostic factors in 8500 patients with cutaneous melanoma, in Balch CM, Houghton AN, Milton GW, et al (eds). Cutaneous Melanoma, 2nd ed. Philadelphia: JB Lippincott; 1992;165-187. 397. Keefe M, MacKie RM: The relationship risk of death from clinical stage I cutaneous melanoma and thickness of primary tumour: no evidence for steps in risk. Br J Cancer. 1991;64:598-602. 398. Balch CM, Soong S-J, Gershenwald JE, et al: Prognostic factors analysis of 17,600 patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19: 3622-3634.

CHAPTER 28 Tumors with Hair Follicle and Sebaceous Differentiation Mark R. Wick Raymond L. Barnhill

GENERAL CONSIDERATIONS For many years, the classification of adnexal tumors has been based on morphologic and histochemical findings that many believe are to some degree outdated. As a result, various authors have questioned the validity of traditional classifications of adnexal neoplasms, particularly those specified as either apocrine or eccrine in light of a reexamination of criteria for classification.4 Particular aspects of the arguments against the traditional classification of these lesions include the developmental biology of adnexal neoplasms; neoplasms consistently showing two or more lines of differentiation; striking associations of particular entities; the anatomic distributions of various adnexal neoplasms; and finally the lack of specificity of many histologic, histochemical, immunohistopathologic, and ultrastructural findings. It is currently accepted that the embryologic origin of the hair folliculo–sebaceous–apocrine units and eccrine units are different. Thus, whereas the sebaceous and apocrine ducts and glandular elements develop near the bulge of the hair follicular unit, the eccrine apparatus undergoes a separate embryologic development. These developmental differences provide the basis for the categorization of adnexal neoplasms into two

such as carcinoembryonic antigen (CEA), gross cystic disease fluid protein (GCDFP-15), epithelial membrane antigen (EMA), S-100 protein, and various cytokeratins at times. The authors clearly acknowledge the latter perspectives but nonetheless at all times attempt to maintain a balanced and scholarly approach to adnexal neoplasms throughout Chapters 28 and 29.

SEBACEOUS TUMORS AND TUMOR-LIKE CONDITIONS Sebaceous proliferations are seemingly less common than those showing differentiation toward the sweat glands. Moreover, sebocytic neoplasms manifest less morphologic diversity than sudoriferous tumors and therefore are not as complicated nosologically.

BENIGN SEBACEOUS PROLIFERATIONS

Sebaceous Hyperplasia CLINICAL FEATURES The most common proliferative abnormality of the sebaceous glands is hyperplasia, which most often is seen in elderly individuals (Table 28-1).5-12 Clinically, this condition most commonly presents itself in the form of a localized eruption of yellowish-tan umbilicated papules usually on the face or eyelids, but occasionally affecting the mammary areola or genital skin with the potential for confluence.13-15 The lesion may also macroscopically resemble the papulonodular profile of

Table 28-1 Sebaceous Hyperplasia

Clinical Features Older individuals Face, mammary areola, genital skin Yellowish to tan papules, often umbilicated Rare linear or giant forms Histopathologic Features Single follicular canal opens to umbilicated epidermal surface Four or more sebaceous lobules attached to central infundibulum of sebaceous follicle Fully mature sebaceous lobules composed of sebocytes with compact nuclei and abundant multivacuolated clear cytoplasm Differential Diagnosis Sebaceus adenoma Nevus sebaceus

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

The pathology of adnexal tumors of the skin—including sudoriferous, sebaceous, and pilar neoplasms—is a complex and voluminous subject. In keeping with the aims of Chapter 29 on sweat gland lesions, the following discussion of pilosebaceous tumors is meant to be practical and diagnostically oriented in its focus. Readers wishing to supplement the information presented here are referred to several comprehensive texts covering appendageal cutaneous neoplasms.1-3

general groups: (1) folliculo–sebaceous– apocrine and (2) eccrine. The occurrence of adnexal tumors with two or more lines of differentiation such as cylindroma, spiradenoma, and trichoepitheilioma in the same tumor and the association of such tumors in a syndrome (Brooke syndrome) are additional factors suggesting a biologic relationship between hair follicular and apocrine-related neoplasms. The high frequency (or alternatively the absence) of particular adnexal neoplasms at the anatomic sites bearing a high concentration or exclusive concentration of particular adnexal structures provides clear circumstantial evidence favoring or arguing against particular lines of adnexal differentiation. For example, whereas sweat glandular neoplasms occurring in regions with numerous apocrine gland are most likely apocrine, those occurring on the palms and soles are most probably of eccrine origin. Finally, one must consider to what extent one is helped by conventional microscopy, histochemistry, immunohistochemistry, and electron microscopy as directly applied to the classification and diagnosis of adnexal tumors. Hair follicular differentiation can be recognized by the presence of (1) basaloid epithelium closely resembling follicular germinative epithelium with closely associated dermal mesenchymal cells resembling hair papilla or (2) matrical corneocytes, that is, “shadow” or “ghost” cells. Sebaceous differentiation is typified by cells with coarsely vacuolated cytoplasms and scalloped nuclei. On the other hand, histologic attributes clearly specific for either apocrine or eccrine differentiation may not exist. For example, decapitation secretion (“snouting”) has been considered by many to be specific for apocrine glandular differentiation. However, this finding may be observed in eccrine-derived neoplasms. In a similar fashion, an eosinophilic cuticle within a ductal structure has been considered specific for eccrine differentiation. However, such a cuticle may be found in both apocrine and sebaceous ducts. With regard to the distinction of apocrine and eccrine lineages, various ancillary techniques including immunohistochemistry and electron microscopy all lack specificity and have not proved useful to date. Enzyme histochemistry, which was once used as a research technique for studying sweat gland tumors, is a completely outdated, and in any event yielded nonspecific results. The current use of immunohistochemistry has shown that both eccrine and apocrine tumors may express markers

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basal cell carcinoma (BCC), and rare forms have been termed linear (zosteriform) or giant solitary sebaceous hyperplasia (SH).5,8,9 In premature SH, an autosomal dominant pattern of inheritance may be noted, and the clinical onset of the process occurs early in life.9,10 Farina and colleagues have suggested that SH is the sebaceous analogue of trichofolliculoma (TF), and because SH does not involute clinically, they conclude that it is probably a benign neoplasm rather than a form of hyperplasia.14

690

HISTOPATHOLOGIC FEATURES One may define SH by the presence of four or more sebaceous lobules attached to the infundibulum of each pilosebaceous unit seen in the biopsy specimen (see Table 28-1 and Fig. 28-1). The cells comprising the lobules are predominantly fully mature sebocytes, showing compact nuclei and abundant multivacuolated lucent cytoplasms. However, a thin rim of basaloid cells is often present at the periphery of the sebocytic aggregates. The overlying epidermis may be atrophic in unusually expansive examples of SH. DIFFERENTIAL DIAGNOSIS The primary entities to be considered are nevus sebaceous (NS) and sebaceous adenoma (SA). Nevus sebaceous differs from SH by its general breadth, the presence of hamartomatous (rudimentary) folliculosebaceous units, papillomatous epidermal hyperplasia, and frequent apocrine elements. SA is distinguished from SH by

showing a larger basaloid germinative component (up to half of the sebaceous lobules) than is observed in SH.

Sebaceous Adenoma CLINICAL FEATURES SA presents as a pale yellow nodular facial lesion that slowly enlarges and makes its appearance after the age of 50 years (Table 28-2). This tumor ranges in size from less than 1 cm (the usual size) to greater than 5 cm in maximum dimension.16-21 Clinical misdiagnosis of SA as BCC is a common problem. There may be an association with Muir-Torre syndrome (MTS), wherein the patient has metachronous or synchronous visceral malignancies and cutaneous SAs, sebaceous carcinomas (SCs), BCCs with sebaceous differentiation, or squamous carcinomas of the “keratoacanthoma” type.22-29 Malignant tumors of internal organs in MTS are most often carcinomas of the larynx and gastrointestinal tract, but virtually any visceral site may be affected; rarely, nodal or extranodal malignant lymphomas may be encountered as well.25,27,29 The SAs seen in this context may either be “classical” microscopic lesions or may demonstrate histologic peculiarities and thus be labeled as variant adenomas.28 HISTOPATHOLOGIC FEATURES The microscopic characteristics of “classical” SA are probably the most clear-cut of any sebaceous proliferation, except for SH (see Table 28-2).18,20,21 They are represented by the sharply circumscribed proliferation of enlarged sebaceous

 FIGURE 28-1 Sebaceous hyperplasia. Numerous sebaceous lobules are attached to the infundibulum of a single pilosebaceous unit.

Table 28-2 Sebaceous Adenoma

Clinical Features Patient often older than 50 years of age Head and neck, especially face Yellowish nodule Usually <1 cm but can be ≥ 5 cm Association with Muir-Torre syndrome (sebaceous neoplasms, squamous cell carcinomas, and visceral carcinomas [laryngeal and gastrointestinal]) Histopathologic Features Classical type Well-defined enlarged sebaceous lobules Frequent attachment to epidermis with epidermal thinning Fully mature sebocytes Lobules may contain ductlike structures Variant type (Muir-Torre) Sharp demarcation of lobules may be lacking Lobules show admixture of peripherally located basaloid epithelium (≤ 50%) centrally mature sebocytes Basaloid epithelium may show slight nuclear pleomorphism, distinct nucleoli, and occasional mitoses Differential Diagnosis Sebaceous hyperplasia Basal cell carcinoma with sebaceous differentiation

lobules, comprised by fully mature sebocytes, frequently attenuating the overlying epidermis, and sometimes attaching to its basal aspect (Fig. 28-2). A fibrous pseudocapsule commonly surrounds the lesion and attests to its slow growth, as do appendageal “collarettes” that may form at the periphery of the tumors. The cellular lobules of SA may contain ductlike structures into which holocrine secretion occurs; this phenomenon may result in the formation of intralesional cysts. Modest nucleolar prominence may be appreciated in the constituent cells of SA, but nuclear hyperchromasia or pleomorphism and mitotic activity are only rarely observed. Occasional examples of SA are situated deep in the dermis, with prominent cystic change. Rutten and coworkers30 have emphasized that finding as a clue to the existence of MTS. Additional information with regard to the latter condition can be acquired through immunostaining for MLH1, MSH2, and MSH6 proteins. If a sebaceous tumor lacks one or several of these nuclear markers, additional testing (by microsatellite instability analysis) can then be done to identify patients with MTS.31

terminology. The authors have no particular conceptual or practical objections to this suggestion except that it would undoubtedly result in the erroneous inclusion of some examples of BCC in the sebomatricoma group. Whether or not this would have adverse clinical effects is debatable.

On the other hand, “variant” SAs of the Muir-Torre type differ from the preceding descriptions in several regards. First, they may lack the exquisite demarcation from the adjacent dermis that is shown by classical SA. Second, the component cellular lobules are composed of an admixture of peripherally disposed basaloid, germinative-type epithelial cells—often with mild nuclear pleomorphism, distinct nucleoli, and modest mitotic activity—and centrally mature sebocytes (Figs. 28-3 and 28-4).28 It must be emphasized that even though the term “Muir-Torre type” has just been used in reference to variant SAs, only a distinct minority of patients with such lesions are ultimately proven to have the syndrome; most adenomatous sebaceous tumors containing a significant number of basaloid cells occur as solitary sporadic neoplasms. In fact, although it is the authors’ opinion that patients with the Muir-Torre complex more often have variant-form than classical SAs, it is forthrightly stipulated that there has been no systematic analysis of this contention to date.

encompass all such lesions.32 According to that nosologic construction, one would recognize SH, sebomatricoma, and SC as the only “true” sebocytic proliferations, eschewing all prior pertinent

Superficial Epithelioma with Sebaceous Differentiation CLINICAL FEATURES A rare form of sebaceous neoplasia is that represented by the superficial epithelioma with sebaceous

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

 FIGURE 28-2 Sebaceous adenoma. Sharply circumscribed lobules of sebaceous glands are separated from the adjacent dermis by an induced cellular fibrous stroma.

DIFFERENTIAL DIAGNOSIS Muir-Torre–type SAs may be difficult to distinguish diagnostically from BCC with sebaceous differentiation (BCCSD) (also known as basosebaceous epithelioma or sebaceous epithelioma).33-38 The salient points of difference between these tumors are subtle but reproducible; whereas BCCSD manifests an at least focally fibromyxoid stroma and epithelial-stromal “clefts,” in similarity to ordinary BCC, Muir-Torre adenoma does not. Moreover, BCCSD is dominated by its basaloid cell constituents, with only a minor proportion of sebocytic elements; SAs of the MuirTorre type contain no more than 50% germinative-type cells.

Sebomatricoma In recognition of the confusion that often surrounds sebaceous tumors that contain a proportion of basaloid cells, SanchezYus and colleagues have proposed that yet another term, sebomatricoma, be added to the lexicon of sebaceous neoplasia to

 FIGURE 28-3 Sebaceous adenoma, Muir-Torre variant. The architectural features of lesions in MuirTorre syndrome have been likened to keratoacanthoma. Tumor lobules are less distinct than in typical forms of sebaceous adenoma.

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Sebaceoma

692

 FIGURE 28-4 Sebaceous adenoma, Muir-Torre variant. At higher magnification, an admixture of basaloid cells and sebocytes replaced the more orderly transition seen in typical sebaceous adenoma. Nonetheless, the cells are benign, and most sebocytes assume a mature phenotype.

differentiation (SESD).37,38 Based on observation of a limited number of examples, SESD appears to present as a slowly evolving, smooth-surfaced papule or an erythematous hyperkeratotic nodule; lesions have been observed in the skin of the face, trunk, and thigh, and multiplicity in the same patient is potentially observed. A possible association with MTS is as yet unproven. HISTOPATHOLOGIC FEATURES There are certain similarities among SESD and tumor of the follicular infundibulum (TFI), inverting follicular keratosis, and superficial BCC. The first of these lesions is composed of an interanastomosing, “fenestrated” constellation of compact polyhedral cells that connects broadly to the basal epidermis over a limited span and is sharply circumscribed (Fig. 28-5). As such, SESD forms a platelike growth in the superficial corium. Peripheral palisading of nuclei, as seen in superficial BCC, may be observed in the cellular cords of SESD, but this finding is inconstant.38 Squamoid elements (as seen in inverting keratoses) may also be seen focally, with formation of cellular “eddies,” and ductlike lumina are also appreciated in most cases. The latter have an eosinophilic cuticle similar to that seen in eccrine ducts. Mature sebocytes are dispersed to the periphery and the deep aspects of SESD, and they are usually observed in small aggregates. DIFFERENTIAL DIAGNOSIS Fibromyxoid stroma, matrical-epithelial clefting, apop-

tosis, mitotic activity, continuity with the skin surface, and stromal hypercellularity are all absent in SESD, unlike the anticipated attributes of BCCs, keratoses, or tumors of the follicular infundibulum.

The tumor called sebaceoma was described by Troy and Ackerman.39 That circumscribed nodular dermal lesion is basically a histologic amalgam of SESD, classical trichoepithelioma (TE), “dermal duct tumor,” and cylindroma. As such, it has also been dubbed sebocrine adenoma and infundibular adenoma by other authors.40,41 A more general—and, it is thought, more appropriate—term for neoplasms such as sebaceoma is benign adnexal neoplasm with divergent differentiation. Kiyohara and colleagues42 have described an unusual variant in which a “rippled” microscopic image is observed, with aligned tumor cell nuclei simulating the Verocay bodies of schwannomas. Similar lesions have been documented by Kazakov et al,43 who also noted a resemblance to the organoid growth patterns of neuroendocrine tumors in some cases.

Sebaceous Neoplasms of “Borderline” Malignancy There is only one cutaneous tumor with sebaceous differentiation that is properly classified as a “borderline” malignancy; that is, a neoplasm that may recur locally

 FIGURE 28-5 Superficial epithelioma with sebaceous differentiation. The platelike growth of this lesion resembles the so-called “tumor of follicular infundibulum” (see Fig. 28-12). Clusters of sebaceous cells, some with sebaceous ducts, are admixed with squamous elements. In this example, the sebaceous cells are clustered at the base of the lesion.

SEBACEOUS CARCINOMAS Traditionally, SCs have been considered in two categories: ocular and extraocular.18-20,44-55 The proposed justification for this paradigm was based on a putative difference in the behavior of these two groups of tumors; it was contended that ocular SC had a more aggressive nature than that of extraocular lesions. However, a redactive examination of the pertinent literature fails to support that premise. Both ocular and extraocular sebaceous malignancies are attended by an approximate risk of 30% to 40% for local tumor recurrence, 25% to 35% for distant metastases, and 10% to 20% for tumor-related death.45 Hence, there is, in fact, no inherent biologic difference between them, with the exception that an ocular location is, by far, more common than an origin in the skin outside of the eyelids. CLINICAL FEATURES SC is typically seen in middle-aged or elderly patients, with a mean age of 62 years (Table 28-3). For unexplained reasons, ocular neoplasms show a marked predilection for Asian individuals. These patients present with nontender masses at the eyelid margin or in the conjunctiva, and, as such, they are commonly misdiagnosed as having

Table 28-3 Sebaceous Carcinoma

Clinical Features Middle-aged and elderly patients (mean age, 62 years) Predilection for Asians Ocular (eyelids) more often than extraocular sites (head and neck more often than trunk, genitalia, extremities) Nontender mass Histopathologic Features Pagetoid spread of atypical epithelial cells within epidermis or conjunctival epithelium Lobular dermal aggregates of variably atypical polyhedral cells Central necrosis (“comedo” pattern) common Well-differentiated tumors: cells with abundant multivacuolated cytoplasm, vesicular nuclei, and discernible nucleoli Poorly differentiated tumors: nondescript cells with high nucleocytoplasmic ratios, prominent nuclear pleomorphism, prominent nucleoli, prominent mitotic activity Basaloid SC: small cells with scanty cytoplasm, peripheral palisading, nuclear anaplasia Squamoid SC: prominent squamous metaplasia with keratin pearls Sarcomatoid SC: spindle cell features Differential Diagnosis Balloon cell melanoma Clear cell squamous cell carcinoma Clear cell basal cell carcinoma Clear cell eccrine carcinoma Trichilemmal carcinoma Metastatic clear cell carcinomas of visceral origin

chalazions, blepharitis, or conjunctivitis. Multicentricity is observed in 5% to 10% of cases, and other ophthalmologic conditions confused with SC include cicatricial ocular pemphigoid, basal cell or squamous cell carcinoma (SCC), and cutaneous horn.46 In reference to extraocular tumors, most SCs are seen on the head and neck followed, in relative order, by the trunk, genitalia, and extremities.44,45,49-51,53,56 They present as relatively nondescript nodular masses that are occasionally painful or rapidly growing; a proportion are ulcerated as well. As discussed previously, a subpopulation of patients has MTS.28 Kazakov et al57 have also reported the emergence of SC from NS in some instances. Ho and colleagues58 have suggested that the sentinel lymph node biopsy

technique should be used in cases of SC. However, we fail to grasp the logic of that treatment approach. There is no evidence whatsoever that lymphadenectomy improves the survival of patients with this tumor type. HISTOPATHOLOGIC FEATURES The microscopic characteristics of SC feature the presence of lobular dermal aggregates of variably atypical polyhedral cells, separated from each other by fibrovascular stroma that lacks obvious desmoplasia (see Table 28-3 and Fig. 28-6). The resulting image is that of an organoid neoplasm. Central portions of the tumor cell nests may become necrotic, yielding a “comedo” pattern on scanning microscopy (Fig. 28-7). Cytologically, the constituent elements of well-differentiated SCs show abundant multivacuolated lucent cytoplasms and oval vesicular nuclei with discernible nucleoli but sparse mitoses (Fig. 28-8). At the other end of this spectrum, poorly differentiated tumors are composed of more nondescript cells with high nucleocytoplasmic ratios, more prominent nuclear pleomorphism, prominent nucleoli, brisk mitotic activity with possibly atypical division figures, and amphophilic to basophilic cytoplasm (Fig. 28-9).18-20,44-46 Intracellular compartmentalized vacuoles are not nearly as prominent in the latter lesions and may require the use of special techniques— such as oil red O or Sudan IV stains on fresh tissue or EMA immunostains in paraffin sections—to highlight their presence. In further reference to immunohistology, no single marker is currently available that is specific for sebaceous differentiation. Grading of SCs is accomplished most reproducibly using tumor growth patterns rather than nuclear features.45 Neoplasms that are composed of generally rounded, demarcated, roughly equally sized lobules of cells are graded as I/III, and those that show an admixture of rounded and distinct with infiltrative and confluent cell nests are graded as II/III. Grade III SCs feature the presence of highly permeative cellular aggregates with jagged profiles or demonstrate medullary sheetlike growth. Regardless of grade, all examples of SC share a possible association with in situ carcinoma or extramammary Paget disease (EPD) of the sebaceous type (or both) in the surface epithelium overlying the dermal tumor mass.45,46,52,59 The mechanisms linking these abnormalities are similar to those attending sudoriferous Paget disease, as considered in Chapter 27.

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

but is extremely unlikely to metastasize distantly. This is the BCCSD, as briefly discussed previously.34-36 BCCSD differs from ordinary BCCs in that its constituent cells are generally somewhat larger, with more eosinophilic cytoplasm. Furthermore, the expected stromal change of conventional BCCs— with fibromyxoid alteration and cleavage away from epithelial cell nests—is only focally seen and therefore feebly represented in BCCSD. Points of synonymity include a potential for peripherolobular nuclear palisading, zones of typical basaloid cell differentiation with internal apoptosis, the potential for multilineage differentiation (including formation of melanin and eccrine ductal structures), and connection to the stratum basalis or to dermal epithelial appendages, as well as possible recurrence of the BCCSD after electrodesiccation or curettage.19 The sebaceous elements of the latter lesion are fully mature and are usually disposed toward the centers of cellular lobules. In the authors’ experience, BCCSD is an important entity with which pathologists should be familiar. It is often confused with SA on the one hand and SC on the other, and it is certainly more common than either of those neoplasms.

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SC is dominated by foci of prominent squamous metaplasia complete with keratin pearls; spindle cell change, with assumption of a “sarcomatoid” morphotype, is yet another potentiality of this tumor variant.7,8

 FIGURE 28-6 Sebaceous carcinoma. Typical examples of sebaceous carcinoma consist of discrete tumor lobules separated by a nondesmoplastic fibrous stroma.

 FIGURE 28-7 Sebaceous carcinoma. Comedonecrosis may be conspicuous in high-grade lesions.

694

From a practical perspective, the pathologist should especially consider an underlying invasive oculocutaneous SC whenever a conjunctival or eyelid biopsy demonstrates such pathologic changes because its relationship with intraepithelial neoplasia is strongest in those sites. Outside of the ocular region, however, EPD that does not label for epithelial mucin content or apocrine-selective immunohistologic markers may also have this association.

Particular histologic variants of SC are worthy of special attention because they are capable of causing diagnostic confusion with other cutaneous lesions.18-20,44-46,60 Basaloid SC is a form that is composed of small cells with scant cytoplasm and the common presence of nuclear palisading at the periphery of cell nests. It most often has a high-grade growth pattern with nuclear anaplasia and demonstrates only a small minority of dispersed, vacuolated, obviously sebocytic elements. Squamoid

DIFFERENTIAL DIAGNOSIS As one might expect, the pathologic differential diagnosis of SC is broad, encompassing virtually all of the malignant clear cell tumors of the skin. These have been well summarized by Suster61 and include such entities as balloon cell melanoma, hydropic squamous carcinoma and BCC, clear cell eccrine carcinoma, trichilemmal carcinoma (TLC), and metastatic clear cell carcinomas of visceral origin. With the possible exception of selected balloon cell melanomas, however, none of these neoplasms exhibits the particular vacuolization pattern that is seen in sebocytes, which is a multivesicular “bubbly” compartmentalization of the cytoplasm of each cell, rather than a unilocular vacuole.45,61 As discussed, immunostains for EMA or histochemical analyses for neutral lipid may be necessary to confirm the presence of the former of these two patterns. Furthermore, SC lacks several specialized protein products that may be seen in sweat gland tumors or metastatic visceral carcinomas; included among these are CEA, S-100 protein, gross cystic disease fluid protein-15, CA-125, and CA19-9.62 Recently, Sramek et al63 have examined the utility of two particular markers—EMA and BER-EP4—in the differential diagnosis of SC, BCC, and squamous carcinoma. Those authors found that EMA+/BER-EP4+ tumors were SCs, EMA+/BER-EP4- tumors were squamous lesions, and EMA-/BER-EP4+ neoplasms were BCCs. Cho and colleagues64 have also observed frequent immunoreactivity for c-erbB-2 oncoprotein in SCs. Basaloid SC is also distinguishable from BCC on a cytologic basis because the nuclei of poorly differentiated sebaceous tumors are much more vesicular than those of BCC. In addition, the stroma of basaloid SC is not fibromyxoid in nature, and the number of obviously identifiable sebocytes is extremely small in that variant. In contrast, BCCSD regularly demonstrates easily observable clusters of mature sebaceous elements. As mentioned previously, both basaloid SC and BCCSD appear to be capable of expressing the glycoprotein target for the BER-EP4 antibody in immunohistochemical studies, but they do differ in their expression of EMA. Whereas SC is diffusely EMA-reactive, BCCSD is either completely EMA negative or shows

throughout them; otherwise, immunoreactivity for keratin is necessary to exclude a true mesenchymal tumor.66 Unfortunately, a specific diagnosis of sarcomatoid SC may not be possible, even with special techniques, if vesiculated clear cell elements are altogether lacking because the neoplastic cells appear to abjure their ability to display sebocytic features with a progressive loss of differentiation.

Pseudoneoplastic Sebaceous Proliferations: Nevus Sebaceus

 FIGURE 28-8 Sebaceous carcinoma. In well-differentiated sebaceous carcinoma, abundant multivacuolated cytoplasm is identified readily. Nuclei are large, with variably prominent nucleoli, but mitoses are few.

 FIGURE 28-9 Sebaceous carcinoma. Poorly differentiated lesions consist predominantly of cells with less well-defined intracytoplasmic compartments, although lower grade elements may be admixed. Nuclei are pleomorphic, with striking atypia.

discrete positivity only in foci of obvious sebocytic differentiation.62 Squamoid SC can be separated diagnostically from ordinary SCC by attention to the presence of multivesiculated sebocytes in the first of these lesions, as well as a usual lack of

continuity of the dermal tumor with the epidermis and a dissimilarity in BER-EP4immunoreactivity.65 Sarcomatoid forms of SC are recognizable generically as epithelial malignancies if small foci of ordinary carcinoma are interspersed

Table 28-4 Nevus Sebaceus

Clinical Features Congenital onset Head and neck, usually scalp; upper trunk Oval or elongated yellowish or tan-brown alopecic plaque Rough to verrucous surface An association with other developmental abnormalities, including oculocerebrocranial defects that may result in seizures, mental retardation, visual field lost Histopathologic Features All ages Rudimentary hair follicle structures with basaloid epithelium resulting in clinical alopecia Variable papillomatosis of epidermis and sebaceous gland underdevelopment or prominence After puberty Prominent papillomatosis of epidermis Prominence of sebaceous glands Prominent apocrine glands in a subset Development of various hamartomas and tumors Basaloid (basal cell) hamartomas Trichilemmoma Proliferating pilar tumor Syringocystadenoma papilliferum Apocrine hamartomas or adenomas Sebaceous hamartomas or adenomas Basal cell carcinoma Ductal apocrine adenocarcinoma Differential Diagnosis Epidermal nevus Verruca Sebaceous hyperplasia Sebaceous adenoma

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

CLINICAL FEATURES NS (also known as organoid nevus or pilosyringosebaceous nevus) is typically present at birth and gradually enlarges thereafter (Table 28-4).

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A

696

B

 FIGURE 28-10 Nevus sebaceus. (A) Slightly yellowish, well-defined alopecic plaque involving the scalp. (B) In the early stages of this lesion, irregular lobular proliferations of basaloid (immature sebaceous) cells proliferate in the superficial dermis.

It produces a localized area of alopecia or is a tan-brown, roughly surfaced plaque in the skin of the face or neck that becomes overtly verrucoid during puberty (Fig. 28-10A). A minor proportion of these lesions are also associated with multisystem abnormalities, including structural oculocerebrocranial defects that may cause seizures, mental retardation, and visual field cuts.67-72 HISTOPATHOLOGIC FEATURES NS is characterized by slight epidermal papillomatosis in its earliest form, often with an accompanying proliferation of basaloid cells that take on an appearance resembling that of germinative or rudimentary hair follicles (see Table 28-4). Sebaceous and apocrine glands are not conspicuous in NS during childhood, but they become so in adolescence and are associated with more striking surface papillomatosis of the lesion (Figs. 28-10B and 28-11). A variety of cutaneous tumors have been reported to arise potentially in NS, including BCC, trichilemmoma (TL), proliferating pilar tumor, syringocystadenoma papilliferum, apocrine adenoma, SA, SC (see above), and pilar leiomyoma.73 It has been suggested that these contextual proliferations are not truly neoplastic in nature, but rather are hamartomatous in keeping with the general character of NS.74 This is an attractive hypothesis, but it is one that the author believes to be oversimplified. Several examples have been documented wherein NS gave rise to undisputed neoplasms that demonstrated aggressive behavior, including SCC and ductal apocrine adenocarcinoma.75,76 DIFFERENTIAL DIAGNOSIS The papillomatous epidermal hyperplasia in NS may

suggest verruca and epidermal nevus. NS is distinguished from the latter conditions by the presence of rudimentary hair follicles; usually, but not always, prominent sebaceous elements; and apocrine glandular elements. NS is discriminated from SH by greater breadth, the latter morphologic features, and clinical presentation.

PILAR NEOPLASMS AND PSEUDONEOPLASTIC LESIONS Because the hair follicles are more complicated than the sebaceous glands at a microanatomic level, the nosologic scheme pertaining to pilar neoplasms is

also more extensive. One can approach this topic by dividing hair follicle tumors into those that differentiate toward the outer hair sheath epithelium, others whose target is the germinative epithelium, and lesions with mixed epithelial–mesenchymal features or lineages resembling those of the follicle-related mesenchymal tissues. It must be admitted before embarking on this nosologic enterprise that it is perhaps the most contentious area of cutaneous adnexal pathology. Several competing classification schemes for pilar tumors have been advocated in the past, and new variations continue to appear, often with little more to recommend them than rather ethereal theoretical considerations.1

 FIGURE 28-11 Nevus sebaceus. In older lesions, mature sebaceous lobules become prominent. Epidermal hyperplasia is also evident.

BENIGN HAIR FOLLICLE TUMORS For reasons that are unknown (at least to the authors), there are many more benign pilar tumors than malignant ones. These will be covered as a group in respect to their presumed targets of differentiation, followed by a general discussion of pilar carcinomas and tumor-like conditions of the follicular apparatus.

Tumors of the Outer Hair Sheath and Infundibulum

Clinical Features Middle-aged or elderly patients Women more often than men Head and neck Solitary papule or nodule Usually <1 cm Histopathologic Features Well-demarcated Subepidermal plate of compact polyhedral cells Multifocal connection to overlying epidermis by strands of epithelium Peripheral palisading of nuclei Variable clear cell change (glycogen) Cytologic atypia usually absent Differential Diagnosis Trichilemmoma Basal cell carcinoma

nuclear palisading and contain glycogen, in likeness to the trichilemmal sheath. A prominent layer of eosinophilic basement membrane material often is seen surrounding the cords as well. Nuclei are bland, and mitotic activity and apoptosis are consistently absent (Fig. 28-12). Hair is not formed in TFI, but “bystander” follicles may be entrapped in the tumor, and intralesional acrosyringia are seen in

some examples.83 Cribier and Grosshans found that there is an accentuated deposition of dermal elastic tissue immediately beneath TFIs.82 An infundibular nature for the lesion is more inferential than proven, and it is predicated largely on the microanatomic relationship of TFI to the acrotrichium. DIFFERENTIAL DIAGNOSIS Distinguishing TFI from superficial BCC may be challenging in selected cases. However, TFI is more highly differentiated, with regular formation of basement membrane and more voluminous cytoplasm, and differs from BCC in being negative with the BER-EP4 antibody immunohistochemically.65

Pilar Sheath Acanthoma CLINICAL FEATURES Middle-aged or elderly patients, with no gender predilection, are typically affected by pilar sheath acanthoma (PSA), which manifests itself as a single tan-pink papule or plaque, usually on the upper lip or in the central facial skin (Table 28-6). A small central keratotic plug is often appreciated clinically.84-86 HISTOPATHOLOGIC FEATURES This tumor has a central infundibular microcyst that contains keratinous material and opens focally to the epidermal surface

Tumor of the Follicular Infundibulum CLINICAL FEATURES (TFI is also known as basal cell hamartoma with follicular differentiation or infundibuloma (Table 28-5).77-82 It is a relatively uncommon lesion that shows a marked predilection for middle-aged or elderly women and presents as a solitary papulonodular tumor measuring less than 1 cm in greatest dimension. Multiplicity is rarely seen but has indeed been reported, and there may be an association with concomitant nevus sebaceous or Cowden syndrome (see Trichilemmoma below).82 HISTOPATHOLOGIC FEATURES TFI is typified microscopically by a subepidermal plate of compact polyhedral cells that forms a latticework structure and connects to the stratum basalis multifocally (see Table 28-5). The lesion is sharply demarcated laterally, and its internal image has been described as fenestrated. Peripherally disposed tumor cells in the constituent cellular cords may demonstrate

 FIGURE 28-12 Tumor of follicular infundibulum. A peripheral palisade of basaloid cells is evident in this lesion.

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

Even though it shows many morphologic similarities to the epidermis, the follicular infundibulum (the hair pore and the follicular segment above the insertion of the sebaceous duct) is a specialized modification of the outer hair sheath. Whereas cells in that structure mature with an outward polarity, maturation in the isthmic portion of the follicle—between the sebaceous duct and the insertion of the arrector pili muscles—shows the converse of that orientation. Moreover, whereas infundibular keratinization features an intermediary granular cell layer, isthmic keratin formation is “abrupt” and lacks keratohyaline granules. These keratinization patterns are used, in part, to classify the differentiation of pilar neoplasms and provide a nosologic structure for them. However, follicular tumors that lack overt keratin formation must be categorized in a more indirect fashion.

Table 28-5 Tumor of the Follicular Infundibulum

697

Table 28-6 Comparison of Pilar Sheath Acanthoma and Dilated Pore of Winer

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

PILAR SHEATH ACANTHOMA

DILATED PORE OF WINER

Clinical Features Middle-aged or elderly patients Women equal to men Face, especially upper lip Solitary tan-ink papule or plaque Central keratotic plug or comedone Histopathologic Features Central infundibular microcyst Cystic opening to epidermal surface Keratinous material in cyst Polygonal cells in epithelial lining with variably pale or clear cytoplasm (containing glycogen) or basaloid appearance Bland cytologic characteristics No hair formation Epithelial wall proliferative Greater cystic opening to with lobular cellular buds surface Proliferative buds may contain Cystic wall less keratinous accumulations proliferative than PSA Differential Diagnosis Epidermoid cyst Trichofolliculoma Perifollicular fibroma Fibrofolliculoma

(see Table 28-6). The wall of the cyst is acanthotic and proliferative, sending many lobular cellular buds out radially into the adjacent dermis (Fig. 28-13). Constituent cells are variably polygonal, with pale eosinophilic or clear cytoplasm (which is glycogenated as shown by the periodic acid-Schiff [PAS] stain), or basaloid. The proliferating cellular projections may themselves contain small keratinous accumulations (“horn cysts”). Nuclei are bland, mitoses are absent, and hair is not formed in PSA. The histologic features of this tumor are so singular that the differential diagnosis is academic. In view of the probable incorporation of cellular elements in PSA that show infundibular as well as follicular–isthmic differentiation, Hurt has proposed the term lobular infundibuloisthmicoma as a replacement for PSA.87 However, the latter of these two names has the benefits of greater familiarity and brevity, and it is likely to persist in common usage for the foreseeable future.

as a solitary or multifocal nodular lesion in the skin of the head and neck in adults, the microscopic distinction between PSA and DPW is, perhaps,

more imagined than real (see Table 286).88,89 The only morphologic differences between these lesions are that DPW shows a larger, more obvious cystic opening to the skin surface, often has small sebaceous glands or vellus hairs incorporated into its base, and demonstrates a lesser degree of peripheral epithelial proliferation that assumes the appearance of accentuated rete ridges (Fig. 28-14). Occasional examples of DPW may exhibit a superficial dishlike invagination. DIFFERENTIAL DIAGNOSIS As discussed previously for PSA, DPW is distinctive. On occasion, the differential diagnosis might include an epidermoid cyst, TF, fibrofolliculoma, and perifollicular fibroma (PF).

Trichoadenoma CLINICAL FEATURES Trichoadenoma (of Nikolowski) (TA) is an infrequently encountered neoplasm that is represented clinically by a nondescript solitary nodule in the skin of the head, neck, or trunk (Table 28-7).90-94 It generally measures less than 1 cm in greatest dimension. HISTOPATHOLOGIC FEATURES The histologic image of TA is one featuring a proliferation of microcystic arrays of pilartype keratinizing epithelium, separated from one another by fibroblastic stroma in the dermis, without any attachment to the epidermis (see Table 28-7). The

Dilated Pore of Winer 698

CLINICAL AND HISTOPATHOLOGIC FEATURES Although dilated pore of Winer (DPW) is a rather common clinical entity, occurring

 FIGURE 28-13 Pilar sheath acanthoma. A central microcyst derived from the infundibulum (complete with epidermal-type keratinization) has areas of acanthosis with small lobules of keratinocytes budding into adjacent dermis.

form of solid “buds” from microcysts, is apparent. DIFFERENTIAL DIAGNOSIS The lack of both basaloid epithelium and non–cystforming epithelium distinguishes TA from syringoma, desmoplastic TE (see Trichilemmoma below), and microcystic adnexal carcinoma (MAC), all of which feature prominent noncystic cellular proliferations.

Trichilemmoma

keratin-filled cysts are comprised by polyhedral cells that often contain keratohyaline granules and eosinophilic or clear cytoplasm. Nuclei are bland,

without nucleoli or mitotic figures (Fig. 28-15). There are no basaloid elements, and only a minor component of non–cyst-forming epithelial cells, in the

HISTOPATHOLOGIC FEATURES Regardless of whether TL is sporadic and solitary or syndromic and multicentric, its histologic attributes are the same (see Table 28-8). One sees a prototypically lobular, folliculocentric proliferation of bland, amitotic, relatively uniform polygonal cells

Table 28-7 Trichoadenoma

Clinical Features Usually adults Head, neck, and trunk Nondescript papule <1 cm Histopathologic Features Dome shaped Symmetric Keratinous cysts lined by uniform cuboidal cells Eosinophilic or clear cytoplasm Granular layer No basaloid epithelium Differential Diagnosis Syringoma Trichoepithelioma, especially desmoplastic type Microcystic adnexal carcinoma Tumor of the follicular infundibulum Basal cell carcinoma

 FIGURE 28-15 Trichoadenoma (of Nikolowski). A nodular growth of keratinizing epithelium, trichoadenoma is distinguished from dilated pore and pilar sheath acanthoma by the presence of trichilemmal type keratin within small horn cysts and the absence of an obvious connection to the epidermis.

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

 FIGURE 28-14 Dilated pore of Winer. Although the dilated pore characteristically opens at the epidermal surface through a cystic infundibulum, cross-sections of the intradermal component may be difficult to distinguish from pilar sheath acanthoma.

CLINICAL FEATURES TL is a relatively frequently encountered lesion of the face or neck that may be seen throughout life, but with a predominance in adults (Table 28-8).95-97 There is also a potential association between multiple TLs and Cowden syndrome.98-100 This disorder features the autosomally determined presence of multifocal hamartomatous polyposis of the intestines, an increased risk of mammary carcinoma or other internal malignancies, and various other cutaneous tumors such as sclerotic fibromas (“collagenomas”) and adnexal hamartomas or nevi. These associated lesions may be synchronously or metachronously in reference to the TLs.

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Table 28-8 Trichilemmoma

700

Clinical Features Adults Head and neck, especially upper lip and nose Keratotic pink papules Solitary or multiple Association with Cowden syndrome Multifocal hamartomatous polyposis of the intestines Increased risk of breast carcinoma and other internal malignancies Autosomal dominant Histopathologic Features Verrucous surface configuration often Lobular proliferation of polygonal cells with variably clear cytoplasm (containing glycogen) Peripheral palisading of nuclei Occasional apoptotic bodies Lobules bounded by eosinophilic basement membranes Differential Diagnosis Tumor of the follicular infundibulum Inverted follicular keratosis Verruca Eccrine acrospiroma Basal cell carcinoma

with variably clear PAS-positive cytoplasm, surrounded by a distinct cuff of eosinophilic basement membrane material (Fig. 28-16). The tumor commonly shows peripheral nuclear palisading within the cellular lobules and may encroach upon the overlying basilar epidermis (Fig. 28-17). However, the interfollicular surface epithelium is normal. Sometimes adjacent lobular profiles in TL may coalesce, yielding a nodular dermal mass. Circular profiles (“eddies”) of squamoid cells are lacking in this neoplasm, as are foci of overt keratinization.101,102 Hunt and colleagues103 and Tellechea and coworkers104 have described a peculiar variant of TL in which there is a pseudoinvasive interface between tumor cell clusters and the subjacent dermal stroma instead of a “pushing” lobular configuration (Fig. 28-18). The corium underneath such lesions manifests a fibromyxoid proliferative response, accounting for the name of desmoplastic TE. Limited mitotic activity may be observed in the neoplastic cell population, and this observation, together with the overall growth pattern, may result in a mistaken diagnosis of BCC or infiltrative SCC. A helpful clue to the correct interpretation in these cases is the previously cited peritumoral basement membrane in desmoplastic

 FIGURE 28-16 Trichilemmoma. A lobular proliferation of bland cells with clear or pale eosinophilic cytoplasm is surrounded by a distinct basal lamina.

 FIGURE 28-17 Trichilemmoma. Nuclear palisades are evident at the periphery of the lesion. Basement membrane material is conspicuous at this magnification.

TLs, which is retained despite the other disturbing histologic findings and is potentially highlighted with the PAS method or immunostains for collagen type IV or laminin. DIFFERENTIAL DIAGNOSIS TL shows significant overlap with TFI. Whereas TL is notable for a lobular configuration, TFI

has a platelike pattern with interconnecting epithelial cords. Two histologically similar pilar proliferations, namely, follicular verruca vulgaris and inverted follicular keratosis (which may, in fact, be one and the same lesion), must be considered. In general, TL differs from the latter entities by the lack of squamous eddies and overt keratinization.

attention. Erosion through the skin surface may occur.

Benign Proliferating Pilar Tumor CLINICAL FEATURES Benign proliferating pilar tumor (BPPT) (also known as proliferating trichilemmal tumor, proliferating trichilemmal cyst, and pilar tumor) shows a marked predilection to occur during middle or old age, with striking preference for women (Table 28-9).105-110 Its usual location is in the scalp, but isolated

examples of this nodular lesion have also been reported in other topographic sites.107 The neoplasm arises in the deep dermis and grows slowly over the span of years, typically to a size of several centimeters, before the patient seeks medical

Table 28-9 Benign Proliferating Pilar Tumor

Clinical Features Usually older individuals Women more often than men Scalp most common site Often large exophytic tumors, measuring ≤ 10 cm in diameter Recurrence after removal is infrequent Metastases to regional lymph nodes occur rarely Histopathologic Features Lobular proliferation of squamous epithelium with tricholemmal differentiation Usually well-demarcated at periphery A trichilemmal cyst remnant usually present The epithelium often shows Variable clear cell change Disordered proliferation Nuclear pleomorphism Prominent nucleoli Mitoses Differential Diagnosis Squamous cell carcinoma

 FIGURE 28-19 Proliferating pilar tumor. A central cystic area is encompassed by nests and cords of keratinizing epithelial cells. Communication with the epidermis is present.

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

 FIGURE 28-18 Desmoplastic trichilemmoma. Within the lesion or at the dermal interface, nests of cells may divide a fibromyxoid stroma in a pattern suggestive of invasion.

HISTOPATHOLOGIC FEATURES BPPT is characterized by sharp peripheral circumscription on scanning microscopy (see Table 28-9). This is an important observation because the architecture of proliferating pilar tumors is crucial to determining their biologic potential. Accordingly, piecemeal excisions or curettage should be strongly discouraged if BPPT is in the clinical differential diagnosis. Cords of large polyhedral tumor cells with obviously squamoid characteristics comprise this neoplasm; these interanastomose with one another, often encompassing a central cystic area that is filled with trichilemmal-type keratinous debris (Fig. 28-19). Clear cells are often present in the tumor cell population, and a cuff of basement membrane material may enclose the advancing edge of the tumor. These features link BPPT to other tumors of the outer hair sheath. The cytologic features of BPPT differ substantially from those of other benign pilar neoplasms in that they often include nuclear pleomorphism, vesicular nuclear chromatin, prominent nucleoli, and brisk mitotic activity (up to 10 per 10 highpower [x400] fields) (Fig. 28-20). Because

701

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Table 28-10 Trichofolliculoma

 FIGURE 28-20 Proliferating pilar tumor. Abrupt (trichilemmal) keratinization typifies this lesion. Cells are relatively uniform in size, the cytoplasm is clear or weakly eosinophilic, and mild cytologic atypia and mitotic activity may be seen.

of this constellation of findings, it is easy to understand why a number of such tumors have been confused with SCCs in the past.111 Nevertheless, it must be reiterated that the architecture of BPPT, rather than its cytomorphology, is of paramount behavioral importance. If the lesion shows a well-demarcated, generally rounded interface with the surrounding connective tissue, it will behave in a benign fashion.112 Alternatively, infiltrative margins should be viewed with concern. Foci of dystropic calcification are common in the stroma and within the cell nests of BPPT, and areas of “abrupt” trichilemmal keratinization are regularly interspersed throughout the lesion. DIFFERENTIAL DIAGNOSIS The principal distinction is between BPPT and SCC. The overall growth pattern of squamous cancers is typically infiltrative, unlike that just described, and SCC does not feature the presence of pilar-type keratinization. Last, the clinical history has an important role in this contextual diagnosis because BPPT typically evolves over a much longer period of time than SCC does.

Tumors of the Germinative Follicular Epithelium 702

The germinative components of the hair follicle include matrical cells, cortical cells, and cells of the inner hair sheath.

Neoplasms differentiating toward these elements are capable of reproducing the entire gamut of hair formation in embryonic and mature skin. A pathognomonic pattern of cellular maturation typifies a subset of such tumors, in which immature matrical cells lose their cytoplasmic organelles and, at the same time, accumulate intracellular keratin. The resulting elements are called ghost cells or shadow cells, in that they have been transformed into homogeneously eosinophilic cells with ghostlike, karyolytic nuclear profiles. Accordingly, shadow cells are synonymous with matrical follicular differentiation, in either monolinear or multilinear neoplasms of the cutaneous adnexa.113 Four appendageal neoplasms are commonly classified as showing germinative pilar features: TF, TE, pilomatricoma (PM), and trichogerminoma (TG).

Trichofolliculoma CLINICAL FEATURES TF is an infrequently seen lesion that is restricted in topographic distribution to the head and neck (Table 28-10). Generally, it affects adults and presents as a small flesh-colored nodule with a central keratinous plug from which vellus hairs emanate.105,114,115 HISTOPATHOLOGIC FEATURES TF is a pilar proliferation that is centered on a dilated primary follicle that is lined by infundibular

Clinical Features Usually adults Head and neck, especially the nose Small skin-colored papule or nodule, usually solitary Central keratinous plug with vellus hairs Histopathologic Features Dilated hair follicle structure opening to surface Infundibulum or isthmic-type epithelium Secondary follicular structures radiate (or “bud”) from the central structure The secondary follicles show varying degrees of differentiation from germinative to formation of mature hair An organoid fibrous stroma surrounding the follicle structure, well-demarcated from adjacent dermis Considerable heterogeneity of epithelial cells Isthmic, clear cells with peripheral nuclear palisading, basaloid matrical cells Differential Diagnosis Trichoepithelioma Basal cell carcinoma Fibrofolliculoma

or isthmic-type epithelium and opens to the epidermal surface (see Table 28-10 and Fig. 28-21). From that central structure, several secondary follicles bud in a radial fashion, and these either differentiate toward germinative epithelium or form mature hairs (Fig. 28-22). The dermal stroma within and around TFs are densely collagenized and are arranged in parallel layers. This process clearly demarcates the tumor from the adjacent corium. Constituent cells of TF show a range of cytologic features, with some representing isthmic, keratinizing elements; others showing outer hair sheath features with clear cytoplasm and peripheral nuclear palisading in cell groups; and still others having a compact polyhedral or basaloid matrical appearance. Rare examples of TF may exhibit partial sebocytic differentiation in the secondary follicles, spurring some authors to modify the name of the lesion to sebaceous TF.116,117 DIFFERENTIAL DIAGNOSIS TF must be distinguished from another follicular tumor, TE, as well as “keratotic” (pilar-type) BCC.118 TE does not have a dilated primary follicle at its center, and is typically dominated by basaloid cells rather than showing the mixture that is characteristic of TF. The stromal collagen pattern in TF is altogether different from the loose,

exophytic papules or nodules. Simple excision is curative.

 FIGURE 28-21 Trichofolliculoma. A dilated infundibulum supports a complex proliferation of small germinative hair elements and small follicles.

DIFFERENTIAL DIAGNOSIS Aside from TF (see Trichofolliculoma above), the differential diagnosis of FCH principally centers on steatocystoma and dermoid cyst of the skin. The luminal cuticle of steatocystoma is not seen in FCH. Whereas a single central lumen also characterizes both steatocystoma and dermoid cyst, multiple cystic spaces are seen in FCH.

Trichoepithelioma

 FIGURE 28-22 Trichofolliculoma. Both basaloid clusters and small immature hair follicles are evident.

fibromyxoid matrix of BCC, and the former of these tumors demonstrates a much higher degree of cytologic differentiation than the latter.

Folliculosebaceous Cystic Hamartoma Folliculosebaceous cystic hamartoma (FCH) was described in 1991 by Kimura and colleagues,119 as a distinctive malformative lesion in the skin of the head and neck. It has been included at this point in the current discussion because the authors believe it to be a variant of sebaceous TF. That

view has also been advanced by Schulz and Hartschuh.120 CLINICAL FEATURES Similar to TF, FCH is a papulonodular lesion that typically arises on the face121,122; however, both of those tumors may also involve the genital skin.123 FCH is encountered over a wide age range, from childhood to the fifth decade, in people of both genders. There are no syndromic associations with this lesion. Individual tumors range up to several centimeters in maximal dimension (so-called giant FCH),124 and they are nonulcerated, yellowish-tan,

CLINICAL FEATURES TE of the “classical” type is usually seen as a solitary, slowly growing, flesh-colored nodule in the skin of the face, which typically arises during childhood (Table 28-11).126-128 The clinical distinction between TE and BCC is nearly impossible in some cases, and, as discussed subsequently, this dilemma may extend to a microscopic level as well. Multiple TEs are seen in the “epithelioma adenoides cysticum” (Brooke-Fordyce) syndrome, which is transmitted in an autosomal dominant fashion.119–122 In that disease complex, TEs may literally cover the face, with each lesion being smaller than 1 cm (Fig. 28-23A); extracranial skin fields may be involved as well. It is interesting that multiple TEs may coexist with multifocal cylindromas, spiradenomas, salivary glandular “dermal analogue tumors” (which resemble cylindromas), TLs, or BCCs, in the context of the Brooke-Fordyce or Cowden syndromes or in related, “derivative” genodermatoses.129-133 Systemic conditions that may potentially coexist with multifocal trichoepitheliomatosis include the Rombo syndrome (milia, hypotrichosis, atrophoderma, TEs, BCCs, and vasodilatation with cyanosis), systemic lupus erythematosus, and myasthenia gravis.134,135

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

HISTOPATHOLOGIC FEATURES As one might expect from the foregoing comments, FCH represents a caricature of TF. One sees a conglomeration of infundibulocystic epithelial units from which immature sebaceous lobules and follicular epithelial aggregates radiate (see Fig. 28-22). The intervening stroma contains a mixture of mesenchymal tissue types, including neural, vascular, and adipocytic elements.119,121,122 It is unclear whether these components are integral to the lesion or simply represent entrapped or metaplastic tissues. Stromal mucin deposition in FCH was also described by Aloi and colleagues.125

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 28-11 Trichoepithelioma

704

Clinical Features Children and adults Solitary or multiple (“epithelioma adenoides cysticum”—Brooke-Fordyce syndrome) Head and neck, especially face Skin-colored papule or nodule, pearly appearance Usually < 1 cm Multiple TE associated with multiple cylindromas, spiradenomas, salivary glandular tumors, trichilemmomas, or basal cell carcinomas Histopathologic Features Organoid arrangement of mature collagenous hypocellular stroma about lobules of uniform basaloid cells, welldemarcated from surrounding dermis Basaloid cells tend to show peripheral palisading of nuclei, lacelike or cribiform in patterns, and hair matrix-like differentiation Keratinous microcysts frequent Often hair papilla-like structures (“mesenchymal papillary bodies”) in stroma adjacent to hair matrical-like epithelium Minimal or no mitotic figures and necrotic cells Differential Diagnosis Trichofolliculoma Basal cell carcinoma

HISTOPATHOLOGIC FEATURES Regardless of whether they are sporadic or syndromic tumors, TEs have the same histologic image (see Table 28-11). They are composed of lobular arrays of relatively uniform basaloid cells in the dermis, separated from one another by mature, collagenous, hypocellular stroma (Fig. 28-23B). The lobular constituents often connect to one another focally and contain variably sized keratinous microcysts mantled by cells showing infundibular or isthmic differentiation (Fig. 28-24). The remaining (predominant) cell population is embryonic and germinative in appearance, and, as such, is very similar to that encountered in nodulocystic or pilar-type BCCs. The likeness between those tumors is even more problematic in examples of TE that exhibit retiform or adenoid foci, as commonly seen in BCC. The cited distinction also is particularly difficult in TEs that lack obvious keratinous microcyst formation and are composed of solidly cellular basaloid clusters; such variants have been termed immature

A

B  FIGURE 28-23 Trichoepithelioma. (A) Multiple papules involving nasolabial folds of central face and beyond. (B) This lobular proliferation of basaloid cells induces its own tumoral stroma that sharply demarcates the lesion from corium. The epidermis is not involved.

TEs (Fig. 28-25).136 In the authors’ opinion, these difficulties likely have a biologic underpinning. In contradistinction to conventional doctrine, we believe that “classical” TE is, in reality, a highly differentiated form of BCC. TE rarely behaves aggressively, especially in multifocal syndromic form, but the same could be said of several variants of BCC as well. Genetic analysis has affirmed a synonymity between classical sporadic TE and BCC, both of which demonstrate the same chromosomal deletion at 9q22.3.137

In contrast, syndromic (Brooke-Fordyce) TE appears to have a different genetic constitution, featuring mutations in the CYLD gene at 16q12-13.138 DIFFERENTIAL DIAGNOSIS Traditionally, several points of difference between TE and BCC have been cited, including the lack of a loose, fibromyxoid BCC-like stroma in TE; the presence of abortive hair papilla formation in TE but not BCC; an absence of apoptotic foci in TE and their existence in BCC; and melanin pigmentation in the latter but not the former

of the two neoplasms.139 Although these dissimilarities do indeed exist in most instances, the authors have been increasingly struck over the years that TE and

BCC have similar images and, in fact, are points in a single continuum of tumors. This somewhat iconoclastic view—as enunciated above—is supported by the

Desmoplastic Trichoepithelioma Another contentious point surrounds the question of whether desmoplastic TE (DTE), also known as sclerosing epithelial hamartoma, does indeed have a nosologic relatedness to TE (Table 28-12).147,148 CLINICAL FEATURES The former of those neoplasms is virtually always solitary, is not seen in the epithelioma adenoides cysticum syndrome or in association with systemic diseases, and typically presents as a slightly umbilicated nodule or plaque in the central facial skin of young or middle-aged women.149,150

 FIGURE 28-25 Trichoepithelioma. Solid basaloid proliferations devoid of keratocyst formation comprise a pattern referred to as immature trichoepithelioma.

HISTOPATHOLOGIC FEATURES More histologic than clinical dissimilarities can be seen between TE and DTE. The second of those tumors is usually represented by a discoid lesion in the dermis that is wider than it is deep and whose lateral margins are sharply circumscribed (see Table 28-12). Narrow linear or slightly branching cords of compact polygonal cells comprise DTE without a truly basaloid component. There is also an admixture of keratinous microcysts that are very often filled with calcified material and are connected directly to the linear polyhedral-cell configurations (Fig. 28-26). The intervening stroma is

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

 FIGURE 28-24 Trichoepithelioma. Note organoid basaloid epithelial aggregates with fibrous stroma resembling hair papillae.

previously cited clinical observation that multiple TEs may commingle with BCCs in selected patients and kindreds, as well as histopathologic cases-in-point where all of the microscopic “discriminants” mentioned are shared by the two neoplasms under discussion here.131,140,141 Other investigators have attempted to use immunostains for bcl-2 protein and CD34 to separate TE from BCC; reported observations in those studies have included a lack of bcl-2 protein in TE and the regular presence of that marker in BCC and the presence of CD34 in the stroma immediately adjacent to cellular clusters in TE but not in BCC.142-145 Our laboratories, however, have been unable to reproduce these findings, and therefore we must conclude that there are no reproducible adjunctive-morphologic methods to separate the two neoplasms in question.146 Whether one espouses the view that TE and pilar-type BCC are truly distinct from one another or, alternatively, that TE represents a differentiated form of BCC, the clinical impact of that opinion probably is negligible. Dermatologists aim to conservatively but completely excise both tumor types and should do so.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 28-12 Desmoplastic Trichoepithelioma

706

Clinical Features Young to middle-aged adults Women more often than men Central face, especially the cheeks Solitary, often skin-colored or slightly yellowish plaque Raised borders and slightly depressed central area Firm or scarlike Histopathologic Features Discoid lesion in upper dermis with well-defined margins Narrow linear or slightly branching cords of compact polygonal cells Keratinous microcysts often filled with calcified material Densely collagenized stroma surrounds epithelial elements Dystrophic calcification Foreign body giant cell reaction to keratin No appreciable cytologic atypia or mitotic activity Differential Diagnosis Morphea form basal cell carcinoma Syringoma

densely collagenized and hypocellular, without fibromyxoid foci or retraction from the epithelial cell groups.151 Unlike both TE and BCC, DTE is immunoreactive for EMA as well.152 For unknown reasons, DTE also demonstrates consistent but “occult” neuroendocrine differentiation, demonstrating scattered cellular immunoreactivity for keratin-20,

CD56, chromogranin-A, and synaptophysin.153,154 DIFFERENTIAL DIAGNOSIS The immunophenotype of DTE is helpful in making the distinction between that tumor and its principal differential diagnostic alternatives, morpheaform BCC (MBCC) and MAC, in small biopsy specimens. MBCC simulates DTE in exhibiting narrow, slightly branching cords of epithelial cells—often with areas of dystrophic calcification—embedded in a hypocellular stroma. Comparably, the tubular cell profiles of MAC may be so compact that they simulate solid cords as seen in the other two lesions. BCCs of all types lack the sharp circumscription of DTE and are composed of truly basaloid elements. Moreover, even morphea-like BCC exhibits small zones in which the stroma is fibromyxoid and retracted—in likeness to other BCCs—and it also focally manifests larger cellular aggregates than those seen in DTE or MAC.144 All three of the tumors under discussion may be labeled with BER-EP4, albeit in differing proportions.155,156 However, reactivity for neuroendocrine markers is unique to DTE in this narrow setting. Even though other forms of BCC may occasionally harbor endocrine cells as well,157 morpheaform or infiltrative BCCs—with which DTE might be confused—do not do so.

Pilomatricoma CLINICAL FEATURES PM, also known as calcifying epithelioma of Malherbe, pilomatrixoma, and trichomatrioma, is a

 FIGURE 28-26 Desmoplastic trichoepithelioma. Keratocysts commonly contain calcified material.

distinctive neoplasm that represents the prototype of matrical follicular differentiation (Table 28-13). It is most often seen in children and adolescents as a slowly growing, deeply seated, cystic nodule in the skin of the head and neck, but this neoplasm may certainly be observed in adults as well as in extracranial locations.158-163 HISTOPATHOLOGIC FEATURES Several stages of development have been observed for PM, and distinctive clinicopathologic variants of the tumor also exist (see Table 28-13). Ackerman1 has suggested that PM begins as a subepidermal cyst that is lined in part by infundibular-type epithelium and, in its inferior-peripheral aspects, by germinative-matrical cells. The latter elements are the most distinctive component of this neoplasm; they are represented by compact basaloid polygonal cells with monotonous round nuclei, dark chromatin, small nucleoli, consistently observable and often-brisk mitotic activity, and amphophilic cytoplasm (Figs. 28-27 and 28-28). The peripherally disposed germinative cells blend into an intermediate zone nearer the cyst lumen, where nuclei variably assume a washed-out, ghostlike appearance and the cytoplasm becomes more uniformly

Table 28-13 Pilomatricoma

Clinical Features Children and adolescents, but any age may be affected Head and neck most common Solitary slowly developing hard nodule, usually deeply seated Histopathologic Features Well-defined lobular tumor in dermis or subcutis Initially the tumor may be cystic with infundibular and germinative-matrical cellular components Germinative-matrical cells are uniform basaloid cells with monotonous round nuclei, dark chromatin, and small nucleoli Prominent mitotic activity Transition of matrical epithelium to “ghost” or “shallow” cells that exhibit an imprint of a nucleus that has been lost Formation of hard nail-like keratin Progressive loss of basaloid epithelium Foreign body giant cell reaction to keratin Calcification, ossification Differential Diagnosis Basal cell carcinoma Pilomatrical carcinoma

that are retained in the dermis. Another unusual form of PM is that in which peripheral “buds” of tumor cells are seen to infiltrate from the main mass into the surrounding corium and incite a desmoplastic response, in analogy to the image of low-grade malignant acrospiromas (see Chapter 27). These lesions are otherwise typical morphologically and may therefore be labeled appropriately as invasive (or, alternatively, low-grade malignant) PMs.162,163,170 The biologic correlate of such findings is a potential for local recurrence that is virtually unknown in banal PM.

Trichogerminoma In 1992, Sau and colleagues165 seminally reported 14 cases of a rare cutaneous adnexal neoplasm that they elected to designate as TG because of the conclusion that it demonstrated differentiation toward the hair germ epithelium.

 FIGURE 28-28 Pilomatrixoma. The morphologic analogy of this neoplastic lesion to the hair matrix is obvious.

CLINICAL FEATURES Patients with this lesion ranged in age from 16 to 73 years, and males predominated by a factor of two. They presented with slowly growing, dermal or subcutaneous masses on the head and neck, trunk, or extremities, ranging up to 4 cm in maximum dimension. Follow-up showed that the patients all had an uneventful course after excision of their masses, except for one, whose tumor transformed into a highgrade carcinoma and died from distant metastasis of that component.

of a cutaneous osteoma if attention is not paid to residual basaloid or ghost cell elements. Histologic variants of PM include a “perforating” form of the tumor in which it is seemingly eliminated through the overlying epidermis; it may be posited that PMs associated with clinical anetoderma illustrate an earlier stage of this phenomenon.162,164-169 Transepidermal extrusion therefore would appear to be one way in which PMs resolve or mature; conversely, transformation of the lesion into an osteocalcific mass is the apparent outcome for those neoplasms

HISTOPATHOLOGIC FEATURES TG is a welldemarcated, highly cellular lesion that has its epicenter in the deep dermis. The neoplastic cells are basaloid and monotonous, with round nuclei, dispersed chromatin, distinct nucleoli, and often numerous mitoses. They are arranged in lobules that are separated from one another by variably cellular fibrovascular stroma, which may contain matrical mucin. The most characteristic feature of this tumor is the formation of “cell balls” throughout the mass, represented by micronodular aggregates of neoplastic cells with internal concentricity and peripheral condensation, nuclear palisading, or both. Many

cornified and eosinophilic. In the center of the lesion, ghost cells are seen exclusively (Fig. 28-29), and these often undergo regional dystrophic calcification. With the passage of time, the number of basaloid cells in PM decreases progressively, eventually to be replaced entirely by aggregates of ghost cells, calcium deposits, and even foci of metaplastic bone. Extravasated keratin often elicits a foreign body–type giant cell reaction in the surrounding dermis; in fact, these changes may dominate “ancient” PMs.162,163 Moreover, extensive secondary heterotopic ossification may simulate the appearance

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

 FIGURE 28-27 Pilomatrixoma. Islands of basaloid cells that resemble hair matrix are associated with abundant keratinous debris.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of PM principally concerns the subtype of pilar BCC in which follicular matrical differentiation—complete with aggregates of ghost cells—may be seen.171 Overall, however, there are many points of cytologic and architectural dissimilarity between these neoplasms, as enumerated previously.

707

follicular epithelium and follicle-related mesenchyme. These representatives are basaloid follicular hamartoma (BFH)— arguably included in this section as a tumor in the generic sense of that term— and TBL.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Basaloid Follicular Hamartoma

 FIGURE 28-29 Pilomatrixoma. Matrical keratinization results in preservation of cell borders, but loss of nuclei (ghost cells).

cell groups are surrounded by PAS-positive eosinophilic membranes, resembling the vitreous layer of the outer root sheath. Small keratin microcysts may be appreciated within the cellular balls, as may foci of apoptosis, clear cell change (Fig. 28-30), structures resembling abortive hair bulbs, and divergent sebaceous differentiation. DIFFERENTIAL DIAGNOSIS Because of its diverse microscopic attributes, TG has a lengthy differential diagnosis, which includes BCC, TE, and trichoblastoma (TBL) (see Trichoblastoma below). Indeed, skeptics may choose to regard

A

708

this neoplasm as a variant of pilar-type BCC because of several points of microscopic similarity with TG as outlined previously. However, in light of the aggregate clinicopathologic characteristics of TG, we believe that it does withstand scrutiny as a distinctive entity. More complete delineation of its biologic nature and morphologic spectrum will require study of additional cases.

Mixed Epithelial and Mesenchymal Follicular Proliferations Two adnexal neoplasms are typified by conjoint differentiation toward the

CLINICAL FEATURES BFH, also known as generalized hair follicle hamartoma and linear unilateral basal cell nevus, is generally regarded today as a malformative developmental lesion rather than a true neoplasm (Table 28-14).172-178 However, it should be noted in that regard that this condition may develop for the first time during adulthood. It likewise may be linear or regionalized, pale or erythematous, plaquelike or papular, and solitary or generalized. Some examples of BFH have caused alopecia or arisen in patients with myasthenia gravis.175,177 In the authors’ opinion, the lesion described by Alessi and Azzolini as “localized hair follicle hamartoma” is a hybrid variant of BFH that also incorporates some of the elements of NS.179 Another probably related entity is the lesion known as hemifacial mixed appendageal tumor.180 This proliferation is typically seen as a facial plaque in children. It microscopically resembles either BFH or linear basal cell nevus, except that eccrine and apocrine tissues are also included. HISTOPATHOLOGIC FEATURES The microscopic image of BFH features a folliculocentric proliferation of bland, uniform basaloid cells that are arranged in cords and clusters and separated from each other by an organized fibrous stroma (see Table 28-14). Adenoid or reticulated patterns can often be appreciated in the

B

 FIGURE 28-30 Trichogerminoma. Nuclei with vesicular chromatin and prominent nucleoli are seen. Mitotic activity is readily identified, as are apoptotic cells.

Table 28-14 Basaloid Follicular Hamartoma

 FIGURE 28-32 Basaloid follicular hamartoma. A reticular pattern of growth may be seen. epithelial component, and small keratinous cysts may be evident as well (Figs. 2831 to 28-33). These may become calcified; vellus hairs or sebaceous glands may also be included in BFH. DIFFERENTIAL DIAGNOSIS Because of the particular nature of the interface between the epithelium and stroma in individual lesions of BFH, differential diagnosis with the “fibroepitheliomatous” variant of BCC may be difficult, as

may the distinction between BFH and multifocal-superficial BCC in other instances. Follicular hamartomas lack the foci of apoptosis, myxoid alterations in tumoral stroma, and epithelial–stromal retraction seen in BCC. Also, clinical information obviously is extremely useful in making the interpretative separation under discussion.

 FIGURE 28-31 Basaloid follicular hamartoma. A small folliculocentric proliferation of basaloid cells is present.

Trichoblastoma After the 1993 publication of a textbook by Ackerman and colleagues on follicular neoplasms, it has become fashionable to follow the recommendation of those authors to use the term TBL in a nosologically egalitarian fashion as an umbrella term over not only the bulk of benign pilar tumors but also many lesions that classically would be considered as BCC variants.1,181,182 This practice is defended by some on conceptual grounds and certainly by many others who are interested in a condensed and “user-friendly” nomenclatural scheme as applied to adnexal neoplasms.183 However, we believe that a negative impact accrues from such an approach. Headington’s original intent in creating the term TBL (with the synonym trichogenic adnexal tumor) was to bring two salient elements of this lesion into focus. These are its relatively primitive histologic appearance, resembling that of the embryonic hair, and other morphologic attributes that suggest an epithelial– stromal interaction as the underlying mechanism for the peculiar image of this tumor.184 Depending on whether the epithelium or stroma is predominant in neoplasms in this category, additional diagnostic modifications, such as trichoblastic TBL or trichoblastic fibroma may be used as desired.185 However, we would stress that regardless of such

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

Clinical Features Children or adults Any location Solitary or multiple forms: localized, linear, or generalized Papules, plaques Comedones, keratotic plugs Alopecia may occur Histopathologic Features Folliculocentric Proliferation of bland uniform basaloid cells in cords and aggregates Organized fibrous stroma Adenoid or reticulated patterns Small keratinous cysts Calcification may occur Differential Diagnosis Fibroepithelioma of Pinkus Superficial basal cell carcinoma Trichoepithelioma Reticulated seborrheic keratosis

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

three cells in thickness anastomose with one another and are separated by cellular stroma (Figs. 28-34 and 28-35). A hyaline membrane may invest the cellular cords as well, and globular deposits of eosinophilic matrix may be seen between them or in the adjacent stroma. Hair differentiation is evident, either as immature cellular clusters that bud from the mass and are indented by stroma in the manner of a primitive hair papilla and hair bulb or as more mature proliferative foci that resemble hair root structures.184-187 Occasional examples of TBL may exhibit the formation of melanin pigment, as described by Aloi and coworkers.188 A multinodular variant of TBL showing desmoplastic stroma has been reported by Chan and colleagues189; this lesion also differed from classical forms of the tumor in showing small foci of keratinization, mucomyxoid stromal alteration, and focal spindle-cell differentiation with infiltration of perineural spaces and arrector muscles. Despite these worrisome findings, the clinical evolution was innocuous.

 FIGURE 28-33 Trichoblastoma. Cords and clusters of basaloid cells form a discrete mass in the dermis.

nuances, the basic designation of TBL is associated with a distinctive, well-recognized, visual and clinicopathologic profile; consequently, the correspondingly narrow meaning of the term should be retained. To do otherwise would, in our opinion, be tantamount philosophically to describing all malignant epithelial tumors of the viscera as “carcinoma, not further specified.” Experience has taught us the inadvisability of that approach. CLINICAL FEATURES In this narrow sense, TBL may arise in almost any skin field, except possibly in the distal extremities (Table 28-15). It is generally a solitary, nondescript, nodular lesion that is situated at any level of the dermis; the size is usually less than 2 cm, but “giant” tumors of this type have been documented. No syndromic associations pertain.184,186

710

HISTOPATHOLOGIC FEATURES TBL is a basaloid proliferation in which the neoplastic cells are arranged in cords, sheets, or discrete clusters (see Table 28-15). The most common of these patterns is the first, in which strands of two to

Table 28-15 Trichoblastoma and Related Tumors

Clinical Features Adults Women as often as men Almost any location, especially the face and scalp Usually does not involve distal extremities Solitary nondescript papule or nodule Usually < 2 cm , but may be giant Histopathologic Features Well-demarcated from surrounding tissue Symmetric Basaloid epithelial proliferation in cords, sheets, or discrete clusters Fibrotic investment of epithelium Follicular germinative epithelium Peripheral palisading of nuclei Follicular differentiation resembling hair bulbs and papillae Keratinous cysts on occasion Fibrotic stroma Occasional necrosis Limited numbers of mitoses Differential Diagnosis Basal cell carcinoma

DIFFERENTIAL DIAGNOSIS Depending on its particular histologic constituency, the differential diagnosis of TBL encompasses BCC of the nodulocystic and morpheaform types, TG, and BFH. Of these, the most difficult distinction is between TBL and BFH because of their shared potential for cellular growth in single-file strands and an “interactive” interface between epithelial and stromal cells in those lesions. However, structures resembling embryonic hairs are not a part of the histopathologic repertoire of BFH, as they are in TBL.176

Cutaneous Lymphadenoma Cutaneous lymphadenoma (CL) was first described by Santa Cruz and colleagues in 1991190 as a dermal neoplasm with a distinctive histologic appearance. That tumor entity is included in this section because it has been thought by some observers to represent a benign lesion that is related to TBL.191,192 CLINICAL FEATURES CL typically presents as a slow-growing, nondescript, nonulcerated, flesh-colored nodule in the skin of the head and neck in young or middleaged adults (average age, 40 years).190-195 The maximum tumor diameter is usually no larger than 2 cm. No syndromic associations have been reported in connection with lymphadenoma of the skin, and it is cured by simple excision.

 FIGURE 28-34 Trichoblastoma. Basaloid cells are often arranged in cords that are two or three cells thick. The cellular fibrous matrix induced by the tumor is analogous to normal perifollicular mesenchyme.

NEOPLASMS SHOWING DIFFERENTIATION TOWARD FOLLICLE-RELATED MESENCHYME Tumors demonstrating differentiation toward the stromal elements that are associated with developing hair follicles are extremely rare. Moreover, their clinical presentations and histologic images are quite similar. These factors taken together make it easy to understand why this small area of adnexal tumor pathology is unfamiliar to most pathologists. Those lesions that are grouped in this category include trichodiscoma, PF, fibrofolliculoma, follicular myxoma, and pilar leiomyoma.

Trichodiscoma

 FIGURE 28-35 Trichoblastoma. A more sclerotic stroma typifies a variant that has been referred to as trichoblastic fibroma.

HISTOPATHOLOGIC FEATURES The typical microscopic image of CL closely simulates that of intradermal thymic tissue. It is characterized by rounded lobules of uniform, cytologically bland basaloid cells, with numerous interspersed mature lymphocytes (Fig. 28-36). Lymphoid cells may also be seen in the intervening stroma. The neoplastic cell groups tend to conform to one another, and peripherally located cells within them have a tendency to palisade. Foci of keratinization and apparent ductal differentiation have been reported as well, and occasional lesions in this group may demonstrate a subepidermal network of cells similar to that seen in

TFI.190 The tumor cells in CL have open nuclei with discernible nucleoli, but mitotic activity and apoptosis are sparse. Immunophenotyping of the lesion shows diffuse keratin reactivity, with specific antibodies to keratin 20, demonstrating the presence of scattered positivity (putatively representing Merkel cell differentiation).192 Intratumoral lymphoid cells are predominantly T cells, with the majority labeling for CD3, CD5, CD43, and CD45R0. A generous number of apparent Langerhans cells, which stain for CD1a and S-100 protein, are also usually observed. Intralesional histiocytes that label for CD68, with or without CD30, have also been reported.192

Trichodiscoma was so named because this tumor was presumed to show differentiation toward the hair discs, or Haarscheibe.196 In normal skin, the latter structures are receptor complexes composed of nerve ends and supporting fibrovascular stroma, which are associated with intraepidermal Merkel cells. In reality, no objective evidence supports the presence of morphologic or functional attributes of the hair disc in trichodiscoma. CLINICAL FEATURES This neoplasm becomes manifest as a grouping of otherwise banal small nodules in the skin, most often in the head and neck region but also possibly in other locations, in patients of virtually any age (Table 28-16).196-199 These nodules may be grouped in a regional fashion, or the patient may have a generalized trichodiscomatosis.197,200 Contrary to what may be expected intuitively because of its putative relationship

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

DIFFERENTIAL DIAGNOSIS The differential diagnosis of CL includes BCC, TE, TBL, dermal thymic tissue, and lymphoepithelioma-like carcinoma of the skin (LELCS). BCC shows stromal myxomucinosis that is lacking in lymphadenoma, and apoptosis is much more marked in the former of those tumor types. TE and classical TBL do not exhibit an investment by lymphocytes, as seen in CL. Dermal thymic tissue manifests the presence of perivascular spaces filled with serum and lymphocytes, inside of epithelial cell groups; these are not seen in lymphadenoma. Finally, LELCS has much more anaplastic cytologic features than those of the other lesions in this differential diagnostic group.

711

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

B

C

A

 FIGURE 28-36 Cutaneous lymphadenoma. (A) A lobular growth pattern is visible on low-power microscopy. (B) Some of the tumor cell nests demonstrate slight dyscohesion. (C) Numerous mature lymphocytes are interspersed among bland epithelioid tumor cells.

with the Haarscheibe, trichodiscoma is not a painful lesion. There may be an association between this lesion and other follicular malformations or neoplasms in the same individual.201

HISTOPATHOLOGIC FEATURES The histologic diagnosis of trichodiscoma is predicated on the presence of a superficial dermal “plate” of paucicellular fibrovascular tissue containing nerve twigs (seen only

by silver impregnation stains), stromal mucin, and elastin (see Table 28-16).196,200 The overlying epidermis is attenuated, and hair follicles are usually present at the periphery of the dermal abnormality

Table 28-16 Comparison of Trichodiscoma, Perifollicular Fibroma, and Fibrofolliculoma TRICHODISCOMA

PERIFOLLICULAR FIBROMA

FIBROFOLLICULOMA

Clinical Features Usually adults Head and neck, trunk, extremities Often multiple May be generalized Small skin-colored papules, flat or dome shaped Stromal component expands dermis, forming nodule

712

Histopathologic Features Stromal component: stroma composed of delicate collagen bundles, scattered fibroblasts, mucin deposition, and numerous microvessels Stromal component oriented about central hair follicle

Well-demarcated stromal component oriented about central hair follicular infundibular structure. Thin epithelial cords extend from infundibular structure into surrounding stroma. The cords have an anastomosing pattern

acrochordons in the autosomal dominant Birt-Hogg-Dubé syndrome, were the real culprits in regard to related colonic pathology.212,213

Fibrofolliculoma

(Fig. 28-37). Interestingly, immunostains show an absence of Merkel cells in the overlying epithelium, contrary to theoretical predictions.

and an increased risk of colorectal carcinoma.211 Those authors concluded that the latter paradigm was erroneous and that multiple fibrofolliculomas (vide infra), as seen with multiple trichodiscomas and

DIFFERENTIAL DIAGNOSIS The microscopic image of trichodiscoma is so distinctive that there is virtually no tenable differential diagnosis. In fact, this same truism also applies to most of the remaining lesions presented in this section.

Perifollicular Fibroma PF is also primarily a fibroblastic proliferation, with clinical features that are similar, if not identical, to those of trichodiscoma (see Table 28-16).202-206 In the past, much literature was devoted to a consideration of whether PF was kin to fibrous papule of the face and adenoma sebaceum.207,208 Inasmuch as those proliferations are basically angiofibromatous, we do not recognize any relatedness between them and PF.209 The latter lesion differs from them histologically in showing a vaguely nodular proliferation of bland, paucicellular fibrous stroma—with or without mucin deposition—around hair follicles. This process assumes a lamellar image and may or may not be associated with fibrosis of the adjacent interfollicular dermis as well (Fig. 28-38). Junkins-Hopkins and Cooper210 have considered the significance of a multiplicity of PFs, revisiting traditional teaching that this finding was sometimes associated with familial colonic polyposis

 FIGURE 28-38 Perifollicular fibroma. The perifollicular mesenchyme is expanded by a paucicellular fibrous stroma similar to that seen in trichodiscoma.

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

 FIGURE 28-37 Trichodiscoma. A superficial plate of paucicellular fibrous stroma expands the corium. The lesion is bordered by a hair follicle.

Fibrofolliculoma is similar to PF clinicopathologically but differs from that tumor in being associated with central follicular dilatation or distortion and showing interanastomosing septa of follicular epithelium that traverse the lamellated fibrous mantle around the affected pilosebaceous unit or units (see Table 28-16 and Fig. 28-39).214,215 Weintraub and Pinkus216 have referred to this as an “epithelial net.” Besides the previously mentioned role played in the Birt-Hogg-Dubé syndrome, fibrofolliculoma also may be linked in selected patients to the concurrent presence of connective tissue nevi.216 Steffen217 has described several examples of neoplasms that were called mantleomas, in which cords of nondescript bland polygonal cells were attached to the follicular infundibulum and proliferated in parallel to the hair follicle as a “mantle.” Because small nests of sebocytes were seen at the termini of the cellular cords in such lesions, they were classified as sebaceous

713

hair follicles or follicular cysts are formed. The overlying epidermis often exhibits papillomatous change that is probably reactive in nature. Lesions that are similar to follicular myxomas have been described in patients with the NAME (nevi-atrial myxomas-myxoid neurofibromas [or cutaneous myxomas]ephelides) syndrome.220

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Pilar Leiomyoma

714

Leiomyomas of the skin that are confined to the superficial half of the corium are presumed to be of pilar origin, although direct continuity between the tumor and the arrector pili muscles is extremely rare (see also Chapter 32).

 FIGURE 28-39 Fibrofolliculoma. Perifollicular fibrous proliferation is identical to that seen in perifollicular fibroma, but the central follicle is dilated, and septa of proliferating epithelium and sebaceous lobules divide the fibrous mantle.

in nature. However, we believe it is just as likely that the cited neoplasms may have been benign pilar sheath tumors, akin but not identical to fibrofolliculomas, with divergent sebaceous differentiation.

Follicular Myxoma CLINICAL AND HISTOPATHOLOGIC FEATURES Follicular myxoma is an extraordinarily rare tumor that is seen in patients younger than age 25 years, and it may coexist with other follicular tumors,

showing germinative epithelial differentiation. This neoplasm is typified by the localized deposition of myxoid stroma surrounding a confined group of pilosebaceous units; the latter structures are often distorted and may interconnect with one another, yielding a lobular configuration (Fig. 28-40).68,218,219 Arborizing capillaries are present within the myxoid matrix, as well as small aggregates of presumably follicular epithelial cells— sometimes showing matrical differentiation—and rare foci in which diminutive

 FIGURE 28-40 Follicular myxoma. A prominent myxoid stroma distorts a follicle-based epithelial proliferation, which, in this example, includes diminutive hair follicles.

CLINICAL FEATURES As such, pilar leiomyomas (PLs) are usually solitary, sometimes tender, nodular lesions that generally measure less than 1 cm in greatest dimension.221,222 However, a regionally “eruptive” multifocal version of this neoplasm also is recognized.223 Patients of all ages and both genders are affected without preference. HISTOPATHOLOGIC FEATURES The microscopic profile of PL features skeins of spindle cells with blunt-ended, fusiform nuclear profiles and fibrillar eosinophilic cytoplasm, which are intertwined in a “whorling” fashion. Fascicles of tumor cells cut in cross-section often exhibit zones of perinuclear clarity; areas demonstrating nuclear palisading, in likeness to those of neural tumors, may sometimes be seen. PLs are sharply demarcated and amitotic, and similarly they lack nuclear pleomorphism and necrosis. DIFFERENTIAL DIAGNOSIS One must primarily consider solitary myofibroma of the skin, cutaneous neurilemmoma, or palisaded neuroma.224-226 The first of these three alternatives does not show the tightly whorled microscopic pattern of “pure” smooth muscle tumors. Instead, myofibromas are composed of loosely aggregated micronodular arrays of bland spindle cells in a variably myxoid stroma, often with a biphasic pattern of cellular density and prominently branching (“staghorn”-shaped) stromal blood vessels. Neural tumors such as neuromas and neurilemomas may be perplexingly similar to smooth muscle neoplasms in selected cases, and immunohistology may be necessary to distinguish between these classes of tumors. Whereas PLs are reactive for actin, desmin, caldesmon, or calponin, benign neurogenic lesions lack those determinants.62

MALIGNANT PILAR NEOPLASMS

Trichilemmal Carcinoma TLC was introduced as an entity by Headington in 1976, but that diagnosis was not embraced by pathologists until several years later.184,227-230 Recently, publication of a number of series has made it clear that TLC does exist as a distinctive lesion in the follicular tumor group.217-220 CLINICAL FEATURES This lesion arises in hair-bearing skin that is also actinically damaged and therefore usually affects the face, scalp, or ears (Table 28-17). Patients older than age 50 years are favored, with no gender predilection. Clinically, TLC may be nodular or plaquelike, whitish and hyperkeratotic or reddish and smooth surfaced, or ulcerated, and it typically is smaller than 3 cm in diameter. It is commonly mistaken for proliferative actinic keratoses, BCC, or squamous carcinoma by dermatologists; more uncommonly, keratoacanthoma is favored because of relatively rapid tumor growth. There is no known association between TLC and Cowden syndrome, unlike the case with TLs (see Trichilemmoma above), and “remnants” of the latter of these two neoplasms are never seen in conjunction with TLC. Therefore, it appears that they both arise as de novo proliferations and do not share a common pathogenesis. HISTOPATHOLOGIC FEATURES TLC is a lobulated, folliculocentric tumor that may replace the epithelial sheath of one, or more commonly, several hair follicles, yielding a pattern wherein groups of neoplastic cells replace the perifollicular epidermis but are separated by normal surface epithelium (see Table 28-17). The general image may thus be one of multifollicular and perifollicular epidermal carcinoma in situ. Alternatively, invasive foci may emanate from either

Clinical Features Patient often older than 50 years of age Head and neck Nodular or plaque-like lesion, whitish and hyperkeratotic, reddish with smooth surface, or ulcerated Usually <3 cm Histopathologic Features Lobulated, folliculocentric tumor Atypical epithelium replaces epithelial sheath of one or more hair follicles There may be intervening unaffected epidermis between the hair follicles affected Invasion of dermis may occur from the involved hair follicles Some tumor cells have PAS-positive, diastase labile clear cytoplasm Peripheral palisading of tumor lobules Trichilemmal keratinization The tumor otherwise shows cytologic atypia and mitotic activity as in squamous cell carcinoma Pagetoid spread in epidermis on occasion Differential Diagnosis Clear cell tumors as listed for sebaceous carcinoma

of these two sites and involve the adjacent dermal connective tissue in an irregular fashion, with surrounding lymphoplasmacytic inflammation and stromal

desmoplasia (Fig. 28-41). At least a portion of the tumor cells have PAS-positive, diastase-labile lucent cytoplasm, and many lobules in TLC show peripheral nuclear palisading. Foci of trichilemmal-type keratinization are scattered randomly throughout the lesion, which otherwise resembles squamous carcinoma in regard to the degree of nuclear atypia, mitotic activity, and cytoplasmic eosinophilia that are apparent. Some examples of TLC are singular in that they include pagetoid spread of the tumor cells into the overlying epidermis. Perineural or vascular infiltration in the dermis is unusual but may be observed. DIFFERENTIAL DIAGNOSIS One must consider virtually all other cutaneous malignancies that may show an epithelioid clear cell constituency. These include hydropic BCC and squamous carcinoma, clear cell eccrine carcinoma, SC, balloon cell melanoma, and metastatic clear cell adenocarcinomas of the viscera. Attention to the constellation of histologic findings presented in concert with procurement of clinical information (regarding duration of growth and macroscopic appearance of the lesion) usually allows for satisfactory recognition of TLC. Nonetheless, application of PAS stains and selected immunostains may be necessary in some instances for definitive interpretation (Table 28-18). In particular, the application of antibodies

 FIGURE 28-41 Trichilemmal carcinoma. Infiltrating lobules of tumor cells incite a focally prominent inflammatory infiltrate in a desmoplastic stroma.

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

Malignant tumors of the follicular apparatus are rare, even more so than adnexal malignancies that demonstrate sweat glandular differentiation. This factor probably explains why, in the experience of the authors, most pilar carcinomas are mistaken for other lesions or otherwise misdiagnosed. Also, it is a truism of this group of tumors that they commonly demonstrate a mixture of features that defy facile classification into neoplasms of the outer hair sheath, germinative follicular cells, and so on. Hence, diagnostic categorization in this context is a “best fit” enterprise.

Table 28-17 Trichilemmal Carcinoma

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Table 28-18 Special Stains in the Differential Diagnosis of Clear-Cell Cutaneous Tumors

716

TUMOR

PAS-W

PAS-S

TLC HBCC HSCC CCEC SC BCM MCCA

0 0 0 0 0 0 +/−

+ +/− +/− + +/− +/− +/−

AE13/14 + 0 0 0 0 0 0

S-100

EMAa

CEA

0 0 0 +/− 0 + +/−

+ 0 +/− + +∗ 0 +

0 0 0 +/− 0 0 +/−

CA-125 0 0 0 0 0 0 +/−

CA19-9 0 0 0 0 0 0 +/−

Key: PAS-w = Periodic acid-Schiff (PAS) stain with diastase digestion PAS-s = PAS stain without diastase digestion AE13/14 = Pilar-selective keratin immunostains S-100 = S-100 protein EMA = Epithelial membrane antigen CEA = Carcinoembryonic antigen TLC = Trichilemmal carcinoma HBCC = Hydropic basal cell carcinoma HSCC = Hydropic squamous cell carcinoma CCEC = Clear cell eccrine carcinoma SC = Sebaceous carcinoma BCM = Balloon cell melanoma MCCA = Metastatic visceral clear-cell adenocarcinomas a EMA reactivity in sebaceous carcinomas is uniquely multivacuolated within the cytoplasm of the tumor cells.

to pilar-selective keratins (eg, AE13/ AE14) may be helpful in this context; Liang et al.231 have recently suggested that podoplanin is useful as well. These authors found the latter marker in primary cutaneous adnexal carcinomas, including TLC, but not in metastatic carcinomas involving the skin.

Malignant Proliferating Pilar Tumor CLINICAL AND HISTOPATHOLOGIC FEATURES The basic clinicopathologic profile attending malignant proliferating pilar tumor (MPPT), also known as malignant trichilemmal cyst, malignant pilar tumor, giant hair matrix tumor, and trichochlamydocarcinoma, is basically identical to that which was delineated previously in reference to BPPT (Table 28-19).232-247 That is true, at least in part, because it appears that some MPPTs arise in transition from BPPT, in a manner similar to that attending sweat gland carcinoma ex dermal cylindroma or eccrine spiradenoma. The first pathologic issue that must be addressed in connection with this neoplasm is the caution with which it should be diagnosed. Brownstein and Arluk111 properly drew attention to the fact that BPPTs have cytologic features that, at first glance, suggest an interpretation of carcinoma.However, as stated previously in this chapter, the pattern of growth is of greater importance in

determining the biologic potential of pilar neoplasms of this type. With that caveat in mind, there are two forms of MPPT with dissimilar

Table 28-19 Malignant Proliferating Pilar Tumor (MPPT)

Clinical Features Similar to benign proliferating pilar tumor (BPPT) Middle-age to elderly females Scalp Nodules, often ulcerated Histopathologic Features Low-grade MPPT: features similar to BPPT except Irregular invasion of surrounding connective tissue by irregularly shaped and sized cords of epithelium High-grade MPPT Lack of lobular growth pattern of BPPT Foci of geographic necrosis Cellular anaplasia Abnormal mitotic figures Spindle cell transformation Differential Diagnosis Low-grade MPPT Squamous cell carcinoma High-grade MPPT Poorly differentiated eccrine ductal carcinoma Metastatic carcinoma with squamous metaplasia

behavioral attributes (see Table 28-19). The first is a close mimic of BPPT, except for the fact that low-grade MPPT demonstrates irregular invasion of the surrounding and intervening connective tissue by irregularly shaped and sized cords and nests of neoplastic cells (Figs. 28-42 and 28-43). The cytologic attributes and the remaining architectural features of lowgrade MPPT are synonymous with those of BPPT. In contrast, high-grade MPPT lacks the lobular growth pattern of BPPT and demonstrates foci of obvious geographic necrosis.239 Moreover, it shows a much more anaplastic cytologic image with striking nuclear pleomorphism, abnormally shaped mitotic figures, and potential spindle cell transformation.241,242 Separation of MPPT into the mentioned subtypes facilitates the prognostication of these lesions. Low-grade tumors are expected to show the potential for local recurrence only (which may, nevertheless, be mutilating and difficult to control), whereas high-grade neoplasms also possess the capability for distant metastasis.112,232,233 DIFFERENTIAL DIAGNOSIS One principally focuses attention on SCC, but high-grade MPPT may also be confused with poorly differentiated ductal eccrine adenocarcinomas or metastatic carcinomas showing extensive squamous metaplasia. Unlike primary cutaneous squamous carcinomas,

DIFFERENTIAL DIAGNOSIS Because of the unique histologic image of pilomatrical tumors, with ghost cell keratinization, recognition of PMC generally is not a problem. However, small biopsies might yield specimens that could be confused with LELCS or metastatic undifferentiated carcinoma. Again, clinical information would allow for exclusion of the latter possibility, but no adjunctive methods are capable of separating the carcinomatous epithelium of PMC from that of LELCS in limited tissue samples.

“Malignant Trichoepithelioma”

 FIGURE 28-43 Malignant proliferating pilar tumor. Basaloid and polygonal cells populate these invasive tumor lobules.

MPPTs do not communicate with the overlying epidermis, and they manifest the presence of trichilemmal keratinization. Ductal eccrine carcinomas lack the last of these findings and exhibit at least limited foci of glandular differentiation that is absent in MPPTs. The distinction between metastatic carcinoma and MPPT is best made on the basis of clinical information, typically revealing the solitary nature and relatively long duration of growth attending follicular neoplasms in general, but application of pilar keratinselective immunostains again may be helpful in this setting.62

Invasive Pilomatricoma and Pilomatrix Carcinoma CLINICAL AND HISTOPATHOLOGIC FEATURES Many similarities can be drawn between the foregoing discussion of proliferating pilar tumors and pilomatrical neoplasms, in regard to features that can be used in a determination of their biologic potentials. Invasive PM differs from ordinary type PM only in demonstrating irregular “budding” cellular growth into the surrounding stroma at the periphery of the lesion, much in the same way that lowgrade MPPT infiltrates the dermis or sub-

Scattered reports may be found in the pertinent literature on malignant TEs (or trichoepitheliocarcinomas).243,256-258 These appear to be defined as tumors with the general structure of banal TE, but with either infiltrative growth, cytologic atypia, or both. In any event, the clinical evolution of such tumors has been uneventful after simple excision. As elucidated in an earlier section of this chapter, the authors have a bias toward the interpretation that even ordinary TE is, in fact, a highly differentiated variant of “pilar” BCC.244,259 Acceptance of this view as correct would make the term malignant TE nosologically redundant. In any event, there are no accepted pathologic criteria to define the latter entity, so it is not a diagnosis that we would care to make or encourage others to render.

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

 FIGURE 28-42 Malignant proliferating pilar tumor. Irregularly shaped aggregates of cells infiltrate the dermis. The epithelium suggests squamous differentiation.

cutis (Table 28-20).162,163,170,244-255 On the other hand, overt pilomatrix carcinoma (PMC) is typified by broad zones of geographic necrosis; infiltrative growth; and, most important, an alteration in the cytologic features of the tumor cells.245-255 They acquire high nucleocytoplasmic ratios, obviously vesicular nuclear chromatin, and large nucleoli, and as such resemble the neoplastic elements of lymphoepithelioma-like carcinomas of the skin (Figs. 28-44 and 28-45). However, the retention of focal ghost or shadow cell keratinization betrays the matrical differentiation of PMC. Behaviorally, invasive PM has the potential for local recurrence but not for distant metastasis.162 In contrast, PMC may spread secondarily to the regional lymph nodes or the viscera, and tumorrelated fatality obviously is a possibility under those circumstances.247,255

Adnexal Carcinomas with Mixed Differentiation As discussed in the Chapter 29, pathologists who evaluate a substantial number

717

Table 28-20 Invasive Pilomatricoma and Pilomatrix (Matrical) Carcinoma INVASIVE PILOMATRICOMA

Clinical Features Features similar to pilomatricoma

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Histopathologic Features Features similar to pilomatricoma except invasion of surrounding tissue at periphery of umor by tirregular cords of cells

Differential Diagnosis Pilomatricoma

PILOMATRIX CARCINOMA Adults Face, trunk, and extremities Nodules, possibly ulcerated Large tumors with atypical matrical epithelium and shadow cells Zones of geographic necrosis Infiltrative growth Sheets of atypical epithelium High nucleocytoplasmic ratios Vesicular nuclear chromatin Large nucleoli Prominent mitoses Lymphoepithelioma-like carcinoma of the skin Metastatic undifferentiated carcinoma

of adnexal skin tumors not infrequently encounter some that are not easily classified, according to accepted diagnostic schemes. Often, these manifest multilineage differentiation along more than one appendageal route and therefore include elements showing a combination of sudoriferous, sebaceous, and pilar characteristics.260 General categorization as carcinomas of lesions in this group that are infiltrative, cytologically anaplastic, or both is not difficult, and the best approach to labeling them more precisely is to use the designation of “adnexal carcinoma with mixed (or divergent) differentiation.” A similar tactic can also

be used when dealing with benign mixed-lineage appendage neoplasms. In the authors’ view, this is preferable to the application of such alternative, but complicated, diagnostic terms as pilary complex carcinoma or complex adnexal tumor of the primary epithelial germ with distinct patterns of SESD, immature TE, and apocrine adenocarcinoma.261,262 As discussed, LELCS may be a primitive member of this group of tumors. Two reports have now documented the presence of focal sweat glandular, follicular, or sebaceous differentiation in this otherwise cytologically anaplastic neoplasm.263,264

Pilar Leiomyosarcoma The classification of superficial (dermal) leiomyosarcomas as “pilar” in nature has more inferential than objective support (see also Chapter 32). In general, these lesions differ from cutaneous leiomyomas in showing infiltrative rather than circumscribed growth, more striking nuclear atypia, and the presence of mitotic activity.265-267 An arrector pililike lineage for pilar leiomyosarcoma (PLMS) is implied by its occurrence in a compartment of the dermis that harbors the former normal structures, as well as shared immunoreactivity in both the normal hair-related musculature and in PLMS for such determinants as S-100 protein.267 The typical biology of this usually well-differentiated neoplasm is that of a “borderline” mesenchymal malignancy, with limited potential for local recurrence but only rare examples of metastasis.267,268 The differential diagnosis is not commonly a problem in cases of PLMS, but it theoretically involves several other spindle cell malignancies of the skin. These principally include spindle cell squamous carcinoma, sarcomatoid melanoma, and atypical fibroxanthoma. Immunohistochemistry is a cost-effective and timely technique that can be used for the separation of these tumor entities, as summarized in Table 28-21.267

PSEUDONEOPLASTIC PROLIFERATIONS OF HAIR FOLLICLES AND FOLLICLERELATED MESENCHYME Several other tumefactive lesions of the skin demonstrate pilar features and may be mistaken for true neoplasms. In fact, some of these, such as BFH, have already been discussed somewhat arbitrarily as neoplastic in the preceding material. Others are considered in the following sections.

Hair Follicle Hamartoma A form of follicular hamartoma has been described that is probably related to BFH. It resembles a multifocal superficial of TE, replacing each hair follicle in a confined segment of skin and featuring an association with hyperplastic sebaceous glands.179

718

 FIGURE 28-44 Pilomatrix carcinoma. Irregular nests and lobules of large polygonal cells infiltrate dermis. The cytoplasm is pale eosinophilic or amphophilic, and central zones of keratinization and necrosis are evident.

DIFFERENTIAL DIAGNOSIS Points of distinction from true TE include the presence of mature hair and proliferating outer root sheath elements in this form of follicular hamartoma.

Smooth Muscle Hamartoma and Becker Nevus

Hair Follicle Nevus

stroma is composed of variably dense fibrovascular tissue.

CLINICAL AND HISTOPATHOLOGIC FEATURES Hair follicle nevi are seen in patients of all ages, as nondescript, 1- to 5-mm, flesh-colored, smooth-surfaced papules in hair-bearing skin. Histologically, they are constituted by a localized proliferation of miniature hair follicles, the contents of which approximate the size of vellus hairs.269-272 The interfollicular

DIFFERENTIAL DIAGNOSIS Misdiagnosis as a form of TE may be avoided by attention to the fact that TE does not demonstrate the advanced degree of hair formation seen in follicular nevi. Constituent cell populations are also different in these lesions, with TE featuring much more basaloid elements.

Table 28-21 Immunohistochemical Differential Diagnosis of Pilar Leiomyosarcoma TUMOR

KER

VIM

S-100

CD57

DES

CD31/UEA

Leiomyosarcoma MPNST Spindle cell angiosarcoma Spindle cell squamous cell carcinoma Spindle cell malignant melanoma Kaposi sarcoma

0 0 0

+ + +

+/− +/− 0

0 +/− 0

+ 0 0

0 0 +

+

+/−

0

0

0

0

0

+

+

+/−

0

0

0

+

0

0

0

+/−

Key: KER = Keratin VIM = Vimentin S-100 = S-100 protein DES = Desmin UEA = Ulex europaecus I lectin binding MNPST = Malignant peripheral nerve sheath tumor

HISTOPATHOLOGIC FEATURES There are abnormal bundles of smooth muscle in the reticular dermis and subcutis, arranged in haphazard or widely separated skeins. These often have an attachment to arrector pili muscles. “Pure” myogenous hamartomas are not associated with abnormalities in the epidermis. Nevertheless, Slifman and colleagues276 reported that some examples of Becker nevus—in which surface acanthosis, papillomatosis, hypertrichosis, and hyperpigmentation are observed— also exhibit the presence of dermal myogenic proliferations that are indistinguishable from those of SMH. DIFFERENTIAL DIAGNOSIS The distinction between SMH and true cutaneous smooth muscle tumors necessitates correlation between clinical data and histologic findings. Myogenous neoplasms of the skin are rare in children, but it is typical for SMH to be found in early life. Moreover, whereas leiomyomas usually have a sharp microscopic interface with the adjacent stroma, SMH exhibits a “ragged” peripheral margin and disorganized fascicular growth similar to that of muscular sarcomas. In specific counterpoint to the latter tumors, it is important to note that mitoses, nuclear atypia, and necrosis are not apparent in SMH.

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

 FIGURE 28-45 Pilomatrix carcinoma. Large polygonal cells with abundant cytoplasm, large vesicular nuclei, and prominent nucleoli impart a resemblance to lymphoepithelioma. Central zones of matrical (ghost cell) keratinization are seen.

CLINICAL FEATURES Cutaneous smooth muscle hamartomas (SMHs), which may be confused with either pilar leiomyoma or pilar leiomyosarcoma, may be either congenital or acquired in childhood. In addition, they probably comprise part of the spectrum of Becker nevus.272-281 These proliferations are solitary and are usually seen on the trunk or the extremities; they are manifest as lightly pigmented patches or plaques and measure up to 10 cm in diameter. Hypertrichosis is also commonly associated with SMH. Slight manual irritation of the lesion produces pseudo-Darier sign in which a short-lived elevation (pseudo-urtication) of the lesion eventuates; however, SMHs are painless.

Neurofollicular and Pilar Neurocristic Hamartomas Two other peculiar dermal mesenchymal proliferations that are putatively related to the hair follicles have been described within the past 15 years. These have been dubbed neurofollicular hamartoma (NH) and pilar neurocristic hamartoma

719

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

(PNH), although a true relationship of such lesions to the hair follicles is inferred at best, and their hamartomatous nature is also questionable.283-285 CLINICAL AND HISTOPATHOLOGIC FEATURES Neurofollicular hamartoma is said to present as a solitary papule in the skin of the face, in children as well as adults. Histologically, it bears a resemblance to both angiofibroma and neurofibroma, consisting of a tangle of bland spindle cell fascicles that are laterally bounded by hyperplastic pilosebaceous units. Because S-100 protein and silver-positive material are seen in NH by special staining methods, they are thought to represent a malformation of nerve endings serving the hair follicles. However, it should be noted that Sangueza and Requena282 found no reproducible differences between NH and trichodiscoma in a formal comparative analysis, making it more than possible that these tumefactions are synonymous. Pilar neurocristic hamartoma differs from the description just given, both clinically and pathologically. It is a pigmented papule or plaque in the skin of the head and neck, potentially affecting patients of all ages. Microscopically, one sees an interdigitating proliferation of bland, spindle cells— with some containing melanin pigment— in a tight perifollicular configuration in the dermis. Ultrastructural studies have demonstrated a mixture of melanocytic and Schwann cell features in this lesion, likening it to the blue nevus.285 Moreover, Pathy and colleagues286 and Pearson and coworkers287 have described several cases in which malignant melanomas have arisen secondarily in PNH. Based on those findings, the authors prefer to view the latter lesion as a melanocytic nevus variant rather than a pilar-related hamartoma. This construct has also been proposed by Mezebish and colleagues.288

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720

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alopecia and myasthenia gravis: clinicopathologic and immunohistochemical study and comparison with classic and desmoplastic trichoepithelioma. J Am Acad Dermatol. 1986;15:1104-1112. Long SA, Hurt MA, Santa Cruz DJ: Immature trichoepithelioma: report of six cases. J Cutan Pathol. 1988;15:353-358. Matt D, Xin H, Vortmeyer AO, et al: Sporadic trichoepithelioma demonstrates deletions at 9q22.3. Arch Dermatol. 2000;136:657-660. Salhi A, Bornholdt D, Oeffner F, et al: Multiple familial trichoepithelioma caused by mutations in the cylindromatosis tumor suppressor gene. Cancer Res. 2004;64:5113-5117. Brook JD, Fitzpatrick JE, Golitz LE: Papillary mesenchymal bodies: a histological finding useful in differentiating trichoepitheliomas from basal cell carcinomas. J Am Acad Dermatol. 1989;21: 523-528. Chen S: Trichoepitheliocarcinoma: report of five cases. Zhonghua Binglixue Zazhi. 1982;11:143-145. Howell JB, Anderson DE: Transformation of epithelioma adenoides cysticum into multiple rodent ulcers: Fact or fallacy? Br J Dermatol. 1976;95: 233-242. Kirchmann TT, Prieto VG, Smoller BR: CD34 staining pattern distinguishes basal cell carcinoma from trichoepithelioma. Arch Dermatol. 1994;130:589-592. Bryant D, Penneys NS: Immunostaining for CD34 to determine trichoepithelioma. Arch Dermatol. 1995;131:616-617. Morales-Ducret CR, van de Rijn M, LeBrun DP, Smoller BR: bcl-2 expression in primary malignancies of the skin. Arch Dermatol. 1995;131:909-912. Nakagawa K, Yamamura K, Maeda S, Ichihashi M: bcl-2 expression in epidermal keratinocytic diseases. Cancer. 1994; 74:1720-1724. Fitzpatrick M, Adesokan PN, Ritter JH, et al: Immunohistologic differential diagnosis of basal cell carcinoma, squamous cell carcinoma, and trichoepithelioma in small cutaneous biopsy specimens. Am J Clin Pathol. 1995;103:508. Brownstein MH, Shapiro L: Desmoplastic trichoepithelioma. Cancer. 1977;40: 2979-2986. Bernstein G, Roth GJ: Sclerosing epithelial hamartoma. J Dermatol. Surg Oncol. 1978;4:87-90. Dammert K, Kallionen M: Das desmoplastiche trichoepitheliom: klinik, histologie, und differentialdiagnose. Hautarzt. 1987;38:606. MacDonald DM, Wilson-Jones E, Marks R: Sclerosing epithelial hamartoma. Clin Exp Dermatol. 1977;2:153-160. Takei Y, Fukushiro S, Ackerman AB: Criteria for histologic differentiation of desmoplastic trichoepithelioma (sclerosing epithelial hamartoma) from morphea-like basal cell carcinoma. Am J Dermatopathol. 1985;7:207-211. Wick MR, Cooper PH, Swanson PE, et al: Microcystic adnexal carcinoma: an immunohistochemical comparison with other cutaneous appendage tumors. Arch Dermatol. 1990;126:189-194. Abesamis-Cubillan E, El-ShabrawiCaelen L, LeBoit PE: Merkel cells and sclerosing epithelial neoplasms. Am J Dermatopathol. 2000;22:311-315.

154. Hartschuh W, Schulz T: Merkel cells are integral constituents of desmoplastic trichoepithelioma: an immunohistochemical and electron microscopic study. J Cutan Pathol. 1995;22:413-421. 155. Krahl D, Sellheyer K: Monoclonal antibody Ber-EP4 reliably discriminates between microcystic adnexal carcinoma and basal cell carcinoma. J Cutan Pathol. 2007;34:782-787. 156. Hoang MP, Dresser KA, Kapur P, et al: Microcystic adnexal carcinoma: an immunohistochemical reappraisal. Mod Pathol. 2008;21:178-185. 157. George E, Swanson PE, Wick MR: Neuroendocrine differentiation in basal cell carcinoma: an immunohistochemical study. Am J Dermatopathol. 1989;11: 131-135. 158. Forbis R, Helwig EB: Pilomatrixoma (calcifying epithelioma). Arch Dermatol. 1961;83:606-618. 159. Moehlenbeck FW: Pilomatrixoma (calcifying epithelioma). Arch Dermatol. 1973;108:532-534. 160. Taaffe A, Wyatt EH, Bury HPR: Pilomatrixoma (Malherbe). A clinical and histological survey of 78 cases. Int J Dermatol. 1988;27:477-480. 161. Kaddu S, Soyer HP, Cerroni L, et al: Clinical and histopathological spectrum of pilomatricoma in adults. Int J Dermatol. 1994;33:705-708. 162. Marrogi AJ, Wick MR, Dehner LP: Pilomatrical neoplasms in children and young adults. Am J Dermatopathol. 1992; 14:87-94. 163. Kaddu S, Soyer HP, Hodl S, Kerl H: Morphological stages of pilomatricoma. Am J Dermatopathol. 1996;18:333-338. 164. Ter Poorten HJ, Sharbaugh AH: Extruding pilomatricoma: report of a case. Cutis. 1978;22:47-49. 165. Tsoitis G, Mandinaos C, Kanitakis JC: Perforating calcifying epithelioma of Malherbe with a rapid evolution. Dermatologica. 1984;168:233-237. 166. Zulaica A, Peteiro C, Quintas C, et al: Perforating pilomatricoma. J Cutan Pathol. 1988;15:409-411. 167. Alli N, Gungor E, Artuz F: Perforating pilomatricoma. J Am Acad Dermatol. 1996;35:116-118. 168. Lee WS, Yoo MS, Ahn SK: Anetodermic cutaneous changes overlying pilomatricoma. Int J Dermatol. 1995;34:144-145. 169. Shames BS, Nassif A, Bailey CS, Saltzstein SL: Secondary anetoderma involving a pilomatricoma. Am J Dermatopathol. 1994; 16:557-560. 170. Inglefield CJ, Muir IF, Gray ES: Aggressive pilomatricoma in childhood. Ann Plast Surg. 1994;33:656-658. 171. Aloi FG, Molinero A, Pippione M: Basal cell carcinoma with matrical differentiation. Am J Dermatopathol. 1988;10:509-513. 172. Sau P, Lupton GP, Graham JH: Trichogerminoma: report of 14 cases. J Cutan Pathol. 1992;19:357-365. 173. Mehregan AH, Baker S: Basaloid follicular hamartoma: report of three cases with localized and systematized unilateral lesions. J Cutan Pathol. 1985;12:55-65. 174. Anderson TE, Best PV: Linear basal cell nevus. Br J Dermatol. 1962;74:20-23. 175. Brown AC, Crounse RG, Winkelmann RK: Generalized hair follicle hamartoma: associated with alopecia, aminoaciduria, and myasthenia gravis. Arch Dermatol. 1969;99:478-493.

200. Starink TM, Kisch LS, Meijer CJLM: Familial multiple trichodiscomas: a clinicopathologic study. Arch Dermatol. 1985;121:888-891. 201. Moreno A, Puig LL, deMoragas JM: Multiple fibrofolliculomas and trichodiscomas. Dermatologica. 1985;171:338-342. 202. Duperrat B, Menanteau Y: Le fibrome perifolliculaire. Ann Dermatol Syphilol. 1969 ;96:121-128. 203. Pinkus H: Perifollicular fibromas: pure periadnexal adventitial tumors. Am J Dermatopathol. 1979;1:341-342. 204. Freeman RG, Chernosky ME: Perifollicular fibroma. Arch Dermatol. 1969;100:66-69. 205. Zackheim MS, Pinkus H: Perifollicular fibromas. Arch Dermatol. 1960;82:913-917. 206. Steigleder GK: Perifollikulaeres fibrom (zackheim und pinkus). Hautarzt. 1962; 13:370-371. 207. Miegel WN, Ackerman AB: Fibrous papules of the face. Am J Dermatopathol. 1979;1:329-340. 208. Reed RJ, Hairston MA, Palomeque RE: The histologic identity of adenoma sebaceum and solitary melanocytic angiofibroma. Dermatologica Int. 1966;5:3-7. 209. Sanchez NP, Wick MR, Perry HO: Adenoma sebaceum of Pringle: a clinicopathologic review, with a discussion of related pathologic entities. J Cutan Pathol. 1981;8:395-403. 210. Junkins-Hopkins JM, Cooper PH: Multiple perifollicular fibromas: review of a case and analysis of the literature. J Cutan Pathol. 1994;21:467-471. 211. Schachtschabel AA, Kuster W, Happle R: Perifollicular fibroma of the skin and colonic polyps: Hornstein-Knickenberg syndrome. Hautarzt. 1996 ;47:304-306. 212. Balus L, Fazio M, Sacerdoti G, et al: Fibrofolliculomes, trichodiscomes, et acrochordons: syndrome de Birt-HoggDubé. Ann Dermatol Venereol 1983;110: 601-609. 213. Birt AR, Hogg GR, Dubé WJ: Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977;113:1674-1677. 214. Foucar K, Rosen T, Foucar E, Cochran R: Fibrofolliculoma: a clinicopathologic study. Cutis. 1981;28:429-432. 215. Scully K, Bargmann H, Assaad D: Solitary fibrofolliculoma. J Am Acad Dermatol. 1984;11:361-363. 216. Weintraub R, Pinkus H: Multiple fibrofolliculomas (Birt-Hogg-Dubé) associated with a large connective tissue nevus. J Cutan Pathol. 1977;4:289-299. 217. Steffen C: Mantleoma: A benign neoplasm with mantle differentiation. Am J Dermatopathol. 1993;15:306-310. 218. Headington JT: Differentiating neoplasms of hair germ. J Clin Pathol. 1970; 23:464-471. 219. Carney JA, Headington JT, Su WPD: Cutaneous myxomas: a major component of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol. 1986;122: 790-798. 220. Aterhton DJ, Pitcher DW, Wells RS, MacDonald DM: A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata, and atrial myxoma: the NAME syndrome. Br J Dermatol. 1980;103:421-429. 221. Montgomery H, Winkelmann RK: Smooth muscle tumors of the skin. Arch Dermatol. 1959;79:32-40.

222. Fisher WC, Helwig EB: Leiomyomas of the skin. Arch Dermatol. 1963;88:510-521. 223. Sangueza P, Sangueza O, Sangueza L, Martin-Sangueza J: Eruptive and progressive cutaneous leiomyomatosis associated with cerebrovascular abnormalities and osteoma of the petrous bone. Med Cutan Ibero Latino Am. 1989; 17:169-173. 224. Beham A, Badve S, Suster S, Fletcher CDM: Solitary myofibroma in adults: clinicopathological analysis of a series. Histopathology. 1993;22:335-341. 225. Argenyi ZB: Recent developments in cutaneous neural neoplasms. J Cutan Pathol. 1993;20:97-108. 226. Megahed M: Palisaded encapsulated neuroma (solitary circumscribed neuroma): a clinicopathologic and immunohistochemical study. Am J Dermatopathol. 1994;16:120-125. 227. Ten Seldam REJ: Tricholemmocarcinoma. Australas J Dermatol. 1977;18:62-72. 228. Krumrey KW: The tricholemmal carcinoma: report of a case with review of the literature. Aktuel Dermatol. 1984;10:70-72. 229. Schell H, Haneke E: Tricholemmal carcinoma: report of 11 cases. Hautarzt. 1986;37:384-387. 230. Grouls V: Tricholemmale Keratose und tricholemmales Karzinom. Hautarzt. 1987;38:335-341. 231. Liang H, Wu H, Giorgadze TA, et al: Podoplanin is a highly sensitive and specific marker to distinguish primary skin adnexal carcinomas from adenocarcinomas metastatic to skin. Am J Surg Pathol. 2007;31:304-310. 232. Amaral A, Nascimento A, Goellner JR: Proliferating pilar (trichilemmal) cyst: report of 2 cases, one with carcinomatous transformation and one with distant metastases. Arch Pathol Lab Med. 1984;108:808-810. 233. Batman PA, Evans HJR: Metastasizing pilar tumor of the scalp. J Clin Pathol. 1986;39:757-760. 234. Dabska M: Giant hair matrix tumor. Cancer. 1971;28:701-706. 235. Dominguez-Arranz M, MorandeiraGarcia MJ, Arraiza-Goicoecchea A, et al: Malignant proliferative tricholemmal tumor: a clinical, morphologic, and ultrastructural study. Rev Esp Oncol. 1984;31:611-621. 236. Jaworski R: Malignant trichilemmal cyst. Am J Dermatopathol. 1988;10:276-277. 237. Kishimoto S, Miyashi A, Araki K, et al: Malignant proliferating trichilemmal cyst with metastasis. Acta Dermatol. 1982;77:125-129. 238. Mehregan AH, Lee KC: Malignant proliferating trichilemmal tumors: report of three cases. J Dermatol Surg Oncol. 1987; 13:1339-1342. 239. Saida T, Oohara K, Hori Y, Tsuchiya S: Development of a malignant proliferating trichilemmal cyst in a patient with multiple trichilemmal cysts. Dermatologica. 1983;166:203-208. 240. Weiss J, Heine M, Grimmel M, Jung EG: Malignant proliferating trichilemmal cyst. J Am Acad Dermatol. 1995;32:870-873. 241. Mori O, Hachisuka H, Sasai Y: Proliferating trichilemmal cyst with spindle cell carcinoma. Am J Dermatopathol. 1990;12:479-484. 242. Alvarez-Quinones M, Garijo MF, Fernandez F, Val-Bernal JF: Malignant aneuploid spindle cell transformation in

CHAPTER 28 ■ TUMORS WITH HAIR FOLLICLE AND SEBACEOUS DIFFERENTIATION

176. Brownstein MH: Basaloid follicular hamartoma: solitary and multiple types. J Am Acad Dermatol. 1992; 27: 237-240. 177. Bleiberg J, Brodkin RH: Linear unilateral basal cell nevus with comedones. Arch Dermatol. 1969;100:187-190. 178. Delacretaz J, Balsiger F: Hamartoma folliculaire multiple familial. Dermatologica. 1979;159:316-324. 179. Alessi E, Azzolini A: Localized hair follicle hamartoma. J Cutan Pathol. 1993; 20:364-367. 180. Robinson HN, Barnett NK: Hemifacial mixed appendageal tumor in an infant. Pediatr Dermatol. 1986; 3:406-409. 181. Requena L, Barat A: Giant trichoblastoma on the scalp. Am J Dermatopathol. 1993;15:497-502. 182. Schirren CG, Rutten A, Sander C, et al: Trichoblastoma: a tumor with follicular differentiation. Hautarzt. 1995;46:81-86. 183. Rosen LB: A review and proposed new classification of benign acquired neoplasms with hair follicle differentiation. Am J Dermatopathol. 1990;12:496-516. 184. Headington JT: Tumors of the hair follicle: a review. Am J Pathol. 1976;85:480-505. 185. Altman DA, Mikhail GR, Johnson TM, Lowe L: Trichoblastic fibroma: a series of 10 cases with a report of a new plaque variant. Arch Dermatol. 1995; 131:198-201. 186. Imai S, Nitto H: Trichogenic trichoblastoma. Hautarzt. 1982;33:609-611. 187. Wong TY, Reed JA, Suster S, et al: Benign trichogenic tumors: a report of two cases supporting a simplified nomenclature. Histopathology. 1993;22:575-580. 188. Aloi F, Tomasini C, Pippione M: Pigmented trichoblastoma. Am J Dermatopathol. 1992; 14:345-349. 189. Chan JK, Ng CS, Tsang WY: Nodular desmoplastic variant of trichoblastoma. Am J Surg Pathol. 1994;18:495-500. 190. Santa Cruz DJ, Barr RJ, Headington JT: Cutaneous lymphadenoma. Am J Surg Pathol. 1991;15:101-110. 191. Diaz-Cascajo C, Borghi S, Rey-Lopez A, Carretero-Hernandez G: Cutaneous lymphadenoma: a peculiar variant of nodular trichoblastoma. Am J Dermatopathol. 1996; 18:186-191. 192. McNiff JM, Eisen RN, Glusac EJ: Immunohistochemical comparison of cutaneous lymphadenoma, trichoblastoma, and basal cell carcinoma: support for classification of lymphadenoma as a variant of trichoblastoma. J Cutan Pathol. 1999;26:119-124. 193. Inaloz HS, Chowdhury MM, Knight AG: Cutaneous lymphadenoma. J Eur Acad Dermatol Venereol. 2001;15:481-483. 194. Pujol RM, Matias-Guiu X, Taberner R, Alomar A: Benign lymphoepithelial tumor of the skin (“cutaneous lymphadenoma”). Dermatol Online. 1999;5:5. 195. Okamura JM, Barr RJ: Cutaneous lymphoepithelial neoplasms. Adv Dermatol. 1997;12:277-294. 196. Pinkus H, Coskey R, Burgess GH: Trichodiscoma: a benign tumor related to Haarscheibe (hair disc). J Invest Dermatol. 1974;63:212-218. 197. Camarasa JG, Calderon P, Moreno A: Familial multiple trichodiscomas. Acta Dermatol Venereol. 1988;68:163-165. 198. Coskey RJ, Pinkus H: Trichodiscoma. Int J Dermatol. 1976;15:600-601. 199. Grosshans E, Dungler T, Hanau D: Le trichodiscome de Pinkus. Ann Dermatol Venereol. 1981;108:837-846.

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a proliferating trichilemmal tumor. Acta Dermatol Venereol. 1993 ;73:444-446. Waligora MJ, Chor PJ, Schneider TA, et al: Malignant proliferating trichilemmal tumor. Eur J Dermatol. 1993;3:279-281. Lopansri S, Mihm MC: Pilomatrix carcinoma or calcifying epitheliocarcinoma of Malherbe: a case report and review of the literature. Cancer. 1980;45:2368-2373. Gray M, Parhizgar B, Beerman H: Malignant pilomatrixoma. Arch Dermatol. 1984;120:770-773. Manivel JC, Wick MR, Mukai K: Pilomatrix carcinoma: an immunohistochemical comparison with benign pilomatrixoma and other benign lesions of pilar origin. J Cutan Pathol. 1986;13:22-29. Gould E, Kurzon R, Kowalczyk AP, Saldana M: Pilomatrix carcinoma with pulmonary metastases: a report of a case. Cancer. 1984;54:370-372. Van der Walt JD, Rohlova B: Carcinomatous transformation in a pilomatrixoma. Am J Dermatopathol. 1984;6:63-69. Weedon D, Bell J, Maize J: Matrical carcinoma of the skin. J Cutan Pathol. 1980; 7:39-42. Reed RJ, Lamar LM: Invasive hair matrix tumors of the scalp: invasive pilomatrixoma. Arch Dermatol. 1966;94: 310316. Martelli G, Giardini R: Pilomatrix carcinoma: a case report and review of the literature. Eur J Surg Oncol. 1994;20:703-704. Panico L, Manivel JC, Pettinato G, et al: Pilomatrix carcinoma. Tumori. 1994 ;80: 309-314. Sau P, Lupton GP, Graham JH: Pilomatrix carcinoma. Cancer. 1993 ;71: 2491-2498. Zagarella SS, Kneale KL, Stern HS: Pilomatrix carcinoma of the scalp. Aust J Dermatol. 1992;33:39-42. Niedermeyer HP, Peris K, Hofler H: Pilomatrix carcinoma with multiple visceral metastases: report of a case. Cancer. 1996;77:1311-1314. Liubskaia OG, Papadiuk VI: A rare case of malignant trichoepithelioma of the external acoustic meatus. Vestn Otorinolaringol. 1995;2:50-51. Aygun C, Blum JE: Trichoepithelioma 100 years later: a case report supporting the use of radiotherapy. Dermatology. 1993;187:209-212. D’Souza M, Garg BR, Ratnakar C, Agrawal K: Multiple trichoepitheliomas with rare features. J Dermatol. 1994;21: 582-585. San Juan EB, Guana AL, Goldberg LH, et al: Aggressive trichoepithelioma versus

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keratotic basal cell carcinoma. Int J Dermatol. 1993;32:728-730. Nakhleh RE, Swanson PE, Wick MR: Cutaneous adnexal carcinomas with mixed differentiation. Am J Dermatopathol. 1990;12:325-334. Rahbari H, Mehregan AH: Pilary complex carcinoma: an adnexal carcinoma of the skin with differentiation towards the components of the pilary complex. J Dermatol. 1993;20:630-637. Sanchez-Yus E, Requena L, Simon P, Sanchez M: Complex adnexal tumor of the primary epithelial germ with distinct patterns of superficial epithelioma with sebaceous differentiation, immature trichoepithelioma, and apocrine adenocarcinoma. Am J Dermatopathol. 1992;14:245-252. Wick MR, Swanson PE, LeBoit PE, Cooper PH: Lymphoepithelioma-like carcinomas of the skin with adnexal differentiation. J Cutan Pathol. 1991;18:93-102. Requena L, Sanchez-Yus E, Jimenez E, Roo E: Lymphoepithelioma-like carcinoma of the skin: a light microscopic and immunohistochemical study. J Cutan Pathol. 1994;21:541-548. Dahl I, Angervall L: Cutaneous and subcutaneous leiomyosarcoma: a clinicopathologic study of 47 patients. Pathol Eur. 1974;9:307-314. Fields JP, Helwig EB: Leiomyosarcoma of the skin and subcutaneous tissue. Cancer. 1981;47:156-169. Swanson PE, Stanley MW, Scheithauer BW, Wick MR: Primary cutaneous leiomyosarcoma: a histologic and immunohistochemical study of 9 cases, with ultrastructural correlation. J Cutan Pathol. 1988;15:129-141. Wolff M, Rothenberg A: Dermal leiomyosarcoma: a misnomer? Prog Surg Pathol. 1986;7:147-162. Choi EH, Ahn SK, Lee SH, Barg D: Hair follicle nevus. Int J Dermatol. 1992;31: 578-581. Komura A, Tani M: Hair follicle nevus. Dermatology. 1992;185:154-155. Happle R: Epidermal nevus syndromes. Semin Dermatol. 1995;14:111-121. Johnson MD, Jacobs AH: Congenital smooth muscle hamartoma. Arch Dermatol. 1989;125:820-822. Tsambaos D, Orfanos CE: Cutaneous smooth muscle hamartoma. J Cutan Pathol. 1982;9:33-42. Bronson DM, Fretzin DF, Farrell LN: Congenital pilar and smooth muscle nevus. J Am Acad Dermatol. 1983;8:111-114.

275. Slifman NR, Harrist TJ, Rhodes AR: Congenital arrector pili hamartoma. Arch Dermatol. 1985;121:1034-1037. 276. Goldman MP, Kaplan RP, Heng MCY: Congenital smooth muscle hamartoma. Int J Dermatol. 1987;26:448-452. 277. Darling TN, Kamino H, Murray JC: Acquired cutaneous smooth muscle hamartoma. J Am Acad Dermatol. 1993; 28:844-845. 278. Wong RC, Solomon AR: Acquired dermal smooth muscle hamartoma. Cutis 1985;35:369-370. 279. Chapel TA, Tavafoghi V, Mehregan AH, et al: Becker’s melanosis: an organoid hamartoma. Cutis. 1981;27:405-415. 280. Karo KR, Gange RW: Smooth muscle hamartoma: possible congenital Becker’s nevus. Arch Dermatol. 1981;117:678-679. 281. Urbanek RW, Johnson WC: Smooth muscle hamartoma associated with Becker’s nevus. Arch Dermatol. 1978;114: 104-106. 282. Sangueza OP, Requena L: Neurofollicular hamartoma: a new histogenetic interpretation. Am J Dermatopathol. 1994;16:150-154. 283. Barr RJ, Goodman MM: Neurofollicular hamartoma: a light microscopic and immunohistochemical study. J Cutan Pathol. 1989;16:336-341. 284. Nova MP, Zung M, Halperin A: Neurofollicular hamartoma: a clinicopathological study. Am J Dermatopathol. 1991;13:459-462. 285. Tuthill RJ, Clark WH Jr, Levene A: Pilar neurocristic hamartoma: its relationship to blue nevus and equine melanotic disease. Arch Dermatol. 1982;118:592-596. 286. Pathy AL, Helm TN, Elston D, et al: Malignant melanoma arising in a blue nevus with features of pilar neurocristic hamartoma. J Cutan Pathol. 1993;20: 459-464. 287. Pearson JP, Weiss SW, Headington JT: Cutaneous malignant melanotic neurocristic tumors arising in neurocristic hamartomas: a melanocytic tumor morphologically and biologically distinct from common melanoma. Am J Surg Pathol. 1996;20:665-677. 288. Mezebish D, Smith KJ, Williams J, et al: Neurocristic cutaneous hamartoma: a distinctive dermal melanocytosis with an unknown malignant potential. Mod Pathol. 1998;11:573-578.

CHAPTER 29 Sweat Gland Tumors Mark R. Wick Raymond L. Barnhill

BENIGN SWEAT GLAND NEOPLASMS

Eccrine Tumors Benign neoplasms showing differentiation toward the eccrine unit are generally the most commonly encountered adnexal cutaneous lesions. They may be found in virtually all topographic sites and are seen in children and adults alike. As discussed in the General Considerations of Chapter 28, various authors have suggested that a number adnexal neoplasms traditionally considered eccrine may in fact have

Eccrine Cylindroma CLINICAL FEATURES Several adnexal tumors with sweat glandular differentiation are observed with regularity in the skin of the face, neck, and scalp (Table 29-1). One such tumor, dermal cylindroma, may be encountered as a solitary sporadic nodular lesion or as a multifocal process in the context of the autosomal dominant “turban tumor” (Ancell-Spiegler) syndrome (Fig. 29-1A).4-9 In the latter condition, which has been mapped to the CYLD1 gene on chromosome 16q12-13,10 multiple raised reddish tumors may cover the entire scalp but may also involve the face and upper body. Cylindromas may develop at any age but are most commonly noted in young adults age 20 to 40 years and are more common in women. Although in most instances this tumor is asymptomatic, a certain proportion is reported to be painful. Cylindromas show an association with both eccrine spiradenoma and trichoepitheliomas involving the central face (Brooke syndrome).11 HISTOPATHOLOGIC FEATURES In either of these contexts, the neoplasm demonstrates two cell populations, one compact

Table 29-1 Eccrine Cylindroma

Clinical Features Head, neck, especially scalp Multiple tumors (turban tumors) Autosomal dominant Association with eccrine spiradenomas and trichoepitheliomas (Brook syndrome) Histopathologic Features Mosaic or jigsaw puzzle pattern of tumor islands Tumor aggregates delimited by basement membrane material that also results in “hyaline” droplets within aggregates Basaloid tumor aggregates with two cellular populations Outer layer composed of small, round cells with scant cytoplasm Inner layer comprised of larger polygonal cells with more abundant cytoplasm Irregular pattern at periphery of tumor (budding) Occasional mitotic figures Differential Diagnosis Basal cell carcinoma Eccrine spiradenoma

and basaloid and the other having a polygonal shape with more abundant amphophilic cytoplasm (see Table 29-1). Nuclear chromatin is dispersed, nucleoli are inconspicuous, and mitotic activity is typically limited in scope. Two salient aspects of this neoplasm facilitate its recognition on low-power microscopy; these are represented by a “jigsaw puzzle” growth pattern with angular cell nests that are molded to one another in a fibrous matrix (Fig. 29-1B), and the regular deposition of eosinophilic hyaline basement membrane material throughout the cellular clusters and immediately around them in the interstitium (Fig. 29-2). Tunggal and colleagues12 have suggested that the latter finding reflects defective processing of laminin 5 by the tumor cells. Cylindroma often displays an irregular pattern of peripheral growth, with “buds” of tumor being seen in the dermis or subcutis, seemingly detached from the main mass. This finding has no untoward prognostic significance and should not be used to label such lesions as malignant. Similarly, rare examples of cylindroma that exhibit easily appreciable mitotic activity show no adverse behavior if the nuclear characteristics and overall microscopic structure are characteristic of that tumor entity.13 As discussed subsequently, truly malignant tumors arising from eccrine cylindroma have a distinctive histologic configuration; they are composed of obviously anaplastic cells14 and lack the organoid qualities seen in banal sweat gland adenomas.

CHAPTER 29 ■ SWEAT GLAND TUMORS

Cutaneous neoplasms showing differentiation toward the sweat gland units are relatively uncommon specimens in general pathology but are not so uncommon in dermatopathology. Despite that fact, their histologic diversity—and the plethora of nosologic schemes that have been applied to them in the past—can be daunting at first glance. In this specific context, one is faced with a decision to adopt a stance of terminologic minimalism, using such diagnostic terms as benign sweat gland neoplasm or to embrace more eclectic nomenclature as applied to adnexal tumors. This chapter (and Chapter 28) presents a moderate stance in reference to the latter issue, using a classification system that is attuned as much as possible to concepts and terms that are commonly embraced in surgical pathology. Because of the relatively nondescript clinical features attending many sweat gland tumors, these are not covered in any detail except for lesions in which they are distinctive and contribute meaningfully to pathologic diagnosis. The topic of cutaneous adnexal neoplasia is a broad and complicated one; indeed, several entire textbooks have been devoted to it.1-3 Hence, the following material is intended to present a practical, diagnostically directed synopsis rather than an encyclopedic treatment of the subject, and interested readers are referred to the reference sources cited above for additional information (see General Considerations, Chapter 28).

apocrine lineages or have apocrine counterparts. Examples of these include cylindroma, spiradenoma, syringoma, poroma, and hidradenoma.

DIFFERENTIAL DIAGNOSIS Cylindroma must be distinguished from eccrine spiradenoma and basal cell carcinoma (BCC). As mentioned, there may be considerable overlap between cylindroma and spiradenoma, and some tumors may be hybrid lesions.15 The essential discriminating feature is the mosaic pattern of many small epithelial aggregates in cylindroma versus the isolated rounded tumor lobules that are often few in number in spiradenoma. BCC differs from cylindroma by showing frequent origin from the epidermis, peripheral palisading of nuclei, separation artifact (from the surrounding stroma), a mucinous stroma, and necrosis and mitoses.

Eccrine Spiradenoma CLINICAL FEATURES This tumor most commonly develops in young adults as a solitary skin-colored or bluish nodule usually smaller than 1 cm but occasionally up to 5 cm in diameter with a cystic or spongelike consistency on the ventral surfaces of

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

as a deeply seated tumor of the lower corium and subcutis.22 Otherwise, the potentials for deposition of basement membrane and irregular, permeative, peripheral growth of the lesion are common to spiradenoma and cylindroma. In occasional instances, it may be a challenge to distinguish between these two pathologic entities microscopically; indeed, some patients have been described who have Ancell-Spiegler syndrome as well as multifocal spiradenomatosis.8,9,17 Lee and Kelly18 have suggested that the two tumor types may be points in the same pathologic spectrum.

A

B  FIGURE 29-1 Cylindroma. (A) Multiple “turban” tumors involving the scalp. (B) Angular and ovoid nests of basaloid cells are molded to one another in a fibrous matrix. Hyalin matrical cylinders are conspicuous.

the upper body (Table 29-2). Multiple forms of spiradenoma have been reported, and they may be grouped or linear in configuration. Approximately half of spiradenomas have been described as painful and another third as tender.

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DIFFERENTIAL DIAGNOSIS The principal entities to be considered in the differential diagnosis include cylindroma, glomus tumor, and BCC. As discussed above, spiradenoma and cylindroma may overlap considerably. The various points in differential diagnosis are discussed above in the section on differential diagnosis for cylindroma. Both spiradenoma and glomus tumors may be vascular. Spiradenoma, in general, is distinguished from glomus tumor by the presence of a peripheral hyalinized basement membrane, hyaline globules within the tumor, the two-cell populations, and the presence of occasional tubular structures. Spiradenoma differs from BCC by the usual lack of connection to the overlying epidermis; the well-demarcated round, lobular character of spiradenoma; the presence of peripheral basement membrane material and hyaline globules within the tumor; the uniformity of cells versus that in BCC; and the lack of significant necrosis and mitotic figures in spiradenoma compared with BCC.

HISTOPATHOLOGIC FEATURES Eccrine spiradenoma differs in appearance only slightly from the histologic description just given for cylindromas. However, the first of these two neoplasms is generally devoid of a jigsaw puzzle profile and instead demonstrates the presence of intratumoral vascular spaces that are often

dilated and are most numerous at the periphery of tumor cell clusters (see Table 29-2 and Fig. 29-3). These channels may contain lymphatic fluid, erythrocytes, or both, and occasionally may be so prominent that they impart a vasogenic appearance to cylindroma at both the clinical and microscopic levels.16-20 Such lesions have been described as giant vascular spiradenomas.21 Other singular characteristics of spiradenoma include the regular distribution of mature lymphocytes throughout the neoplasm, much as one would see in tumors of the thymic epithelium (Fig. 29-4), and the capacity to present

Syringoma CLINICAL FEATURES Syringoma represents another benign eccrine proliferation that is likely malformative in nature rather than neoplastic in most instances. This tumor is commonly multifocal and is largely restricted to the skin of the upper face (particularly the lower eyelids) and the genital region (Fig. 29-5A and Table 29-3).23-32 However, solitary lesions do exist; in general, syringomas have a nondescript papular configuration, are usually white or yellowish, and measure 1 to 4 mm in diameter.25 A number of variants of syringoma have been described: plaquelike lesions; linear forms; variants localized to the penis, vulva, scalp, and acral surfaces; milia-like forms; eruptive and disseminated variants; and a form resembling

 FIGURE 29-2 Cylindroma. Hyalin matrical material is regularly dispersed in a basaloid cell proliferation.

confluent and reticulated papillomatosis of Gougerot-Carteaud.26 Familial examples have also been reported.33 HISTOPATHOLOGIC FEATURES Microscopically, small, comma-shaped tubules of cells, many of which manifest central

lumina and have luminal cuticles, are dispersed throughout a collagenous stroma in the dermis (see Table 29-3). The tumor cells are polygonal or flattened and have either eosinophilic or clear cytoplasm.23,25,31,32 The nuclei are compact, with no nucleoli or mitoses. Syringomas

DIFFERENTIAL DIAGNOSIS Syringoma must be distinguished from desmoplastic trichoepithelioma (DTE), morpheaform BCC, and microcystic adnexal carcinoma (MAC) (sclerosing sweat duct carcinoma). Syringoma may be distinguished from DTE by the presence of basophilic material within tubular lumina rather than keratinous material in general (occasional tubular structures near the epidermis in syringoma may contain keratinous material), the presence of eosinophilic cuticles lining the lumina in syringoma,

CHAPTER 29 ■ SWEAT GLAND TUMORS

demonstrate sharp circumscription on low-power histologic examination, and they lack mitotic activity, nuclear atypia, and infiltrative growth (see Figs. 29-5B and 29-6). Nevertheless, a small superficial biopsy through the center of such a tumor can provide an image that recapitulates a form of appendageal carcinoma,25 making excision the recommended initial approach to the management of syringoma, if at all feasible clinically. A clear cell variant shows the epithelial tubular structures to be composed of somewhat large cuboidal cells with pale or clear cytoplasm. This clear cell change results from glycogen accumulation and may be overrepresented in diabetic patients.34 The clear cell alteration may involve the entire tumor, a portion of the tumor, or only the cells lining the ductal lumina.

Table 29-2 Eccrine Spiradenoma

Clinical Features Trunk Ventral surfaces Skin-colored or bluish with cystic or spongelike consistency Painful or tender Histopathologic Features Rounded tumor lobules, often large and few in number No epidermal connection or jigsaw puzzle pattern Tumor lobules delimited by basement membrane material and contain hyaline droplets Smaller outer cell Larger inner polygonal cells Often highly vascular and infiltrated by lymphocytes Overlap with eccrine cylindroma Differential Diagnosis Basal cell carcinoma Eccrine cylindroma Vascular and glomus tumors

 FIGURE 29-3 Spiradenoma. An organoid pattern of epithelial cells is interrupted by dilated intratumoral vascular channels.

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Table 29-3 Syringoma

 FIGURE 29-4 Spiradenoma. Lymphocytes are scattered throughout the lesion.

A

Clinical Features Usually multiple Plaquelike, milia-like, linear, and eruptive variants Upper cheeks, below eyelids, genitalia, thighs Small, discrete, whitish or yellowish papules, 1-4 mm in diameter Histopathologic Features Superficial dermal well-defined tumor Small tubule or epithelial aggregates, often comma shaped Central lumina with luminal cuticle Polygonal or flattened tumor cells with eosinophilic or clear cytoplasm Absence of cytologic atypia, mitoses, and infiltrative growth Differential Diagnosis Basal cell carcinoma Desmoplastic trichoepithelioma Microcystic adnexal carcinoma

the common presence of clear cell change in cells lining the lumina in syringoma, and the much-less-frequent foreign body giant cell reactions to extruded keratin and dystrophic calcification that are typically seen in trichoepithelioma. Syringoma also tends to show tubular structures with a tadpole-like configuration much more frequently than does trichoepithelioma. In general, morpheaform BCC differs from syringoma by showing a less welldefined tumor, the presence of epidermal connection, the predominance of basaloid epithelial strands without ductal lumina or keratinous cysts, the frequent presence of perineurial infiltration, and much greater frequency of mitotic figures and necrotic cells compared with syringoma. Syringoma may be distinguished from MAC by the superficial and well-demarcated configuration of syringoma versus the deep infiltration of reticular dermis, subcutaneous fat, skeletal muscle, and cutaneous nerves by MAC. In addition, MAC may show follicular differentiation with prominent formation of keratinous cysts, more prominent epithelial lobules, and some degree of cytologic atypia with occasional mitoses.

Eccrine Poroma Group B

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 FIGURE 29-5 Syringoma. (A) Multiple skin-colored papules involve the eyelids and superior aspects of the cheeks. (B) Small ductules, some with inspissated secretory material, populate a densely fibrous stroma.

Poroma is a lesion that is so named because of a microscopic resemblance between epidermal and dermal components of this neoplasm and elements of the acrosyringeal–eccrine coil unit.35-41

Table 29-4 Eccrine Poroma

CLINICAL FEATURES Intraepidermal forms of poroma (hidroacanthoma simplex) are generally flat or slightly raised brownish lesions that often involve the lower extremities of older women (Table 29-4). There may be a slightly verrucous surface suggesting seborrheic keratosis. Other variants of poroma usually present as papules or nodules on the distal extremities, including the palms and soles, but they may be seen in any location. The surface may be keratotic or eroded and often suggests a verruca, pyogenic granuloma, or amelanotic melanoma. Children are potentially affected, as well as adults of all ages. Entirely dermal variants (dermal duct tumor) of poroma are usually nondescript papules or nodules. HISTOPATHOLOGIC FEATURES The hallmark of eccrine poroma is the presence of intraepidermal “lakes” of compact, monotonous polyhedral cells, which are sharply marginated from adjacent keratinocytes of the epidermis (see Table 29-4). The nuclei are bland, without nucleoli or significant mitotic activity, and the cytoplasm is moderate in amount and amphophilic.35-37,41 The form of poroma in which only an intraepidermal component is seen is called hidroacanthoma simplex42 (Fig. 29-7); conversely, the form in which a dermal component predominates, with the formation of ductlike spaces within tumor cell nests, is commonly known as dermal duct tumor43,44 (Fig. 29-8). Nonetheless, these represent the poles in a continuum, most members of which manifest cellular growth in both compartments of the skin (Fig. 29-9). Variations in the dermal

portion of poromas include the presence of focal squamous metaplasia; areas of clear cell changes; and sometimes extensive formation of glandular lumina, microcyst formation (“poroid” hidradenoma), or melanin deposition in the tumor cells.41,45-48 Divergent differentiation, with apocrine, sebaceous, or follicular elements, has also been observed in poromas.49,50 The usual features in each variant of this tumor are those of cytologic blandness and relative monotony. Nevertheless, occasional examples do demonstrate focal nuclear enlargement or nucleolation with or without limited mitotic activity.41 If the overall pattern of the lesion is still that of a banal poroma, one should not succumb to the temptation to label such tumors as malignant; true porocarcinomas show the mandatory presence of infiltrative growth, and foci of spontaneous necrosis are also common therein. Lastly, one sometimes encounters poromatous tumors that differ from usual lesions in this category by their possession of an acanthotic or papillomatous surface. Rahbari51 has suggested that the term syringoacanthoma be applied to such neoplasms, but they probably are variations on the basic structure of poroma. DIFFERENTIAL DIAGNOSIS Intraepidermal forms of poroma (hidroacanthoma simplex) raise the differential diagnosis of so-called intraepidermal epithelioma or the Borst-Jadassohn phenomenon. The major entities to be considered include clonal forms of seborrheic keratosis, squamous cell carcinoma in situ, mammary

and extramammary Paget disease, BCC, and melanoma in situ. In general, seborrheic keratoses of the clonal type do not exhibit epithelial cells as small as those observed in poroma or the association with intraepidermal sweat ducts. The other entities can be discriminated from poroma by characteristic histopathologic features; rarely, one might have to resort to immunohistochemistry to resolve the issue. Deeper variants of poroma must be distinguished from eccrine acrospiroma, BCC, and trichilemmoma and tumor of the follicular infundibulum. There may be considerable overlap between poroma and acrospiroma, and some authors believe them to be variations of a single entity. In general, poroma is characterized by a monomorphous population of basaloid cuboidal cells and tends not to show the squamous differentiation, large cystic

CHAPTER 29 ■ SWEAT GLAND TUMORS

 FIGURE 29-6 Syringoma. These characteristically shaped ductular elements are lined by cytologically bland cells. Mitotic figures are not present.

Clinical Features Hidroacanthoma simplex Lower extremities common Slightly raised verrucous plaques Skin-colored or brownish Poroma and dermal duct tumor Palms, soles, other sites Papules or nodules May have verrucous or moist, eroded surface Histopathologic Features Hidroacanthoma simplex Discrete intraepidermal nests of basaloid cuboidal cells Association with sweat ducts Poroma Anastomosing ribbons of cuboidal epithelium, sharply demarcated from epidermis Ductal structures Vascular stroma Uniformity of cuboidal epithelial cells Occasional focal atypia and mitoses Dermal duct tumor Rounded lobules of epithelium in dermis with little or no epidermal connection Differential Diagnosis Hidroacanthoma simplex Clonal seborrheic keratosis Squamous cell carcinoma in situ Basal cell carcinoma Paget disease Melanoma Poroma Acrospiroma Basal cell carcinoma Porocarcinoma

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moma and tumor of the follicular infundibulum by the lack of a hyalinized basement membrane at the periphery of the tumor, the degree of dyskeratosis noted in trichilemmoma, and often greater depth of involvement than typically observed in trichile-mmoma and tumor of the follicular infundibulum.

Eccrine Syringofibroadenoma

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Synonym: Acrosyringeal nevus

 FIGURE 29-7 Intraepidermal poroma (hidroacanthoma simplex). The epidermis is expanded by a monotonous population of small basaloid cells.

 FIGURE 29-8 Intradermal poroma (dermal duct tumor). Nests of cytologically uniform cells do not communicate with the overlying epidermis. Small, irregular, ductlike spaces are evident.

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spaces, and prominent clear cell change that typifies acrospiroma. Poroma differs from BCC by displaying a more organoid appearance, that is, fairly uniform anastomosing cords of epithelium, the general

lack of peripheral palisading of nuclei and separation artifact, the uniformity of the cuboidal cells, and the lack of consistent mitoses and necrotic cells throughout the tumor. Poroma differs from trichilem-

CLINICAL AND HISTOPATHOLOGIC FEATURES In the few cases reported, this exceedingly rare neoplasm usually presents as a nondescript solitary hyperkeratotic nodule on the extremities. Contrary to the implications of its name, eccrine syringofibroadenoma bears more of a visual resemblance to poroma than to syringoma. This rare neoplasm demonstrates a complex interconnection of regularly spaced cellular cords in the corium with others in the epidermis. The surface epithelium is generally hyperplastic and may be overtly pseudocarcinomatous; the dermal element features the presence of a variably cellular fibroblastic and vascular stroma between the epithelial cellular columns, which are definitely squamoid in character and may demonstrate small intercellular ductal lumina.52,53 Hence, the overall appearance simulates that of mammary fibroadenoma and has a vague likeness to fibroepithelioma of Pinkus (fibroepitheliomatous BCC). Weedon and Lewis54 have used the alternate designation of acrosyringeal nevus to describe syringofibroadenoma, preferring the interpretation that it represents a malformative proliferation of the terminal eccrine duct. That conclusion is supported by the results of immunohistochemical studies done by Takeda and colleagues.55 In any event, this lesion is typically sharply circumscribed and lacks nuclear atypia and mitotic activity in either component. It is likely that the stroma is “induced” by the epithelial proliferation in syringofibroadenoma, as is thought to be true of its counterpart in the breast. Bjarke et al56 also have documented several examples of this tumor that were admixed with porocarcinoma. DIFFERENTIAL DIAGNOSIS The major lesions to be considered are fibroepithelioma of Pinkus and a reticulated form of seborrheic keratosis. The syringofibroadenoma differs from the latter two entities by demonstrating a uniform population of cuboidal basaloid cells and the presence of ducts in the anastomosing bands of epithelium.

identical to that of localized, florid intraductal hyperplasia of the female breast; however, the potential for recurrence of this skin tumor attests to its neoplastic nature.

Papillary Eccrine Adenoma Synonym: Tubulopapillary eccrine hidradenoma CLINICAL AND HISTOPATHOLOGIC FEATURES This lesion develops as a dome-shaped nodule or plaque often measuring approximately 1 cm on the extremities and is more common in black women (Table 29-5). Papillary eccrine adenoma shows a basic composition by uniform polygonal cells that are aggregated into discrete multilayered ductal profiles in the corium, subdivided from one another by fibrovascular stroma of variable density. In addition, the tumor cells line the peripheral aspects of dermal microcysts and form intradermal tubulopapillary complexes57-62 (Fig. 29-10). The latter feature accounts for the designation of tubulopapillary hidradenoma that was applied to this tumor by Falck and Jordaan.63 Both eccrine and apocrine cytologic features may be observed in such lesions (hence, the synonyms tubular apocrine adenoma and papillary tubular adenoma),64 but eccrine differentiation is more common by far. Communication between cellular nests in the corium and similar aggregates in the epidermis may focally occur via columns of cells that superficially resemble the normal acrosyringia, as seen prototypically in poromas (see Eccrine Poroma Group above). Ductal spaces in these structures may contain luminal “cuticles,” as mentioned in reference

to syringoma. Cytologic attributes of papillary eccrine adenoma are again banal, without nucleoli, nuclear anaplasia, or appreciable mitotic activity (Fig. 29-11). The overall image is nearly

Table 29-5 Papillary Eccrine Adenoma

Clinical Features Women >> men Blacks >> whites Extremities Solitary dome-shaped nodule, about 1 cm in diameter Histopathologic Features Well-defined dermal tumor Epithelial aggregates containing cystic or ductal structures Multilayered and papillary appearance of the cystic/ductal structures The epithelium composed of polygonal cells Variable clear cell change and squamous differentiation No significant cytologic atypia or mitotic activity Fibrovascular stroma of variable density Eccrine >> apocrine features Differential Diagnosis Microcystic adnexal carcinoma Syringocystadenoma papilliferum Hidradenoma papilliferum Nipple adenoma Papillary eccrine carcinoma

CHAPTER 29 ■ SWEAT GLAND TUMORS

 FIGURE 29-9 Poroma. As evident in most examples of poroma, both intraepidermal and dermal elements are in continuity.

DIFFERENTIAL DIAGNOSIS The major entities to be considered include MAC, syringocystadenoma papilliferum (SP), hidradenoma papilliferum (HP), nipple adenoma, and papillary eccrine carcinoma. Although there may be some confusion between papillary eccrine adenoma and MAC, MAC differs from eccrine papillary adenoma by the prominence of keratinous cysts and often some degree of follicular differentiation, the lack of papillary differentiation as the predominant feature, deep infiltration, perineurial invasion, and frequent localization to the head and neck. Eccrine papillary adenoma and apocrine tubular adenoma, as discussed above, show considerable overlap and may be part of the same spectrum. Such apocrine tumors may differ only by showing greater or exclusive decapitation secretion. SP may be distinguished from eccrine papillary adenoma by a prominent cystic invagination lined by squamoid epithelium, prominent plasmacellular infiltrates in the stroma, localization to the head and neck area, and frequent association with nevus sebaceus. HP differs from eccrine papillary adenoma by its well-defined dermal nodular configuration, an almost exclusive localization to the vulvar and perineal area, and a predominance in women. Nipple adenoma may show significant overlap with eccrine papillary adenoma but is distinguished by its localization to the breast. In general, eccrine papillary carcinomas are characterized by larger size, infiltrating features, greater cellularity, more frequent necrosis, and greater numbers of mitoses than in eccrine papillary adenoma. However, in many instances, the latter distinction is quite difficult, and one must assess all features in arriving at a final interpretation.

Eccrine Acrospiroma Synonyms: Hidradenoma, solid-cystic hidradenoma, clear cell hidradenoma, clear cell myoepithelioma, nodular hidradenoma, nodular eccrine hidradenoma CLINICAL FEATURES These tumors often present as solitary nodules or sometimes as cystic lesions usually 1 to 2 cm (but occasionally up to 6 cm) in diameter (Table 29-6). They may occur in any

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Table 29-6 Eccrine Acrospiroma

 FIGURE 29-10 Papillary eccrine adenoma. Discrete ductular profiles, some with papillary intraluminal excrescences, loosely infiltrate the corium.

 FIGURE 29-11 Papillary eccrine adenoma. A peripheral cell layer of uniform basaloid cells is overgrown by a cytologically bland micropapillary proliferation.

location and affect women slightly more often than men.

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HISTOPATHOLOGIC FEATURES This form of eccrine adenoma has a micronodular growth pattern in the dermis, with each

of the nodules being composed of a monomorphous population of polygonal cells (see Table 29-6). These aggregates variably demonstrate internal microcystic change, with or without foci of ductal differentiation and the

Clinical Features Wide age range Women > men Almost any location Papule or nodule, 1-2 cm Often skin colored Histopathologic Features Frequent origin from epidermis Large lobular epithelial aggregates, well demarcated Often solid nodules of cuboidal cells with varying degrees of squamous differentiation and clear cell change Occasional focal spindled epithelial cells Ductal structures Cystic spaces Focal decapitation secretion Variable focal cytologic atypia and occasional mitoses Variable hyalinized stroma Differential Diagnosis Eccrine poroma Mixed tumor Squamous cell carcinoma

formation of lumina65,66 (Figs. 29-12 and 29-13). The latter characteristics led Winkelmann and Wolff67 to coin the term solid and cystic hidradenoma in reference to this neoplasm. The peripheral aspects of eccrine acrospiromas have a “pushing” interface with the surrounding dermal stroma, and the lesion is accordingly well circumscribed on scanning microscopy. This is the most important aspect of the tumor in assessing its biologic potential because even acrospiromas that show extremely bland cytologic features may recur if they exhibit budding or irregular peripheral permeation of the corium by cords of neoplastic cells (Fig. 29-14). Indeed, the latter lesions should be considered low-grade hidradenocarcinomas. Other features thought to predict aggressiveness in eccrine acrospiromas include broad zones of clear cell change, global nuclear anaplasia, areas of spontaneous tumor necrosis, and the presence of tumor giant cells.68 However, squamous metaplasia is a common finding in eccrine acrospiroma and has no untoward biologic significance. In fact, it is the underlying characteristic used by Stanley and coworkers69 to define the variant of this tumor known as epidermoid hidradenoma. Mitoses may sometimes be disturbingly obvious in acrospiromas, but as documented by Cooper, these do not imply

 FIGURE 29-13 Eccrine acrospiroma (hidradenoma). Small ductal lumens are evident at higher magnification.

CHAPTER 29 ■ SWEAT GLAND TUMORS

 FIGURE 29-12 Eccrine acrospiroma (hidradenoma). A solid nest of cells with focal ductal differentiation is sharply demarcated from the dermis.

a tumor may present with an intraepidermal portion resembling poroma (hidroacanthoma simplex) and with a deeper dermal component typical of acrospiroma. The final diagnosis may be based on the predominant features present. Other entities to be considered in the differential diagnosis of acrospiroma include mixed tumor (chondroid syringoma), squamous cell carcinoma, BCC, and a malignant form of acrospiroma. On occasion, there may be overlap between acrospiroma and mixed tumor, with some lesions showing prominent cystic spaces, hyalinized stroma, and anastomosing cords of epithelium. The final categorization must be based on the prominence of the stromal component in relationship to the other features present. Thus, for a diagnosis of mixed tumor, a lesion should exhibit a rounded configuration with a significant component of stroma, whether it is chondroid, myxoid, or hyalinized. In contrast, acrospiroma primarily exhibits nodular aggregates of epithelium. A proportion of acrospiromas may show prominence of squamous differentiation, raising the possibility of squamous cell carcinoma. However, careful examination should disclose the lack of significant atypicality and the presence of other features typical of acrospiroma, including ductal structures, cystic spaces, variable degrees of clear cell change, and a hyalinized stroma. Eccrine acrospiroma differs from BCC by the lack of peripheral palisading of nuclei, separation artifact, a mucinous stroma, and the overall basaloid appearance of the tumor that typifies BCC. Eccrine acrospiromas may show slight cytologic atypia and mitotic figures, raising the possibility of malignancy. In general, benign tumors are characterized by a well-circumscribed appearance without evidence of infiltration of the adjacent tissue, only modest nuclear atypia, and a mitotic rate that is usually less than 5 mitoses per 10 high-power field (hpf). Nonetheless, the presence of mitotic activity and cytologic atypia in acrospiroma has been correlated with an increased rate of local recurrence and indeed may be equated to low-grade malignancy.

APOCRINE NEOPLASMS 13

adverse behavior. Focal connections between neoplastic dermal cellular aggregates and the basal epidermis also are appreciated in roughly 50% of cases; this observation has, in part, prompted rather egalitarian authors to use the term acrospiroma as a broad designation that

encompasses tubulopapillary hidradenomas, nodular hidradenomas, and poromas.70 DIFFERENTIAL DIAGNOSIS As discussed above, there is considerable overlap between eccrine acrospiroma and the eccrine poroma group. In some instances,

Benign apocrine tumors are, in general, much less common than eccrine adenomas. Their topographic distribution is also more restricted; it largely centers on the head and neck, axillae, groin, and perineum, where normal apocrine glands are relatively prominent.

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seen. Cytologic atypia is variable but is generally unremarkable; however, tumors that have been subjected to mechanical trauma or other insults may show a frightening degree of nuclear pleomorphism and mitotic activity. Despite such findings, a well-documented case of malignant transformation in SP has yet to be described. Accordingly, simple excision represents adequate therapy for this lesion.

734

DIFFERENTIAL DIAGNOSIS Uncommonly, SP must be distinguished from HP. SP can be distinguished from HP in almost all cases by epidermal invagination and verrucous surface alteration and a location on the head or neck.

Hidradenoma Papilliferum  FIGURE 29-14 Eccrine acrospiroma (hidradenoma). Permeative growth may be seen at the periphery of some examples of acrospiroma and should lead one to consider a low-grade malignancy in such cases. Squamoid nests are commonly seen.

Syringocystadenoma Papilliferum CLINICAL FEATURES SP is a distinctive lesion that is largely, but not exclusively, restricted to the skin of the head and neck and particularly affects the scalp (Table 29-7). It is one of several neoplasms that may be associated with nevus sebaceus of Jadassohn, but it most often occurs as a sporadic tumor.71-75 Rarely, a linear extracranial configuration is encountered.76 HISTOPATHOLOGIC FEATURES The histologic attributes of SP are distinctive. As its name implies, the tumor has a papillary configuration, but it sits in a semicystic “dell” in the integument that is in continuity with the surface epithelium (see Table 29-7 and Fig. 29-15). At the interface between the epidermis and the neoplasm, keratinocytes give way to aggregates of cuboidal or low columnar glandular cells that often exhibit decapitation “snouts” at their apices. These elements line micropapillary structures with easily discernible fibrovascular cores, which are filled with plasma cells and other chronic inflammatory elements (Fig. 29-16). Tubular structures, lined by tumor cells, are seen to take origin from the base of the indentation (“cyst”) in which the tumor resides; these grow randomly into the subjacent and intervening dermis in a limited fashion, such that the

tumor has a circumscribed image on scanning microscopy. The neoplastic cells have compact oval nuclei and amphophilic to eosinophilic cytoplasms, and overt mucinous metaplasia may sometimes be

Table 29-7 Syringocystadenoma Papilliferum

Clinical Features Head and neck, especially scalp Solitary verrucous-like plaque or nodule Often moist or oozing surface Often 2-3 cm Frequently congenital and associated with nevus sebaceus Histopathologic Features Epidermal cystic invagination lined by squamous epithelium with transition to epithelial lining with two cell layers Often verrucous epidermal surface Cystic invagination contains papillary projections lined by luminal columnar cells and inner cuboidal cells Decapitation secretion The stroma of the papillary epithelial structures contains numerous plasma cells Background nevus sebaceus common Differential Diagnosis Nevus sebaceus Hidradenoma papilliferum

CLINICAL AND HISTOPATHOLOGIC FEATURES HP is a dermal neoplasm with a central cystic space into which cellular proliferations project (Table 29-8). It occurs almost exclusively in the genitoperineal skin in women,77-80 although rare examples have been described elsewhere in the body81 and in men. As implied by its name, the basic configuration of the intracystic component of HP is micropapillary; cells mantling the fibrovascular cores of the papillae are very similar in appearance to those in SP, as described above (Figs. 29-17 and 29-18); oxyphilic metaplasia is also possible in HP.82 However, there are more solid zones of cellular proliferation in HP, with more elaborately branching and interconnecting papillae than those seen in SP; limited extracystic dermal growth of tubular cell profiles may also be observed at the periphery of HP (Fig. 29-18). As is true of SP, the cytologic attributes of HP may occasionally be worrisome, and that feature has accounted for past misdiagnosis of the lesion as a malignancy.83,84 This problem may be avoided by attention to the characteristically circumscribed lowpower image of HP, as well as the regular presence of decapitation “snouts” on many individual tumor cells. Stefanato and colleagues described an unusual case of HP that was associated with extramammary Paget disease of the vulva.85 However, those authors concluded that such a concurrence of the two lesions was probably coincidental. DIFFERENTIAL DIAGNOSIS The major entities to be considered include SP and other apocrine adenomas, such as tubulopapillary adenoma. In general, HP is distinguished from other entities by its

Table 29-8 Hidradenoma Papilliferum

 FIGURE 29-15 Syringocystadenoma papilliferum. A papillary proliferation lines a semicystic depression in the dermis that is in continuity with the epidermis.

Tubular Apocrine Adenoma CLINICAL AND HISTOPATHOLOGIC FEATURES Tubular apocrine adenoma is, for all intents and purposes, largely synonymous with the apocrine counterpart of papillary eccrine adenoma (tubulopapillary hidradenoma) in regard not only to its clinical features but also to its basic histologic structure.63,64,88-90 However, occasional tumors have been described under this term that assumed more of the configuration of an acrospiroma but were composed of cells that had unequivocally apocrine cytologic characteristics (Fig. 29-19). One can decide on an individual basis whether to label such lesions as apocrine hidradenomas.

CHAPTER 29 ■ SWEAT GLAND TUMORS

Clinical Features Women, almost exclusively Vulva, rarely other sites such as breast, eyelid, ear canal Dome-shaped nodule with occasional bleeding pain, usually solitary Histopathologic Features Well-circumscribed dermal nodule, solid or cystic Usually no epidermal connection Complex pattern of anastomosing papillary structures, tubules Epithelial lining with myoepithelial cells and luminal columnar or cuboidal cells Decapitation secretion Occasional slight nuclear pleomorphism, mitoses Differential Diagnosis Syringocystadenoma papilliferum Tubular apocrine adenoma

DIFFERENTIAL DIAGNOSIS See the discussion above for differential diagnosis of papillary eccrine adenoma.  FIGURE 29-16 Syringocystadenoma papilliferum. Low columnar cells with apocrine-type decapitation secretion line inflamed fibrovascular cores. The cores are populated by a plasma cell–rich mononuclear infiltrate.

well-demarcated nodular appearance in the dermis, usually without epidermal connection, localization to the vulvar and perineal area, and almost exclusive occurrence in women. Nevertheless, the occasional appearance of HP in males, particularly in the anal skin,86 may cause confusion with

well-differentiated colorectal neoplasms. Careful attention to cytologic, architectural, and (if necessary) immunohistologic features of the tumor in question should be sufficient to make this diagnostic separation. In particular, hormonal receptor proteins are often present in HP87 but not in intestinal tumors.

SWEAT GLAND ADENOMAS SHOWING MIXED DIFFERENTIATION

Mixed Tumors of the Skin (“Chondroid Syringomas”) CLINICAL AND HISTOPATHOLOGIC FEATURES Mixed tumor of the skin (MTS) arises most often on the head and neck as a nondescript dermal or subcutaneous nodule (Table 29-9).91-93 However, this tumor may occasionally be sufficiently chondroid at a histologic level that it

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

 FIGURE 29-17 Hidradenoma papilliferum. This intradermal lesion is composed of variably sized cystic spaces into which papillary cellular proliferations project.

 FIGURE 29-18 Hidradenoma papilliferum. Frondlike growth and decapitation secretion are apparent.

736

assumes a hard consistency macroscopically. The latter potential—that is, for formation of cartilage-like matrix— accounts in part for the historic synonym that was applied to MTS; namely,

chondroid syringoma. That designation is not recommended because MTS is not universally chondroid and has little or no clinicopathologic resemblance to syringoma.

MTS represents a biologic paradigm for a nearly universal potentiality among human tumors. This is the ability for a primordial “stem cell” population (from which virtually all neoplasms emanate) to pursue divergent differentiation at a morphologic level into dissimilar target tissues.94 Electron microscopic and immunohistologic studies support the concept that all tumor cells in MTS are basically epithelial,94-97 but some of them acquire the capacity to assume cartilagelike, fibroblastoid, myoid, myoepithelioid, lipoid, or even osteogenic microscopic appearances. Hence, one is faced with a structural phenotype in which slightly branching tubules and clusters of epithelial cells with variable cytologic appearances (eg, eccrine, apocrine, sebaceous, pilar, mucinous, simple glandular, “hyaline” or plasmacytoid, or squamoid) are admixed intimately but randomly with zones of matrical tissue that look like cartilage, bone, muscle, myxoid mesenchyme, and fat, sometimes all in the same mass98-101 (Figs. 29-20 and 29-21). Thus, the name mixed tumor is particularly apropos because not only are epithelial and mesenchymal tissues interspersed, but the subtypes of those tissues also are heterogeneous, and their relative proportions are greatly variable. The cytologic characteristics of the individual cellular elements of MTS are generally bland, but occasionally prominent nucleoli and mitotic activity can be observed regionally or diffusely in the obviously epithelial component. Providing that the global image of the tumor is that of a well-circumscribed (but potentially multinodular) lesion, these findings have no biologic consequence.103 Similar comments apply to tumors showing focally dense spindle cell growth, limited necrosis, or clear cell change.103,104

DIFFERENTIAL DIAGNOSIS In general, the features of cutaneous mixed tumor are distinctive. Nonetheless, the differential diagnosis, on occasion, may include cutaneous cartilaginous tumors such as chondroma, lipoma variants,105 and other appendageal tumors, particularly eccrine acrospiroma. On occasion, some mixed tumors may show a limited epithelial component consisting of single epithelial cells and minimal tubular structures. Such tumors must be distinguished from cutaneous chondromas or lipomas. Careful examination of the tumor should reveal tubular structures. Rarely, however, these may not be present. It may be necessary to resort to immunohistochemistry to

distinguish these two processes. In addition, whereas mixed tumors are more common in the head and neck area, cartilaginous tumors are more commonly localized to the distal extremities and frequently show prominent calcification. In some cases, mixed tumor must be distinguished from eccrine acrospiroma. As previously discussed, a prominent stromal component is characteristic of mixed

tumor versus the predominance of a lobular epithelial proliferation in acrospiroma.

Other Mixed-Lineage Adnexal Adenomas Those who are experienced in examining appendageal tumors of the skin are accustomed to the fact that one regularly encounters lesions that are undoubtedly

MALIGNANT SWEAT GLAND TUMORS Over the past 30 years, substantial revisionism has occurred in reference to definitions of sweat gland carcinomas. One must no longer rely on metastasis as the only “reliable” determinant of aggressiveness in that context because several histologic factors have been delineated

CHAPTER 29 ■ SWEAT GLAND TUMORS

 FIGURE 29-19 Tubular apocrine adenoma. Unlike hidradenoma papilliferum, this lesion is composed predominantly of tubuloductal profiles, although a distinct pattern of apocrine secretion is retained.

benign but that show more than one route of epithelial adnexal differentiation. In that vein, admixtures of eccrine and apocrine, sudoriferous and pilar, pilar and sebaceous, or sweat glandular and sebaceous tissues may be observed in those neoplasms (Fig. 29-22). Rather than invoking the use of such terms as sebocrine adenoma, infundibular adenoma, or sebaceoma—as proposed by other authors106-108—or forcing the diagnosis into another ill-fitting nomenclatural compartment in describing lesions with the just-cited characteristics, the generic labels adnexal adenoma with divergent differentiation or mixed sweat gland adenoma109,110 are preferable. One can then provide the details of microscopic structure in a commentary in the diagnostic report and offer an opinion on which “standard” appendageal neoplasm is most related in a nosologic sense.

Table 29-9 Mixed Tumor (Chondroid Syringoma)

Clinical Features Head and neck, especially face Men > women Firm dermal or subcutaneous nodule Histopathologic Features Well-circumscribed dermal or subcutaneous lobular tumor Only rare epidermal connection Stromal component: variable chondroid, mucinous, hyalinized, or osteoid matrix Epithelial component heterogenous: eccrine, apocrine, sebaceous, pilar, simple glandular, or squamous differentiation Often small tubular lumina lined by cuboidal epithelium or complex pattern of anastomosing tubular lumina lined by one or two cell layers that are cuboidal or columnar Occasional prominent cystic spaces Differential Diagnosis Cutaneous chondroma Eccrine acrospiroma

 FIGURE 29-20 Benign mixed tumor (chondroid syringoma). An admixture of epithelial and stromal elements is conspicuous at low magnification.

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ECCRINE CARCINOMAS

 FIGURE 29-21 Benign mixed tumor (chondroid syringoma). Ductular and squamous epithelial elements permeate a chondroid–myxoid stroma.

ECCRINE CARCINOMAS THAT ARE DEFINABLE AS PRIMARY TUMORS

Eccrine Porocarcinoma CLINICAL FEATURES This tumor most commonly presents as a verrucous plaque or nodule with frequent ulceration, commonly measuring up to 5 cm in diameter and localized to the lower extremities, followed by the head and neck,112 upper extremities, and trunk (Table 29-10). In general, these tumors tend to present in older individuals, most frequently in the seventh decade of life. In many cases, there is a history of a relatively long-standing lesion.

 FIGURE 29-22 Adnexal adenoma with divergent differentiation. Small basaloid nests with focal sebaceous differentiation are seen.

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In general, the best model for understanding the range of microscopic patterns expressed by cutaneous eccrine malignancies is the spectrum of carcinoma morphotypes seen in the female breast.111 This similarity is not difficult to understand theoretically because it is widely acknowledged that the mammary glands represent large and somewhat specialized versions of the sudoriferous apparatus. In accord with this information, it is a logical extension for dermatopathologists to apply to sweat gland carcinomas a terminologic system that is similar to that used for breast cancer. One might also expect that whereas some malignant adnexal tumors will have clinicopathologic characteristics that are sufficiently singular as to ensure their primary nature, others are, for all intents and purposes, indistinguishable from metastases to the skin. These two major subgroups will be presented below.

that can be used as prospective predictors of potentially malignant behavior. The categorization of carcinomas of the sweat glands obviously represents a microcosm of the nosology of cutaneous adnexal neoplasms in general. One can either pursue a broadly based approach to classification, using the term sweat gland carcinoma to describe

most lesions, or one can adopt a more individualized approach. Because differential diagnostic considerations vary considerably in reference to various specific malignant sudoriferous tumors (and, selectively, biologic characteristics as well), a relatively detailed nomenclatural scheme for such neoplasms is again appropriate.

HISTOPATHOLOGIC FEATURES Eccrine porocarcinomas are notable for the high frequency of local recurrence, regional lymph node metastases, and a peculiar tendency to multiple epidermotropic metastases. Eccrine porocarcinoma is closely related clinically and structurally to ordinary eccrine poroma. The points of histologic dissimilarity between the benign and malignant lesions in this category include the presence in porocarcinomas of infiltrative growth (with desmoplastic stromal response); spontaneous tumor necrosis; obvious global cytologic anaplasia, with high nucleocytoplasmic ratios and nucleolation; extensive clear cell change; or perineural or vascular invasion97-105113-122 (see Table 29-10 and Fig. 29-23). Not all those

Table 29-10 Eccrine Porocarcinoma

features need be present to assign a diagnosis of malignancy; in fact, infiltrative growth is sufficient unto itself in this regard. Akalin and colleagues123 have shown that both poroma and porocarcinoma may demonstrate mutant p53 protein immunohistologically; thus, that determinant is not useful in a distinction between the two tumor types.

involve the epidermis, the particular microscopic attributes of eccrine porocarcinoma make the diagnostic consideration of metastasis to the skin from another organ site a largely academic matter. Isolated cases with intraepidermal growth have been documented in reference to metastatic carcinomas in the skin,131 but this eventuality is so uncommon that the authors have seen only two examples of it. In any event, recent publications have suggested that immune reactivity for keratins 5 and 6, p63 protein, or podoplanin might be useful in the differential diagnosis of adnexal carcinoma versus metastatic carcinoma in the skin. All three of those markers are more often observed in primary appendageal tumors.132-134 DIFFERENTIAL DIAGNOSIS Mainly intraepidermal forms of porocarcinoma must be distinguished from hidroacanthoma simplex, squamous cell carcinoma in situ, mammary and extramammary Paget disease, and melanoma (see previous discussion). Deeper forms of the tumor must be distinguished from invasive squamous cell carcinoma and malignant acrospiroma. In general, eccrine porocarcinoma is characterized by a small cuboidal cell population as opposed to somewhat larger cells in conventional squamous cell carcinoma. Porocarcinoma also shows prominent epidermal involvement and ductal or tubular structures. Porocarcinomas also have more frequent epidermal involvement as opposed to a more prevalent dermal location of malignant acrospiroma. Finally, in rare instances, cutaneous metastases must be differentiated from porocarcinoma. Careful clinicopathologic correlation may be needed to arrive at a final diagnosis.

CHAPTER 29 ■ SWEAT GLAND TUMORS

Clinical Features Older individuals, often > 60 years Lower extremities, head and neck, upper extremities, trunk Verrucous papule or nodule ≤ 5 cm in diameter High rate of local recurrence Regional lymph node metastases Tendency to multiple epidermotropic metastases Histopathologic Features Many features in common with poroma Infiltrative features Desmoplastic stroma often Tumor necrosis Cytologic atypia Mitoses Extensive clear cell change frequent Differential Diagnosis Eccrine poroma Squamous cell carcinoma Malignant acrospiroma Malignant trichilemoma Amelanotic melanoma

As expected, invasive porocarcinoma has both acrosyringium-like and dermal components, by definition. However, a solely intraepidermal form of the tumor has been recognized (and formally termed malignant hidroacanthoma simplex124-127) that falls into the category of Borst-Jadassohn lesions. As such, it shows the clonal, micronodular growth of atypical polygonal cells within the surface epithelium, yielding nests of tumor cells that are sharply marginated from adjacent keratinocytes. It may be necessary to perform immunostains, for such markers as carcinoembryonic antigen (CEA) or S-100 protein, to distinguish intraepidermal porocarcinoma (which is potentially CEA-positive and S-100 protein positive)128 from other histologic look-alikes such as clonal Bowen’s disease or seborrheic keratosis (both CEA-negative and S-100 proteinnegative) or melanoma in situ (CEAnegative and S-100 protein-positive).129 In addition, the scattering of single malignant cells throughout the epidermis— as typically seen in Paget disease of the skin or amelanotic superficial spreading malignant melanoma—is not a feature of porocarcinoma. The last of these considerations is particularly important in cases of porocarcinoma in which the neoplastic cells divergently synthesize melanin (often causing clinicians to make a diagnosis of melanoma), a wellrecognized but rare potentiality of that tumor.130 Together with the extreme rarity with which secondary cutaneous carcinomas

Malignant Acrospiroma This category of carcinoma, also called hidradenocarcinoma, probably encompasses a heterogeneous group of tumors, including porocarcinoma and clear cell eccrine carcinoma (CCEC). CLINICAL FEATURES The cases previously reported have presented as ulcerated nodules involving the head and neck area and extremities of older individuals (Table 29-11).1,2,17,121,135 In general, these tumors have been associated with frequent metastases.

 FIGURE 29-23 Eccrine porocarcinoma. The presence of necrosis helps to distinguish this cytologically atypical proliferation from architecturally similar examples of poroma.

HISTOPATHOLOGIC FEATURES In general, these are dermal-based tumors that are composed of lobules of polygonal clear cells with greater atypicality than that associated with benign acrospiromas

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Table 29-11 Malignant Acrospiroma

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Clinical Features Older individuals (50-70 years) Face and extremities Ulcerated nodules frequent Metastases frequent Histopathologic Features Three morphologic variants Polypoid configuration of tumor Sclerosing variant with marked desmoplasia Comedo variant showing central necrosis within lobular epithelial aggregates Dermal-based tumor composed of lobules of polygonal clear cells Occasional basaloid and squamous foci Ductal structures Degree of cytologic atypia varies from well differentiated to anaplastic Infiltrative growth pattern Mitoses usually significant in number Necrosis Differential Diagnosis Eccrine porocarcinoma Squamous cell carcinoma Sebaceous carcinoma Clear cell eccrine carcinoma

(see Table 29-11).1,2,17,121,135 Three morphologic variants have been described: tumors with a polypoid configuration, tumors characterized by marked desmoplasia, and comedo variants showing central necrosis within lobular epithelial aggregates. Both basaloid and squamous foci may occur to varying extents in a given tumor and may predominate over clear cell alteration. Ductal structures can be detected in the majority of cases. Particular features suggesting malignancy include cytologic atypia, infiltrative pattern at the periphery of the tumor, necrosis, and mitoses in significant number. It should be pointed out that cytologic features may vary from being well-differentiated to anaplastic.136 DIFFERENTIAL DIAGNOSIS The major entities to be considered include other clear cell epithelial malignancies such as porocarcinoma, CCEC, sebaceous carcinoma, tricholemmal carcinoma, squamous cell carcinoma, clear cell BCC, and occasional metastases to the skin. There is substantial overlap of malignant acrospiroma with porocarcinoma and CCEC, and such a distinction in some cases may be more artificial than a viable exercise. Separation of the former tumor from the other entities is based on predominant morphologic pattern;

particular features such as sebaceous differentiation (vacuolated cells); and on occasion, the use of other techniques such as special stains (for glycogen and lipid), immunohistochemistry, or electron microscopy.

Mucinous Carcinoma CLINICAL FEATURES Mucinous carcinoma is a distinctive tumor often presenting on the face and especially the eyelids as a skin-colored or occasionally slightly discolored nodule, measuring up to 3 cm in diameter (Table 29-12). In many cases, the tumor has a soft or spongelike consistency. The vast majority of tumors develop in older individuals in the sixth and seventh decades of life. It is possible that these tumors may be more common in men and African Americans. In general, mucinous carcinoma is prone to local recurrence but has a relatively low rate of regional lymph node metastasis. HISTOPATHOLOGIC FEATURES Mucinous eccrine carcinoma (MEC) represents a form of sweat gland carcinoma that lacks a benign counterpart (see Table 29-12). It is extremely similar, if not identical, histologically to mucinous (colloid) carcinoma of the breast or gastrointestinal tract. Thus, when this tumor is encountered in the skin, it often causes concern over the diagnostic possibility of metastasis from an occult visceral lesion. Nevertheless, on empirical grounds, this is not a known potentiality of mammary or alimentary tract mucinous carcinomas and may be dismissed for that reason. In other words, “colloid” carcinomas of the

Table 29-12 Mucinous Eccrine Carcinoma

Clinical Features Older individuals (50-70 years) Head and neck, especially eyelids, scalp Skin-colored or discolored nodule ≤ 3 cm in diameter Recurrences common Low rate of metastasis Histopathologic Features Aggregates of epithelial cells in lakes of mucin Epithelial nests may be solid, contain lumina, or show cribriform patterns Minimal cytologic atypia Mitoses uncommon Differential Diagnosis Metastases from the breast, gastrointestinal tract, and ovary (unlikely) Myxoid melanoma

breasts, stomach, and intestines do not ever involve the skin unless the patient has a long-standing and disseminated tumor137; these neoplasms appear to lack the ability to selectively affect the dermis early in the course of disease. Thus, as true of porocarcinomas, one can again use the histologic details attending MEC to render a certain interpretation that this cutaneous lesion is primary in nature. MEC is characterized by the presence of large extracellular pools of epithelial mucin in the dermis and possibly the subcutis, in which rounded or irregular nests and slightly branching cords of polyhedral tumor cells are suspended (Figs. 29-24 and 29-25). The overall growth of the lesion is infiltrative, and fibrovascular septa of variable width and prominence subdivide the epithelial elements and mucinous matrix in MEC.138-146 The nuclei are generally oval with dispersed chromatin and small nucleoli; the cytoplasm is amphophilic or slightly eosinophilic and may be vacuolated. Mitotic figures are usually limited in number, and vascular or neural permeation is relatively uncommon. The mucin produced in this tumor is strongly labeled by the mucicarmine or diastase-digested periodic acid-Schiff (PAS) methods; it also stains with the colloidal iron or Alcian blue techniques.141 In likeness to colloid carcinomas of the breast, cutaneous mucinous carcinoma may show “occult” neuroendocrine differentiation immunohistologically,147 with reactivity for such markers as synaptophysin and chromogranin in the tumor cells. DIFFERENTIAL DIAGNOSIS Virtually the only tenable differential diagnosis in cases of MEC is that of “hypermyxoid” mixed tumor of the skin. The distinction between those lesions is usually easily made by conventional microscopy in that the mesenchymoid zones of such mixed tumors do contain fusiform stromal cells, albeit widely scattered. In contrast, the mucinous pools of MEC are strictly acellular except for the neoplastic polyhedral cell clusters themselves. Results of histochemical investigations also differ in this context because the mucomyxoid stromal zones of mixed tumors are negative with the mucicarmine and PAS-D procedures.91 As discussed above, one must consider the possibility of metastatic mucinous carcinoma from the breast, gastrointestinal tract, or ovary.148 However, as mentioned above, the probability of an occult metastasis in the skin with features of mucinous carcinoma is almost nonexistent. If this does occur, it is

with MEC, cutaneous ACC can reasonably be considered to represent a primary tumor whenever it is encountered.

 FIGURE 29-24 Mucinous eccrine carcinoma. Rounded or irregular ductoglandular nests rest in a mucinous matrix.

 FIGURE 29-25 Mucinous eccrine carcinoma. Mucin pools dissect through the dermis. As in mucinous carcinomas in other sites, cords of malignant epithelial cells may only sparsely populate areas of the lesion.

usually a manifestation of very latestage disease. Note that metastatic breast carcinoma almost always follows obvious disease in the breast.

Adenoid Cystic Carcinoma of the Skin CLINICAL FEATURES Adenoid cystic carcinoma (ACC) represents a morphotype common to a number of organs and

tissues, including the salivary glands, respiratory tract, breast, skin, uterine cervix, thymus, and prostate gland. In each of these sites, the usual evolution of the tumor is one of relatively slow growth with aggressive local behavior; secondary spread to other locations occurs only late in the clinical course.145-152 The most common sites of cutaneous involvement are the scalp and chest. Thus, for most of the same reasons cited in connection

DIFFERENTIAL DIAGNOSIS Importantly, the dermal stroma adjacent to clusters of tumor cells in ACC does not show retraction artifact or fibromyxoid alteration, as seen in BCCs. This is a crucial distinction because most tumors thought to be cutaneous ACCs are actually adenoid BCCs (ABCCs).157 The overall growth pattern of both of those tumor types is infiltrative, and permeation of vascular adventitia and perineural spaces is potentially common to both of them as well. Additional minor points of difference between ACCs and ABCCs is that the latter neoplasm manifests the regular presence of apoptotic cells in the center of tumor cell nests and may even show cohesive foci of geographic necrosis, but those observations are rare in ACCs. Moreover, BCCs of all types commonly display evidence of multilinear differentiation (eg, a mixture of adenoid and pilar-keratotic foci) and may contain true melanin pigment. Such attributes are again not part of the morphologic spectrum of ACC. Whenever it is needed, immunostaining is again capable of distinguishing between these tumors; whereas ABCC is epithelial membrane antigen (EMA negative, ACC regularly expresses that marker.128,157 Moreover, immunoreactivity for keratin-7 or CD117 favors a diagnosis of ACC.165,166

CHAPTER 29 ■ SWEAT GLAND TUMORS

HISTOPATHOLOGIC FEATURES This neoplasm is believed to demonstrate eccrine differentiation; it is composed of a “pure” population of monomorphic basaloid cells that are arranged in tubules, elongated nests, and cords. Ductal lumina may be formed by the neoplastic elements, or they may enclose “cylinders” of mucoid matrix with a lightly basophilic hue. Another common feature is the deposition of linear profiles or globules of brightly eosinophilic basement membrane material in the intercellular spaces153-164 (Figs. 2926 and 29-27). Nuclei are compact, with dispersed chromatin and indistinct nucleoli; mitoses are sparse. Cytoplasm is scant and amphophilic.

Papillary Digital Eccrine Adenocarcinoma In 1987, Kao and coworkers167 published the seminal description of a distinctive group of eccrine neoplasms that are unique to the distal extremities, particularly the digits. Although these tumors were originally segregated into two

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adenocarcinoma (PDEA) in reference to such lesions is preferable. The most helpful image to bear in mind in reference to PDEA is that of invasive papillary largeduct carcinoma of the female breast111 because they are identical for practical purposes. Nevertheless, because metastasis to the skin of occult forms of the latter mammary tumor is empirically unknown, a differential diagnosis centering on that point is hypothetical rather than real. Thus, one may once more rightly conclude that a cutaneous lesion with the configuration of papillary adenocarcinoma is a primary neoplasm.

 FIGURE 29-26 Adenoid cystic carcinoma. Large angular clusters of basaloid cells are dispersed in the dermis. Uniform, rounded matrical cylinders interrupt these monomorphic basaloid nests.

HISTOPATHOLOGIC FEATURES On scanning microscopy, PDEAs feature the formation of macropapillae that project into large cystic spaces and, in addition, contain solid nests and tubules composed of polygonal cells that irregularly infiltrate the surrounding dermis and subcutis (see Table 29-13 and Figs. 29-28 and 29-29); involvement of the underlying bone may sometimes be present as well. Nuclear characteristics are bimorphic; one subgroup of PDEAs (so-called aggressive papillary digital adenomas) shows dispersed chromatin, small or indistinct nucleoli, and limited mitotic activity167,168 and may

Table 29-13 Papillary Digital Eccrine Adenocarcinoma

 FIGURE 29-27 Adenoid cystic carcinoma. Smaller clusters of atypical basaloid cells (with or without cylinders of basement membrane–like material) may loosely infiltrate the dermis.

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CLINICAL FEATURES These tumors most commonly present in older individuals as solitary nodules up to 2 cm in diameter localized to the fingers, toes, palms, and soles (Table 29-13). There is a high rate of local recurrence, and approximately 50% of tumors eventuate in distant metastases with a predilection for the lungs. Digital amputation may be necessary for control of the primary neoplasm in such cases.170

groups by those authors—as “aggressive digital papillary adenomas” and “aggressive digital papillary adenocarcinomas”— it is now considered that they represent

points in the same continuum of what is basically a family of universally malignant neoplasms.168,169 Thus, the more unifying term of papillary digital eccrine

Clinical Features Elderly individuals Digits, palms, soles Firm nodules Histopathologic Features Micropapillae projecting into cystic spaces Solid nests and tubules composed of polygonal cells Infiltration of surrounding tissue Nuclear features varying from dispersed chromatin and small nucleoli to vesicular nuclei with prominent nucleoli Differential Diagnosis Hidradenoma papilliferum

DIFFERENTIAL DIAGNOSIS On morphologic grounds, the only vaguely plausible differential diagnostic alternative to PDEA is that of HP, as described above, but that lesion is never observed on the digits and has never been documented convincingly in malignant form. Despite an overlap with PDEA in nomenclature, papillary eccrine adenoma forms micropapillae that project into tubular lumina171 (see above), unlike the features of the former lesion. Therefore, the comparative but dissimilar images of these two skin tumors correspond to papillary carcinoma versus intraductal hyperplasia of the breast.

 FIGURE 29-28 Papillary digital eccrine adenocarcinoma. Solid nests and papillary structures are evident in this intradermal neoplasm.

 FIGURE 29-29 Papillary digital eccrine adenocarcinoma. At higher magnification, areas of mitotic activity are associated with atypical cells with vesicular nuclei and prominent nucleoli.

accordingly be considered as the lowgrade member of the spectrum under consideration here. However, the second variant (ie, aggressive digital papillary adenocarcinoma) manifests vesicular nuclei; prominent nucleoli; numerous, often pathologically shaped, mitotic figures; and foci of spontaneous geographic necrosis167 (see Fig. 29-29). The latter

tumor is a more poorly differentiated form of PDEA. Perineural and lymphatic invasion may be observed regardless of tumor grade, but only poorly differentiated tumors in this category will produce distant metastases. Squamous metaplasia, and clear, ovoid, possibly myoepithelial cells are seen more often in low-grade than in high-grade PDEA.

In 1982, a peculiar tumor of the skin was recognized in which syringoma-like profiles of bland cuboidal epithelial cells—largely lacking nucleoli and mitotic activity—were seen to infiltrate the dermis and subcutis in a random and permeative fashion172 (Fig. 29-30). These cellular aggregates were occasionally punctuated by microcystic arrays containing pilar-type (trichilemmal) keratin. The name MAC was chosen to describe the lesion, which has, in the interim, been shown to demonstrate mixed eccrine and pilar differentiation.173-176 Cooper and colleagues177 assigned the synonym sclerosing sweat duct carcinoma in reference to the densely collagenized stroma that separates the tumor cell aggregates from one another in a variant of MAC that lacks pilar microcysts178; this neoplastic subtype had been referred to as anaplastic syringoma or syringoid carcinoma in the prior literature179,180 (Fig. 29-31). It is for those reasons that the tumor has been discussed in this section rather than in the section that considers mixed-lineage neoplasms (see below).

CHAPTER 29 ■ SWEAT GLAND TUMORS

Microcystic Adnexal Carcinoma

CLINICAL FEATURES MAC usually presents as an indurated lesion involving the face, particularly the upper lip, but also in other locations such as the axilla (Table 29-14). These tumors are generally perceived as slow-growing indolent tumors and may develop in individuals of any age, but especially in young women. The rate of local recurrence approaches 50%, but true metastasis is vanishingly rare, if it truly exists at all.181-185 A causal association with prior therapeutic irradiation has been noted in the past several years.185,186 HISTOPATHOLOGIC FEATURES The features of MAC are basically those that were just described above (see Table 29-14).

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Table 29-14 Microcystic Adnexal Carcinoma

Clinical Features Adults, age 20-76 years Women = men Face, especially upper lip, axilla Slowly developing indurated plaque or nodule Skin-colored, yellowish Local recurrence common Metastasis rare Histopathologic Features Small epithelial aggregates with keratinous cysts, especially superficially Solid epithelial islands and cords, some with lumina Fibrotic to densely sclerotic stroma Deeply invasive with frequent infiltration of subcutis, skeletal muscle, and nerves Minimal or low-grade atypia Mitotic figures generally uncommon Differential Diagnosis Syringoma Desmoplastic trichoepithelioma Morpheaform basal cell carcinoma Papillary eccrine adenoma  FIGURE 29-30 Microcystic adnexal carcinoma. Small, rounded or syringoid profiles consisting of basaloid and squamoid cells—some with keratinization—loosely infiltrate the dermis. cells.177 Another variant of MAC shows a predominance of keratinous microcysts, simulating the trichoadenoma of Nikolowsky.135 Nonetheless, this variant differs from the latter tumor in exhibiting syringoid cell profiles and deeply infiltrative growth as well. Interestingly, despite the obviously aggressive nature of this tumor, it lacks immunohistologic markers (such as p53 protein, Ki-67, bcl-2, and c-erbB-2 protein) that usually correlate with adverse biologic features.196 In accord with the general capacity for divergent differentiation in MAC, it should come as no surprise that occasional examples demonstrate sebaceous foci as well as eccrine and pilar elements.190

 FIGURE 29-31 Microcystic adnexal carcinoma. The absence of microcysts typifies a subset of microcystic adnexal carcinomas. Small angular clusters in these lesions are associated with a desmoplastic stromal response. The term sclerosing sweat duct carcinoma has been applied to such tumors.

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Infiltration of perineural sheaths, vascular adventitia, and even subjacent muscle is a common finding in this lesion.135,187-193 The neoplastic cells may focally aggregate themselves into whorled, concentric profiles in the dermis, and clear cell

change also has been described.194 The latter feature links MAC to “low-grade clear cell carcinoma,” as described by Cooper and colleagues.195 Secretory material can also be observed in the lumina of the syringoma-like profiles of

DIFFERENTIAL DIAGNOSIS The differential diagnosis of MAC does not include metastatic carcinomas of visceral origin, all of which would be expected to show a more confined growth pattern and a higher degree of cytologic anaplasia. Instead, other lesions that must be considered include conventional syringoma, DTE, morpheaform BCC, trichoadenoma, and primary adenosquamous carcinoma (ASC) of the skin. The last two of these entities are discussed in later sections of this chapter. Both conventional syringoma and DTE are distinguishable from MAC simply by attention to adequate clinical information.

Primary Cutaneous Adenosquamous Carcinoma CLINICAL FEATURES A primary neoplasm of the skin has been described that occurs more commonly on the head and neck, without regard to gender or age. This neoplasm demonstrates continuity with the epidermis and conjoint glandular and squamous differentiation microscopically and has been called ASC to distinguish it from MAC and other malignant adnexal neoplasms.202-204 The behavior of ASC has been aggressive, with seven of 10 patients in the largest series succumbing to their tumors or being likely to do so.202 Regional lymph node metastases were observed in some cases. HISTOPATHOLOGIC FEATURES One sees in ASC a growth pattern that closely simulates that of MAC, except that the lesion is multifocally connected to the epidermis in the former neoplasm, and the tumor cells show obvious nuclear anaplasia. As its name suggests, squamous

carcinoma-like and glandular foci are interspersed in ASC, with the adenocarcinomatous areas having a potential for mucinous differentiation as well.205 Mitoses are numerous, and zones of geographic necrosis may be evident. The same propensity for neural and vascular invasion that is manifested in MAC is also seen in ASC.202-204 DIFFERENTIAL DIAGNOSIS One must principally consider other primary tumors of the skin, rather than metastases, because of the prominent epidermal continuity that is appreciable in ASC cases. Obviously, one may have difficulty in excluding ordinary squamous carcinoma if only a small biopsy specimen is obtained; however, if foci of epidermal connection are not seen because of sampling limitations, metastases may indeed be considered diagnostically. Procurement of historical details—providing the information that ASC is a solitary, relatively slowly evolving lesion—is the best method for distinguishing between primary and secondary (multifocal and rapidly growing) adenosquamous tumors in this context. Last, one might consider ductal eccrine adenocarcinoma (DEA) with prominent squamous metaplasia (see below) as an alternative interpretation to one of ASC, but, as Banks and Cooper202 have indicated, the distinction between these two tumors may be somewhat arbitrary.

Primary Mucoepidermoid Carcinoma of the Skin Mucoepidermoid carcinomas (MEDCs) usually arise in the salivary glands or respiratory tree and assume a well-differentiated appearance histologically.206-208 In accord with the latter point, these tumors are slowly growing in most instances and only uncommonly metastasize to distant sites. When the latter eventuality occurs, it is virtually always after the primary neoplasm has been recognized and treated in some manner. These same precepts apply to involvement of the skin by metastatic MEDCs209-212; in other words, when this rare event is observed, it is in a patient who is known to have carcinoma historically rather than an occult visceral neoplasm. Hence, we would take issue with other authors over the contention that metastatic MEDC is a “mimic of sweat gland carcinoma.”209 HISTOPATHOLOGIC FEATURES There are points of difference between primary and metastatic MEDCs; whereas the latter

tumors are usually multinodular and show a sharp interface with the surrounding dermis or subcutis, primary neoplasms of this type have indistinct peripheries and grow as single nodules or with a uninodular predominance. There is also commonly an admixture of chronic inflammatory cells with the neoplastic elements in primary cutaneous MEDC but not in metastases. Otherwise, MEDCs in general are composed of polygonal squamous cells that are admixed with nondescript cuboidal tumor cells and obviously mucinforming cuboidal or low columnar elements.206-208 Mucin-filled microcysts also may be appreciated, as may areas of clear cell change.212,213 The nuclear features of all cell types in this tumor are bland, with only small inconspicuous nucleoli and dispersed chromatin; mitoses are sparse. Because of these attributes, we do not subscribe to the interpretation of Fernandez-Figueras and colleagues214 that primary cutaneous MEDC may represent simple mucinous metaplasia in otherwise banal squamous carcinoma of the skin. Irregular peripheral infiltration of the dermis is evident, and perineural or (rarely) lymphatic invasion may also be present. DIFFERENTIAL DIAGNOSIS The microscopic attributes of MEDC are so typical that the differential diagnosis is largely academic. It is conceivable that one might confuse MEDC with the pseudoneoplasticmetaplastic proliferative lesions of sweat glands that are sometimes seen in response to chronic mechanical or pharmacologic insults. Nevertheless, the latter processes rarely produce a mass lesion and should be separable from MEDC on that basis.

CHAPTER 29 ■ SWEAT GLAND TUMORS

All are predominantly facial lesions, but whereas the first two tumors are small, exquisitely circumscribed papulonodular lesions, MAC is an ill-defined, fixed plaque.23,177,197 Microscopically, an analogy to this information can also be observed; syringoma and DTE show a profile in which the dermal tumor is broader than it is deep, with sharply defined peripheral borders. In contrast, MAC extends to the base of even generous biopsy specimens and “shades off” into the surrounding tissue.25,197 Given these observations, one can readily appreciate the wisdom of diagnostic equivocation if faced with a shave biopsy containing a tumor that may represent MAC in the absence of clinical data. Morphea-like BCC shows more branched cellular nests than those seen in MAC, and luminal differentiation is not apparent therein; the stroma of the former of these lesions also shows a characteristic “cleavage” away from tumor cell clusters,198 but this feature is not evident in MAC. Immunoreactivity with Ber-EP4 favors, but is not definitive for, a diagnosis of MBCC as opposed to one of MAC.199 CD23 positivity has a converse utility.200 The lesion known as syringomatous adenoma of the nipple (SAN) is a tumor seen in the mammary skin in both men and women.201 In the past, it has been regarded as distinct from MAC. However, based on a comparison of their aggregated clinicopathologic features, we believe that SAN and MAC are one and the same.

Carcinoma Ex Dermal Cylindroma and Eccrine Spiradenoma Despite the knowledge that they are usually slowly growing tumors that may have been present for years before coming to clinical attention, sweat gland carcinomas do not generally derive from preexisting adenomas. The only exceptions to this general rule that have any frequency are carcinomas that evolve from “parent” cylindromas or spiradenomas.215 A good number of these neoplasms have been documented in the literature215-232; it appears that their presence is most often signaled by the rapid expansion of a previously indolent cutaneous nodule of long standing, with or without ulceration or pain (Table 29-15). For this diagnosis to be accepted pathologically, there must be remnants of the “parent” lesion along with a carcinomatous component in the

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 29-15 Carcinoma Ex Dermal Cylindroma and Eccrine Spiradenoma

746

Clinical Features Long-standing lesion with recent enlargement, ulceration, pain Common disparity between high-grade appearance of tumor and lack of aggressive behavior Histopathologic Features Remnant of benign cylindroma or spiradenoma Anaplastic epithelium in sheets or nests Epithelioid, stellate, or fusiform tumor cells with pronounced cytologic atypia Resemblance to squamous cell carcinoma, adenosquamous carcinoma, adenocarcinoma, clear cell adenocarcinoma, sarcomatoid carcinoma Prominent mitotic rate Differential Diagnosis Any anaplastic tumor

excised tissue (Fig. 29-32), or one must be able to confirm that a banal cylindroma or spiradenoma was removed previously from the exact site at which a sweat gland carcinoma is now present. Because of such restrictive requirements, it is beyond reason that one would diagnostically consider metastasis to the skin from a visceral carcinoma in this context. HISTOPATHOLOGIC FEATURES Remnants of the parent neoplasm have the typical

appearance of cylindroma or spiradenoma, as detailed above (see Table 29-15). The malignant elements most often assume the character of an undifferentiated carcinoma, showing sheets or clusters of nondescript but highly anaplastic epithelioid, stellate, or fusiform tumor cells with marked anisonucleosis, nucleolar prominence, cellular pleomorphism, and brisk mitotic activity.217,220,225 As such, the image of a “sarcomatoid” carcinoma may be encountered.230 Less commonly, more definable carcinoma morphotypes are reflected in the malignant components of carcinoma ex cylindroma or spiradenoma (CECS)215; these may include squamous carcinoma, ASC, or pure adenocarcinoma, and various subtypes of the last of these three possibilities may be evident (eg, clear cell adenocarcinoma). Under those circumstances, the only factor distinguishing such lesions from “ordinary” malignancies of the skin is the presence of the remnant adenoma. Leonard et al233 have reported a “low-grade” variant of CECS which nonetheless metastasized. We have not encountered such a lesion in our experience. Indeed, its diagnosis would be extremely problematic because benign spiradenomas and cylindromas often have a permeative, poorly circumscribed growth pattern. As another attestation to the possible kinship between spiradenoma and cylindroma, Carlsten and colleagues234 documented a malignant “hybrid” of both tumor types in two cases. The term spiradenocylindrocarcinoma was used to describe them.

One behavioral peculiarity of CECS merits some attention; that is, there may be an inexplicable disparity between the grade of the carcinomatous elements and the biologic evolution of the neoplasm. Several examples have been reported in which highly undifferentiated forms of CECS were attended by a lack of metastasis and long-term disease-free survival.222,225,226

ECCRINE CARCINOMAS THAT HISTOLOGICALLY SIMULATE METASTATIC TUMORS As implied in the foregoing discussion, for some forms of eccrine carcinoma, uncertainties of the clinical picture or the histologic appearance of the mass make it virtually impossible to exclude metastasis to the skin on routine microscopic evaluation. The following sections address such lesions.

Ductal Eccrine Adenocarcinoma DEA is perhaps the most common of the eccrine carcinomas. Its histologic features are virtually identical to those seen in “conventional” invasive ductal carcinoma of the breast,111 metastases of which, for obvious reasons, represent the principal differential diagnostic consideration.179,235 Obtaining a detailed clinical history of the skin lesion in question is therefore most important. CLINICAL FEATURES DEA is virtually always a solitary, slowly growing mass measuring up to 5 cm in diameter that has been present for many months or even years before the patient seeks medical attention (Table 29-16). In contrast, metastases of mammary carcinoma are typically multiple and occur in “crops” that manifest a rapid clinical evolution.235 The reason for emphasis on historical data is that, as one might expect, the detailed pathologic (ultrastructural and immunohistologic) features of ductal breast and eccrine carcinomas are identical; this synonymity even extends to the expression of estrogen and progesterone receptors by both tumors.236 DEA is notable for a relatively high rate of metastasis, that is, approximately half of the cases metastasize.

 FIGURE 29-32 Carcinoma ex eccrine spiradenoma. Invasive carcinoma is juxtaposed with residual benign spiradenoma.

HISTOPATHOLOGIC FEATURES The salient histologic characteristics of DEA include the proliferation of solid cords or tubules

Table 29-16 Ductal Eccrine Adenocarcinoma

of obviously atypical polygonal cells that randomly infiltrate the dermal connective tissue151,237-241 (see Table 29-16 and Fig. 29-33). Focal formation of ductal lumina is often apparent, and entrapped eccrine ducts may sometimes demonstrate the changes of carcinoma in situ.237 The intratumoral stroma is variably desmoplastic and may contain chronic inflammatory cells (Fig. 29-34). When such features

that of poroma and to be composed of compact, almost basaloid cells. Because of the concatenation of these features (ie, a fibromyxoid matrix and an epidermal connection to cords of relatively small polyhedral cells), a mistaken diagnosis of BCC may also be rendered in such cases. When selected circumstances (such as limited, artifactually distorted biopsy material) make it necessary, the latter problem can be addressed by performing immunostains for EMA. Virtually all forms of sweat gland carcinoma are EMA positive, but BCCs are consistently nonreactive for that determinant.128,244 Another variant of DEA is a form in which the neoplastic cells partially or globally assume a fusiform configuration.237 This feature may reflect the presence of myoepithelial differentiation, although that point has not been addressed systematically to date. The spindle cells are capable of focal concentric growth, yielding “tactoid”-like structures, and they often blend imperceptibly with conventional epithelioid areas. Lastly, uncommon examples of DEA have been described in which there was a histologic admixture of MEC-like foci, as described above; this pattern is mirrored in primary breast tumors as well.245 In such instances, the ductal adenocarcinomatous component confers a significant metastatic risk to the lesions (which approximates 40% overall for DEA).

CHAPTER 29 ■ SWEAT GLAND TUMORS

Clinical Features Solitary, slow-growing tumor ≤ 5 cm in diameter Approximately 50% metastatic Histopathologic Features Solid cords and tubules of polygonal cells Ductal structures Variable squamous differentiation Infiltrating features Variably desmoplastic stroma Cytologic atypia Mitotic figures usually readily apparent Differential Diagnosis Metastatic adenocarcinoma, particularly breast carcinoma Basal cell carcinoma Squamous cell carcinoma

are prominent (as they are in only a minority of cases), one can be somewhat confident of the primary nature of the neoplasm; however, their absence does not conversely equate with a diagnosis of metastatic disease. Nuclear chromatin is either dense or vesicular, and prominent nucleoli are commonly present; mitotic activity is almost always appreciable but may be limited in scope. Cytoplasm is usually amphophilic, and small intracytoplasmic vacuoles may be evident; welldefined areas of overtly squamoid differentiation are sometimes seen in DEA as well,242,243 such that differential diagnosis with a form of squamous cell carcinoma may be considered. One variant of DEA that is site-related has been termed ductal eccrine adenocarcinoma with fibromyxoid stroma (DEAFS).128,237 This lesion was probably included under the rubrics of malignant chondroid syringoma or syringoid carcinoma in the past, and the lesion occurs more commonly on the distal extremities (particularly the sole of the foot). As its name implies, DEAFS differs from “usual” DEA by its possession of a uniformly fibromyxoid stroma that recalls one of the attributes of cutaneous mixed tumor (Fig. 29-35). Other peculiarities of this tumoral subtype are its ability to communicate with the surface epithelium in a similar manner to

DIFFERENTIAL DIAGNOSIS Metastatic adenocarcinoma from the breast or a visceral site must be considered in the differential diagnosis of DEA. However, for practical purposes, only metastatic breast carcinoma closely resembles DEA and, as discussed above, may be indistinguishable from DEA without clinical information. Carcinomas with the appearance of DEA may occasionally be seen in the skin of the breast or the mammary tails in the axillae. The question arises under these circumstances as to whether the tumor is a primary cutaneous malignancy or a carcinoma of the breast proper. By convention, the diagnosis of sweat gland carcinoma of any type should not be made in the skin of the breast, and the clinician should be told to manage such cases as mammary parenchymal neoplasms. As mentioned above, other considerations in particular tumors include BCC and squamous cell carcinoma.

Clear Cell Eccrine Carcinoma  FIGURE 29-33 Ductal eccrine carcinoma. This solid and ductular proliferation is composed of pleomorphic cellular elements. Mononuclear inflammatory cells are evident within the tumoral stroma.

As suggested at intervals in the foregoing descriptions, several eccrine neoplasms feature the potential presence of

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

tumor cells with lucent cytoplasm are separated from each other by fibrovascular stroma of variable density. Nuclei may either be compact with evenly distributed chromatin and small nucleoli or vesicular with prominent nucleoli (Fig. 29-36). Mitotic activity is likewise heterogeneous from lesion to lesion. Spontaneous tumor necrosis and infiltration of perineural or perivascular spaces are other potential observations in CCEC cases.246,247

 FIGURE 29-34 Ductal eccrine carcinoma. Stromal desmoplasia may be prominent in some cases of ductal carcinoma.

Primary Malignant Mixed Tumor of the Skin (Carcinosarcoma)

 FIGURE 29-35 Ductal eccrine carcinoma with fibromyxoid stroma. In a small percentage of ductal eccrine carcinomas, cells appear more basaloid and form cords and nests that infiltrate a fibromyxoid matrix.

clear cell change; these tumors include acrospiromas, MACs, poromas, and mixed tumors of the skin. However, one particular type of eccrine malignancy is so dominated by clear cells that it derives its name from them, namely, CCEC.246,247 Nosologically, the latter lesion is most closely related to lowgrade malignant acrospiroma (hidradenocarcinoma),248-255 but its major significance derives from a potential pathologic confusion with metastases of renal cell carcinoma and other adenocarcinomas of urogenital or pulmonary origin.256-257

748

DIFFERENTIAL DIAGNOSIS As discussed above, the major concerns are metastases of renal cell carcinoma and other adenocarcinomas of urogenital or pulmonary origin.258,259 Importantly, one does not see “hobnail” cell profiles or intercellular blood lakes in CCEC, such as those that have been described in a proportion of clear cell carcinomas of urogenital or renal origins, respectively.256,257,260,261 Immunostains for CEA and the CA-125 glycoprotein are potentially discriminatory in this context as well. If the CEA stain is positive, such results would tend to militate in favor of CCEC because renal cell carcinomas are quite uniformly negative and clear cell urogenital carcinomas usually also lack CEA.244 Similarly, carcinomas of the female genital tract are expected to express CA-125 (and renal carcinomas may sometimes do so as well), but that determinant has not been seen in CCEC.

CLINICAL FEATURES The surest approach to excluding the possibilities discussed

above is to obtain detailed clinical information on the solitary or multifocal nature of the lesion and its duration of antecedent growth. In the same line of thought, it should also be remembered that whereas CCEC is most often seen in the skin of the head and neck, the metastatic tumors that may simulate it histologically show a predilection for the truncal surface.235 HISTOPATHOLOGIC FEATURES CCEC is a multilobulated dermal neoplasm that lacks connections to the epidermis and shows a vague peripheral interface with the surrounding dermis and subcutis. Broad sheets or large clusters of polyhedral

Contrary to intuitive expectations, the exceedingly rare neoplasms called malignant mixed tumors of the skin are not synonymous with carcinomas ex mixed tumors, as is true in the salivary glands. Instead, almost all reports of these cutaneous lesions have shown neoplasms that lack any type of “parent” adenoma and appear to represent de novo sweat gland carcinomas, BCCs, or squamous cell carcinomas manifesting divergent mesenchymal-like differentiation.262-272 An exception is the case reported by Sharvill,273 which is more aptly considered a carcinoma ex cutaneous mixed tumor. In the usual malignant mixed tumor, recognizable eccrine carcinoma morphotypes are admixed histologically with tissue foci resembling chondrosarcoma, osteosarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, or undifferentiated sarcoma, all in the same mass262-272 (Fig. 29-37). The biologic evolution of such tumors is again paradoxic in that relatively few of them have demonstrated aggressive behavior despite their alarming pathologic characteristics.

in the skin of the arms or legs and were solitary, nodular, tan-pink, nonulcerated tumors that had been present for at least 1 year before diagnosis. Two of the lesions metastasized to regional lymph nodes, and one proved fatal with distant spread to visceral organs.

 FIGURE 29-36 Clear cell eccrine carcinoma. At higher magnification, the cytoplasm is lucent, and the nuclei are variably pleomorphic.

DIFFERENTIAL DIAGNOSIS All of the other small cell tumors of the skin, including Merkel cell carcinoma as well as metastatic visceral neuroendocrine carcinoma, small cell melanoma, primitive neuroectodermal tumor or Ewing sarcoma, malignant lymphoma, and small cell (basaloid) squamous carcinoma, must be considered. Either electron microscopy or immunohistology are effective in recognizing BEC among the stated possibilities.1 Tables 29-17 and 29-18 outline the results of such studies.

CHAPTER 29 ■ SWEAT GLAND TUMORS

HISTOPATHOLOGIC FEATURES BEC is typified by nests and cords of small, uniform tumor cells with hyperchromatic or vesicular chromatin, distinct nucleoli, and obvious mitotic activity. Cytoplasm is scant and amphophilic, and single-cell necrosis or small foci of geographic necrosis is commonly present. The latter feature may produce zones of apparent microcystification. Lesional stroma in BEC cases is desmoplastic and moderately cellular, but the density of matrical blood vessels is low.

APOCRINE CARCINOMAS Similar to eccrine malignancies, apocrine carcinomas may be divided into those that are histologically distinctive as primary lesions and others that may simulate metastases from visceral tumors to the skin. These are considered as such below.

 FIGURE 29-37 Malignant mixed tumor of skin. Chondroid nests harbor nests of atypical epithelial cells in this case of malignant mixed tumor.

DIFFERENTIAL DIAGNOSIS Metastases to the skin from carcinosarcomas (more properly termed sarcomatoid carcinomas) of the kidney, lung, genital tract, and other sites274 must be excluded through clinical investigations before a diagnosis of primary cutaneous malignancy can be assigned confidently in these circumstances.

Basaloid (Small Cell) Eccrine Carcinoma Past treatises on sweat gland tumors have anecdotally mentioned the existence of a small cell variant of eccrine carcinoma, with “basaloid” features.1,179,275 In fact, Berg

and McDivitt179 mentioned 14 such neoplasms in their report on the subject in 1968, but it is likely that many of those cases ultimately proved to be examples of Merkel cell carcinoma as introduced by Toker in 1972.276 Matsuo and coworkers277 documented a similar case, which was classified as “small cell carcinoma of the skin, non-Merkel cell type,” and Busam and colleagues278 reported two additional lesions termed small cell sweat gland carcinoma, both of which arose in children. CLINICAL FEATURES The authors have seen several cases of basaloid eccrine carcinoma (BEC). All of the lesions arose

APOCRINE CARCINOMAS HISTOLOGICALLY DEFINABLE AS PRIMARY TUMORS Two forms of apocrine carcinoma have sufficiently singular attributes that they may reliably be diagnosed as primary cutaneous disorders. These are ductopapillary apocrine carcinoma (DPAC) and the apocrine type of mammary or extramammary Paget disease of the skin.

Ductopapillary Apocrine Carcinoma CLINICAL FEATURES DPAC is virtually identical to papillary digital eccrine carcinoma (see above) on architectural grounds (Table 29-19 and Fig. 29-38), but the first of these two tumor types is most

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 29-17 Ultrastructural Differential Diagnosis of Cutaneous Small-Cell Tumors

Table 29-19 Ductopapillary Apocrine Carcinoma

TUMOR

ICJ

TYPE I MF

NSG

MEL

MCL

PNFW

BEC MCC MSCC PNET/E SCMM SCSCC ML

+ + + + ± + 0

± Usually 0 0 0 0 + 0

0 + + ± ± 0 0

0 0 0 0 + 0 0

+ Usually 0 0 0 0 0 0

0 + ± 0 0 0 0

KEY: BEC = basaloid eccrine carcinoma; ICJ = intercellular junctional complexes; MCC = Merkel cell carcinoma; MCL = intercellular microlumina; MEL = premelanosomes; MF = microfilaments; ML = malignant lymphoma; MSCC = metastatic visceral small cell carcinoma; NSG = neurosecretory granules; PNET/ES primitive neuroectodermal tumor/Ewing sarcoma; PNFW = perinuclear filament whorls; SCMM = small cell malignant melanoma; SCSCC = small cell squamous cell carcinoma.

often encountered in the eyelids, axillae, and genitoperineal skin instead of the distal extremities.179,279-287 There may be an association with nevus sebaceus on the scalp or extramammary Paget disease in the groin. DPAC most commonly presents as a solitary, often multinodular, nondescript lesion measuring a few centimeters in diameter. DPAC often results in regional lymph node metastases followed by visceral spread in approximately 40% of cases. HISTOPATHOLOGIC FEATURES DPAC is definable as apocrine because the tumor cells possess a generous amount of finely granular eosinophilic cytoplasm, with or without decapitation “snouts” at the luminal aspects of tubular or microcystic profiles within the tumor (Fig. 29-39). Nuclear atypia is obvious, well beyond that which may be present in HP, and mitotic activity is easily appreciated.282 Similar to papillary eccrine carcinomas, DPAC manifests irregular infiltration of

the surrounding skin and may invade perineural sheaths or vascular adventitia. Histochemical and immunohistochemical studies of this tumor may be useful in helping to define its apocrine lineage when morphologic markers of it are less than definitive. The Prussian blue stain for iron is positive in the cytoplasm of tumor cells in DPAC (and apocrine tumors in general) in approximately 40% to 50% of cases,279 and immunostains for gross cystic disease fluid protein-15 (GCDFP-15, an apocrine-selective protein derived from fibrocystic mammary epithelium) are intensely and uniformly positive.244 DIFFERENTIAL DIAGNOSIS For the same reasons cited in connection with PDEA in the foregoing discussion of that tumor, the differential diagnosis is limited. Papillary carcinoma of the breast may have apocrine features in selected cases, but it lacks the capacity to metastasize to the skin in the absence of systemic

Table 29-18 Immunohistochemical Differential Diagnosis of Cutaneous Small-Cell Tumors

750

TUMOR

CK

CGA

CEA

S-100

LCA

MIC2

BEC MCC MSCC PNET/ES SCMM SCSCC ML

+ +a + 0 0 + 0

0 + (33%) + (30%–50%) 0 0 0 0

+ 0 ± 0 0 0 0

± 0 0 0 + 0 0

0 0 0 0 0 0 +

0 ± ± + 0 0 0b

KEY: CEA = carcinoembryonic antigen; CGA = chromogranin-A; CK = cytokeratin; LCA = leukocyte common antigen (CD45); MIC2 = p30/32MIC2 protein; S-l00 = S-100 protein. a Keratin reactivity in Merkel cell carcinoma typically shows a characteristic perinuclear globular pattern. b Lymphoblastic non-Hodgkin lymphoma may be MIC2-positive.

Clinical Features Older individuals Eyelids, axillae, genitoperineal skin Solitary multinodular lesion, usually a few cm in diameter Association with nevus sebaceus and extramammary Paget disease Frequent lymph node metastases and visceral metastases in 40% of cases Histopathologic Features Similar to digital papillary eccrine carcinoma Polygonal cells with finely granular eosinophilic cytoplasm Often decapitation secretion Infiltration of surrounding tissue Cytologic atypia and mitoses Prussian blue iron stain-positive in 40%-50% Gross cystic disease fluid protein-15 positive Differential Diagnosis Digital papillary eccrine carcinoma Hidradenoma papilliferum

dissemination. Thus, it would never present a worry with regard to its possibly occult existence as a cause of secondary skin disease. As mentioned, HP bears a superficial resemblance to DPAC, but it lacks the degree of nuclear atypia, architectural complexity, and infiltrative growth seen in the latter of these two lesions. Spontaneous necrosis and dystrophic calcification are also potential attributes of DPAC278-287 but are not observed in HP.

Paget Disease of the Skin, Apocrine Type Today’s conventional dogma still teaches that mammary and extramammary Paget disease of the skin represents two separate diseases. Whereas mammary Paget disease (MPD) is said to emanate from the “migration” of neoplastic cells into the epidermis from an underlying carcinoma of the breast,288 extramammary Paget disease (EPD) is thought to originate within the epidermis by the proliferation of primitive native stem (basal) cells with the potential for glandular differentiation.289-291 A somewhat iconoclastic and alternate view of this topic holds that both forms of pagetoid proliferation derive from the latter pathogenetic mechanism, as cited traditionally only in connection with EPD. Perhaps the strongest support for this opinion comes from the observation that approximately 3% to 5% of MPD cases are not found to be

unilateral, affecting mainly women age 40 to 60 years. The clinical findings usually suggest eczema or a related process. In contrast, EPD is much less common than MPD, develops in patients often older than 50 years of age, and affects men almost as frequently as women.

associated with an underlying carcinoma despite extensive sampling of the breast.292,293 Thus, we believe that MPD and EPD can be considered together as a unified disorder. Moreover, the classification of that condition as a principally apocrine tumor is justified by the results of GCDFP-15 immunostains, demonstrating positivity in the overwhelming majority of both MPD and EPD lesions.294 (It must be acknowledged that other cellular lineages are occasionally manifest in Paget disease, including sebaceous,

eccrine, and visceral–enteric pathways. However, these account for a small minority of cases.) CLINICAL FEATURES Both mammary and extramammary Paget disease present as erythematous scaling or weeping lesions involving the nipple and areolae on the one hand and extramammary sites such as the vulva, penis and scrotum, perineum, umbilicus, axillae, eyelids, and ear canal (Table 29-20) on the other. Mammary Paget disease is almost always

 FIGURE 29-39 Ductal growth in ductopapillary apocrine carcinoma. Finely granular eosinophilic cytoplasm and decapitation secretion are evident in this glandular neoplasm.

DIFFERENTIAL DIAGNOSIS One must consider pagetoid forms of amelanotic melanoma and “bowenoid” intraepidermal squamous carcinoma while acknowledging that those two lesions may occasionally coexist.301 Paget cells may contain granules of melanin, which are produced by neighboring melanocytes and secondarily engulfed by the tumor cells. Hence, this may lead to diagnostic confusion with melanoma. Conventional histochemistry can be helpful in confirming the diagnosis of Paget disease because neither melanoma nor squamous carcinoma produces mucin. Immunostains can also be beneficial diagnostically.128,129,294,300-305 Reactivity for CEA, GCDFP-15, CD23, or keratin-7 supports the diagnosis of Paget disease in the narrow context under discussion here.200,306 Additional positivity for CA19-9, uroplakin-III, or keratin type 20 in genitoperineal disease should direct attention to the possibility of an associated adenocarci-

CHAPTER 29 ■ SWEAT GLAND TUMORS

 FIGURE 29-38 Ductopapillary apocrine carcinoma. Architectural similarities between ductal apocrine and ductal eccrine carcinomas are obvious at low magnification, although the abundance of eosinophilic cytoplasm in the malignant epithelial cells may suggest apocrine differentiation.

HISTOPATHOLOGIC FEATURES Paget disease shows the presence of “foreign” epithelioid tumor cells within the epidermis (see Table 29-20 and Fig. 29-40). The adjacent skin commonly exhibits hyperkeratosis and acanthosis. The cells are dispersed singly or as small clusters throughout the surface epithelium. Typically, tumor cells in both MPD and EPD are round to ovoid and have pale, amphophilic cytoplasm, which is sometimes vacuolated (Fig. 29-41). The nuclei generally contain evenly distributed or vesicular chromatin, often with a discernible but small nucleolus; mitotic figures are infrequent.295-300 An “anaplastic” form of Paget disease has also been documented.260 This subtype manifests marked variation in the size, shape, and density of tumor cell nuclei, as well as anisocytosis. Another histologic idiosyncrasy of Paget disease is caused by its potentially confluent growth in the basal epidermis. Because the tumor cells have relatively poor intercellular cohesion, they often undergo detachment from one another. This phenomenon results in the formation of “pseudobullae,” which can imitate the acantholysis that typifies forms of pemphigus.275 Tumor cells in MPD and EPD contain mucopolysaccharides that are positive with PAS, mucicarmine, and Alcian blue methods in 50% to 60% of cases.

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Ductal Apocrine Carcinoma

Table 29-20 Mammary and Extramammary Paget Disease MAMMARY

EXTRAMAMMARY

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Clinical Features Age 40-60 years Women >> men Nipple and areolae

Often age 50 years Women ≥ men Vulva, penis and scrotum, perineum, umbilicus, axillae, eyelid, ear canal Erythematous oozing or scaling plaque

Erythematous oozing or scaling plaque Histopathologic Features Hyperkeratosis, parakeratosis Epidermal hyperplasia Epidermis permeated by aggregates of polygonal cells and single cells with abundant pale-staining or eosinophilic cytoplasm Lumen formation may occur Vesicular nuclei with prominent nucleoli Intracellular mucin stained by PAS-D, mucicarmine, Alcian blue in 50%-60% of cases Immunoreactivity for CEA, GCDFP-15, and keratin-7 Differential Diagnosis Squamous cell carcinoma in situ Pagetoid melanoma

noma in the rectum, urinary bladder, or endocervix,307-311 because those markers reflect the presence of a visceral immunophenotype in EPD. In contrast to eccrine carcinomas, extramammary Paget disease is consistently nonreactive for estrogen and progesterone receptor proteins but often exhibits positivity for androgen receptor protein.312,313

APOCRINE CARCINOMAS THAT MAY SIMULATE METASTASES There are basically two forms of apocrine carcinoma whose histologic images simulate those of metastatic tumors: ductal apocrine adenocarcinoma (DAA) and primary signet ring cell carcinoma of the skin. Their features are considered below.

CLINICAL AND HISTOPATHOLOGIC FEATURES As mentioned earlier in this chapter, the anatomic distribution of apocrine tumors in general is relatively restricted. In addition to this topographic relatedness, there are many similarities between the histologic attributes of DAA and DEA. Both are composed of irregular, randomly oriented proliferations of neoplastic ductal profiles in the dermis, with or without changes in entrapped sweat ducts that simulate those of carcinoma in situ of the breast. Obvious cytologic atypia, mitotic activity, spontaneous necrosis, and infiltration of nerves and blood vessels are features that are common to both of these two classes of apocrine gland carcinoma280-287,314,315 (Figs. 29-42 and 29-43). The distinguishing features of DAA are much the same as those of DPAC, namely, the presence of decapitation secretion snouts and abundant, finely granular, eosinophilic cytoplasm. Histochemical and immunohistologic findings also mirror those of DPAC, as described above. Thus, the only real (but nonetheless important) difference between these tumor variants is the potential for papillary differentiation in DPAC. DIFFERENTIAL DIAGNOSIS One must consider cutaneous metastases of those visceral adenocarcinomas that potentially feature a constitution by large “pink” cells; these metastases include apocrine tumors of the breast and selected carcinomas of the lung, kidney, adrenal gland, and liver.316 Immunohistologic evaluation for GCDFP-15 reactivity is capable of narrowing considerations to two tumor entities, DAA and apocrine carcinoma of the breast.128 Nevertheless, as is true of DEA, no reliable discriminators can be applied by the pathologist to refine the diagnosis further. Hence, any patient with a carcinoma of the skin showing an apocrine immunophenotype should have a thorough examination of the breasts—including mammography—before a diagnosis of DAA is made. Historical data concerning duration of lesional growth and potential multifocality are also essential in this process, as outlined above in reference to DEA.

Primary Signet Ring Cell Adenocarcinoma of the Skin

752

 FIGURE 29-40 Paget disease of the skin, apocrine type. Large epithelioid cells with clear cytoplasm infiltrate appear singly or in clusters in the epidermis.

CLINICAL AND HISTOPATHOLOGIC FEATURES Among all the favored skin fields for apocrine neoplasia, one of them—the eyelids—is the principal location in which

and they are displaced to the periphery of the cell by single cytoplasmic vacuoles that actually represent primitive lumina. Secretory material may be observed focally within such spaces. Necrosis is rare, and mitotic activity is usually surprisingly scant in PSRCA.

CHAPTER 29 ■ SWEAT GLAND TUMORS

 FIGURE 29-41 Paget disease of the skin, apocrine type. The nuclei are large and pleomorphic. The cytoplasm is clear or amphophilic.

DIFFERENTIAL DIAGNOSIS A metastasis should be favored when one is confronted with the microscopic image just cited because of the rarity of PSRCA. (The authors have seen only two cases in the past 10 years.) Several visceral organs have a capacity to harbor signet ring cell carcinomas, including the breasts, stomach, intestines, biliary tree, urinary tract, and female genitalia.320-323 Knowledge of the distribution of disease is helpful in diagnosis, because, as mentioned earlier, PSRCA is seemingly limited to the eyelids. In contrast, signet ring cell carcinomas of the abdominal and pelvic organs tend to metastasize to the skin of the trunk. Again, however, metastatic lobular carcinoma of the breast is capable of perfectly simulating the clinicopathologic attributes of PSRCA, including its immunophenotype.321 Thus, historical, physical, and mammographic information is paramount in securing a final interpretation.

Sweat Gland Carcinomas of Uncertain or Mixed Lineage Selected malignant adnexal tumors remain that are capable of exhibiting sudoriferous differentiation but exhibit this feature as histologically occult or simultaneous with obviously divergent appendageal elements. The two neoplasms in this group are lymphoepithelioma-like carcinoma (LELC) of the skin and adnexal carcinoma with mixed differentiation.

Lymphoepithelioma-like Carcinoma of the Skin  FIGURE 29-42 Ductal apocrine carcinoma. Randomly oriented ductal profiles are lined by cells with eosinophilic cytoplasm and apocrine snouts.

primary signet ring cell adenocarcinoma (PSRCA) is seen, as a nodular or plaquelike lesion.317 Only isolated cases have been reported in other “apocrine sites” such as the axilla.318,319 This information is useful in narrowing differential diagnostic considerations, but the possibility of metastasis still remains as a possibility in such cases. PSRCA exhibits the random growth of small epithelioid cells in the dermis,

subcutis, or both, and they are often arranged in single file or cords (Fig. 29-44). Small clusters of tumor cells may also be evident. Perineural invasion is apparent in only a small minority of cases, but this finding is particularly important because it tends to support a primary origin in the skin. Vascular invasion may be seen as well. The individual neoplastic cells have round nuclei with dispersed chromatin and small nucleoli,

In 1988, Swanson and coworkers324 described several cutaneous tumors that apparently arose in the skin primarily but that were seemingly identical microscopically to LELCs of the nasopharynx and other organ sites. CLINICAL AND HISTOPATHOLOGIC FEATURES These lesions were nondescript, slowly growing nodules, most often seen in the skin of the head and neck in adults (Table 29-21).324 Microscopically, they were composed of syncytial or vague clusters of large epithelioid cells in the dermis, with vesicular nuclear chromatin, prominent nucleoli, and obvious

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

LELCs are primitive appendageal neoplasms. Nevertheless, Lind and colleagues326 recently advanced the premise that LELC may be a common pattern rather than a distinctive entity, in analogy to such visceral neoplasms as “malignant rhabdoid tumor.” Interestingly, although the histologic features of cutaneous LELC are those of a largely undifferentiated epithelial proliferation, its biologic behavior is indolent, and few patients with LELC have had metastases of their lesions.324-336 Another intriguing fact is that, unlike LELCs of the nasopharynx, pharyngeal tonsils, salivary glands, and lungs, similar tumors of the skin do not exhibit integration of genomic nucleic acid from the Epstein-Barr virus upon in situ hybridization or polymerase chain reaction studies.325,337,338

 FIGURE 29-43 Ductal apocrine carcinoma. Vascular infiltration is a common feature in apocrine carcinomas.

Adnexal Carcinoma With Mixed Differentiation The examination of a meaningful number of cutaneous adnexal tumors cannot be done without realizing that some of

Table 29-21 Lymphoepithelioma-Like Carcinoma

 FIGURE 29-44 Primary signet ring cell carcinoma of the skin. Intracytoplasmic mucin droplets displace the nucleus, yielding the characteristic signet ring cell appearance.

754

DIFFERENTIAL DIAGNOSIS LELC must be distinguished from conventional adnexal carcinomas, ordinary poorly differentiated squamous cell carcinoma, neuroendocrine carcinoma, primary or metastatic melanoma, and lymphoma.

mitoses (Fig. 29-45). Mature lymphocytes permeated the lesions diffusely and surrounded them as well. Subsequent studies have shown that eccrine or pilar differentiation may be evident in LELC of the skin, with the focal formation of

intercellular ductal spaces or areas of trichilemmal-type keratinization.325 That information, together with the usual (but not exclusive) localization of the tumors to the corium—with no epidermal connection—makes it likely that most cutaneous

Clinical Features Older individuals (50-70 years) Head and neck, especially face and scalp Papules and nodules Histopathologic Features Sheets or nodular aggregates of polygonal cells with vesicular nuclei Monotonous appearance Occasional intracellular vacuoles and mucin Adnexal differentiation may be present Keratinization as in a pilar cyst Sweat gland differentiation Cytologic atypia Mitoses Dense mononuclear cell infiltrate Immunostaining: Cytokeratin positive Epithelial membrane antigen positive Differential Diagnosis Adnexal tumor, benign or malignant Squamous cell carcinoma Neuroendocrine carcinoma Lymphoma Melanoma

them defy predefined nosologic schemes. These most often exhibit bilinear or even multilinear differentiation, showing mixtures of eccrine, apocrine, sebaceous, and pilar elements. This phenomenon has been cited above in reference to adenomas, and it applies to appendageal carcinomas as well. Several tumors have been documented that amalgamate the features of DEA, porocarcinoma, “spiradenocylindrocarcinoma,” DAA, sebaceous carcinoma, pilomatrix carcinoma, and malignant proliferating pilar tumors (see Chap. 30), all intimately admixed within the same mass339,340 (Fig. 29-46). The most appropriate diagnostic label for such lesions is simply the descriptive one of adnexal carcinoma with mixed differentiation (ACMD). Basic recognition of these tumors as malignant is accomplished by attention to the features that have been stressed repeatedly throughout this chapter, namely, infiltrative growth, obvious cytologic anaplasia, spontaneous necrosis, and invasion of nerves or blood vessels. The behavior of ACMDs has been indolent, and no known fatalities have been ascribed to them.

inadequate, but exceptions to that caveat do occur. Such “pseudoneoplastic” adnexal lesions are considered below.

Eccrine and Apocrine Nevi Nevi (malformations) of the eccrine and apocrine apparatus are composed of cellular arrays that recall the images of embryonic sweat glands. Hence, they exhibit well-formed sudoriferous coils that are comprised of compact polygonal cells, sometimes with a luminal cuticle.

CHAPTER 29 ■ SWEAT GLAND TUMORS

 FIGURE 29-45 Primary lymphoepithelioma-like carcinoma of the skin. Syncytial clusters of large pleomorphic epithelial cells occasionally form ductal profiles, bespeaking their apparent adnexal attributes. The admixture of mature lymphocytes and plasma cells typifies this entity.

Each of these tubular aggregates is invested by a basement membrane, and small nerves may also be seen at the lesional periphery. The sweat gland units are slightly disordered structurally, and they are more numerous than those found in mature skin appendages341-351 (Fig. 29-47). This explains the fact that such lesions are commonly thought to represent such neoplasms as hidradenomas (acrospiromas) or syringomas. However, sweat gland nevi do not show the confluent cellular growth of the former of these two tumors or the “comma-tail” glandular configurations of the latter. The lesion known as eccrine angiomatous hamartoma (EAH) is, in all likelihood, also a nevocytic malformation that incorporates sweat glands and mesenchymal elements.352 The lesion commonly is seen in early childhood as a red, yellow, brownish, or tan papule or plaque on the distal extremities and may be associated with localized sweating and pain on palpation. Histologically, EAH differs slightly from uncomplicated adnexal nevi because it incorporates venular blood vessels and small nerve twigs between the nevoid sweat gland coils. These “extra” components probably explain the aforementioned pressure sensitivity of EAH.

Syringometaplasias Other lesions that resemble sweat gland nevi have been documented by Mehregan353 in patients with scarring alopecia or near keratoacanthomas or

PSEUDONEOPLASTIC LESIONS OF SWEAT GLANDS Occasionally, the pathologist may be faced with biopsy specimens in which reactive proliferations of the sweat glands invoke a consideration of neoplastic disease. This is most often true when clinical information on the case is

 FIGURE 29-46 Adnexal carcinoma with mixed differentiation. Areas of pilar keratinization are present in a clear cell and basaloid population that exhibits features of sebaceous differentiation.

755

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 756

 FIGURE 29-47 Eccrine nevus. An increased number of slightly disordered sweat glands form small lobules in association with a small peripheral nerve.

squamous cell carcinomas. Similar lesions may be observed in patients with fibrosing dermatitides,354,355 after infections,356,357 and adjacent to BCCs and malignant melanomas. Other authors have likewise documented the appearance of cutaneous syringoma-like proliferations—with the additional elements of squamous or mucin-forming glandular cells—after the use of oral nonsteroidal antiinflammatory and antineoplastic drugs358-361 (Fig. 29-48). Rarely, there is no known inciting agent or event.362 It is probable that these lesions are reactive

or metaplastic in nature (syringometaplasias) and arise after appendageal injuries. Several of them have regressed after removal of the offending agent.

Eccrine and Apocrine Hidrocystomas Selected cystic lesions of the eccrine and apocrine sweat gland units—usually seen on the face in patients living in warm climates—have variously been described as neoplasms or reaction patterns. Most often, these are termed eccrine and apocrine hidrocystomas,

 FIGURE 29-48 Syringometaplasia. Dermal appendageal injury often results in squamous metaplasia in the eccrine duct.

and they are characterized by dilatation of the sweat ducts and secondary proliferation, which is architecturally bland, of the ductal epithelium.3363-365 The latter phenomenon may produce micropapillary intraluminal cell profiles (as in so-called cystadenomas).366,367 Apocrine hidrocystomas have also been described as Moll gland cysts in the ophthalmologic literature.368 Tumefactions in this general category are probably pseudoneoplastic in nature and represent reactions to terminal sweat duct obstruction and inspissation of sweat glandular secretions. Some authors maintain that whereas the eccrine variant is more likely to be a retention cyst, the apocrine counterpart is a true organoid proliferation, hence the term cystadenoma. It must be emphasized that in many instances, one cannot easily categorize a lesion as clearly eccrine or apocrine. Such a discrimination in reality is probably not important, and describing the lesion simply as hidrocystoma should suffice. Also, apocrine hidrocystoma and cystadenoma are probably variants of a single pathologic entity based on the degree to which the cyst lining is proliferative. CLINICAL FEATURES Both eccrine and apocrine variants tend to present as skin-colored, bluish, or even blue-brown papules or nodules with a translucent quality (Fig. 29-49A and Table 29-22). The lesions generally measure less than 1 cm but on occasion may be larger or, rarely, giant (≤7 cm). The periorbital areas of the face are most commonly affected. Other sites may be involved such as the head, neck, and upper trunk and genital and perineal areas, particularly for apocrine variants. Such lesions occurring on the penis are best classified as a median raphe cyst. Most such lesions are solitary, especially the apocrine variant. Eccrine hidrocystomas may be numerous and exacerbated by heat exposure. HISTOPATHOLOGIC FEATURES The hidrocystomas, notably the eccrine forms, usually show a dilated cyst with edematous or compacted fibrous stroma that is occasionally hyalinized (see Table 29-22 and Fig. 29-49B). The epithelial lining consists of two layers of cuboidal epithelium, sometimes flattened, and in some instances, a single-cell layer. The epithelial lining may also show both hyperplasia and squamous metaplasia. In many cases, the cyst is connected to an eccrine duct. Apocrine variants exhibit an epithelial lining composed of a two-cell layer. The

A

B

inner (luminal) layer consists of cuboidal or columnar cells with decapitation secretion (snouts). The outer layer usually is composed of cuboidal or elongated myoepithelial cells. The epithelial lining may be proliferative and show papillary projections. On occasion, the latter proliferative foci may be somewhat cellular

and exhibit mitoses and slight cellular pleomorphism. DIFFERENTIAL DIAGNOSIS These lesions are usually distinctive. On occasion, one might consider other entities in the differential diagnosis because of squamous metaplasia or proliferation of the cyst

Table 29-22 Eccrine and Apocrine Hidrocystoma or Cystadenoma ECCRINE

APOCRINE

Clinical Features Usually adults Men = Women Periorbital sites but also head and neck, upper trunk Solitary > multiple Solitary almost exclusively Skin-color or bluish papules, nodules Commonly translucent Often <1 cm but rarely ≤ 7 cm Precipitated or exacerbated by heat Histopathologic Features Often dilated cystic structure in dermis Epithelial lining: One or two cell layers Cuboidal or flattened Squamous metaplasia Hyperplasia of lining

Differential Diagnosis Other cysts, eg. epidermoid cyst Papillary

Epithelial lining: Two cell layers Luminal cell is columnar or cuboidal with decapitation secretion Outer layer composed of myoepithelial cells (cuboidal or flattened) Hyperplasia of lining with papillary projections, folding Occasional mitoses, slight pleomorphism Other cysts Papillary adenoma carcinoma

lining. A papillary adenoma or even a malignant tumor might be considered in the latter instance.

Erosive Adenomatosis of the Nipple (Nipple Adenoma) By tradition, the lesion known as erosive adenomatosis of the nipple (EAN) or nipple adenoma369-376 has been included in discussions of cutaneous adnexal tumors. We believe that this decision has more historical than pathologic justification, inasmuch as the proliferation in question probably originates in the terminal subareolar mammary ducts rather than the skin of the nipple itself.369,375 However, for the sake of completeness, a brief discussion of EAN is included here.

CHAPTER 29 ■ SWEAT GLAND TUMORS

 FIGURE 29-49 Apocrine hidrocystoma. (A) Blue nodule beneath the lower eyelid. (B) Hidrocystomas are simple cysts of the sweat gland apparatus formed by dilatation of sweat ducts with secondary epithelial proliferation. The presence of cuboidal eccrine or low columnar epithelium further defines these cystic lesions.

CLINICAL FEATURES Erosive adenomatosis may present as a nondescript mass that is centered under the areolar complex, or it may also distort the nipple and cause eczematoid changes in the overlying skin. As such, EAN is in the macroscopic differential diagnosis of mammary Paget disease, especially because women between the ages of 40 and 90 years are principally affected.372,373 In light of these facts and the particular microscopic attributes of nipple adenoma, as described below, the latter condition has been misdiagnosed as a carcinoma. However, EAN is a uniformly benign lesion that may, in fact, have more in common with mammary fibrocystic change than with true neoplasms of the breast or skin. HISTOPATHOLOGIC FEATURES The usual lesions of EAN consist of proliferations of small glands that are centered on large

757

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 758

files are irregular, and many assume pointed images resembling the prows of ships. Entrapped lactiferous ducts demonstrate intraluminal papillary hyperplasia of ductal epithelial cells, but the rigid bridging patterns of ductal carcinoma in situ are usually absent. In reference to the latter point, however, occasional examples of EAN have featured an admixture of overt ductal breast carcinoma.372 Thus, it is notable that mitoses and foci of single-cellular or geographic necrosis are lacking or extremely scarce in uncomplicated EAN. However, squamous metaplasia, sometimes with formation of squamous microcysts, is a relatively common observation in the lactiferous ducts immediately beneath the skin surface in this condition. DIFFERENTIAL DIAGNOSIS MAC, as well as tubular carcinoma of the breast, must be considered in the differential diagnosis. The demonstration of muscle-specific actin-positive basal cells in each of the proliferating glands in EAN distinguishes it from those pathologic alternatives.310

 FIGURE 29-50 Erosive adenomatosis of the nipple (nipple adenoma). Ductopapillary proliferations are centered on large ducts and lactiferous sinuses beneath the skin of the nipple.

Cutaneous (Neonatal) Adnexal Polyp lactiferous ducts beneath the nipple (Fig. 29-50). The skin surface may be ulcerated or spongiotic and inflamed. The constituent glandular arrays of EAN are configured in a vaguely nodular fashion, but they lack the specialized stroma of true mammary lobules. “Pseudoinvasion” of lesional glands may be observed within

In 1975, Hidano and Kobayashi377 described a polypoid lesion of the skin, usually (but not always378) seen in the neonatal period, in which follicular, eccrine glandular, and sebaceous tissue was present in varying proportions. These elements demonstrate architectural disarray and variable levels of maturation.

bundles of the subareolar musculature. Two cell layers are evident in each gland, with basal elements being bluntly fusiform and occasionally possessing optically lucent cytoplasm. The luminal cells have bland oval nuclei, relatively abundant eosinophilic cytoplasms, and frequent apocrine snouts. Glandular pro-

Table 29-23 Immunohistochemical Findings in Sweat Gland Tumors and Differential Diagnostic Alternatives TUMOR

CK

EMA

CK7

CEA

S-100

GCDFP

CA19-9

CA-125

CD31

VIM

Benign and malignant eccrine neoplasms Benign and malignant apocrine neoplasms EPD and MPD Metastatic visceral carcinoma Melanoma Adenoid basal cell carcinoma Adenoid squamous carcinoma Epithelioid sarcoma Epithelioid angiosarcoma

+

+

7

±

±

±

0

0

0

±

+

+

+

±

0

+

0

0

0

0

+ +

+ ±

+ ±

+ ±

0 ±

± ±

± ±

± ±

0 0

0 ±

0 +

0 0

0 0

0 0a

+ 0a

0 0a

0 0

0 0

0 0

+ 0

+

±

±

0

0

0

0

0

0

±

+ ±

± 0

± 0

± 0

± 0

0 0

0 0

0 0

0 +

± +

KEY: CEA = carcinoembryonic antigen; CK = broad-spectrum cytokeratin proteins; CK7 = keratin type 7; EMA = epithelial membrane antigen; EPD = extramammary Paget disease; GCDFP = gross cystic disease fluid protein-15; MPD = mammary Paget disease; S-100 = S-l00 protein; VIM = vimentin. a Foci of divergent sudoriferous differentiation in basal cell carcinoma may show limited reactivity for these determinants

The most common location for cutaneous adnexal polyps is in the periareolar region of the chest, but they have also been reported in the genital skin.379 We consider them to represent a form of adnexal hamartoma.

11.

12.

Immunohistology does have some application in the differential diagnosis of sweat gland neoplasms, as referenced at several points in this chapter. However, this technique must be applied very specifically to tightly confined questions of interpretation because the immunophenotypes of sudoriferous tumors overlap with each other and—in the case of sweat gland carcinomas—with the antigenic profiles of visceral malignancies.1,128,236,244,380 Hence, the greatest utility of immunostains in this context is in the separation of sweat gland tumors from other primary skin lesions, such as variants of squamous cell carcinoma, BCC, malignant melanoma, and mesenchymal neoplasms with epithelioid cytologic features. Table 29-23 outlines the determinants of interest and expected reactivity patterns.

13.

REFERENCES 1. Wick MR, Swanson PE: Cutaneous Adnexal Tumors: A Guide to Pathologic Diagnosis. Chicago: ASCP Press; 1991. 2. Hashimoto K, Mehregan AH, Kumakiri M: Tumors of the Skin Appendages. Boston: Butterworth, 1987. 3. Abenoza P, Ackerman AB: Neoplasms with Eccrine Differentiation. Philadelphia: Lea & Febiger; 1990. 4. Sharma HS, Meorkamal MZ, Zainol H, Dharap AS: Eccrine cylindroma of the ear canal—report of a case. J Laryngol Otol. 1994;108:706-709. 5. Wollina U, Rulke D, Schaarschmidt H: Dermal cylindroma: expression of intermediate filaments, epithelial and neuroectodermal antigens. Histol Histopathol. 1992;7:575-582. 6. Crain RC, Helwig EB: Dermal cylindroma (dermal eccrine cylindroma). Am J Clin Pathol. 1961;35:504-515. 7. Goette DK, McConnell MA, Fowler VR: Cylindroma and eccrine spiradenoma coexistent in the same lesion. Arch Dermatol. 1982;118:273-274. 8. Welch JP, Wells RS, Kerr CB: AncellSpiegler cylindromas (turban tumors) and Brooke-Fordyce trichoepitheliomas: evidence for a single genetic entity. J Med Genet. 1968;5:29-35. 9. Cecchi R, Crudeli F, Fedi E, Giomi A: Multiple trichoepitheliomas, cylindromas, and eccrine spiradenomas observed in the same family. G Ital Dermatol. 1985;120:149-152. 10. Thomson SA, Rasmussen SA, Zhang J, Wallace MR: A new hereditary cylindromatosis family associated with

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CHAPTER 29 ■ SWEAT GLAND TUMORS

Immunohistochemistry of Sweat Gland Tumors

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372. Rosen PP, Caicco JA: Florid papillomatosis of the nipple: a study of 51 patients, including nine with mammary carcinoma. Am J Surg Pathol. 1986;10:87-101. 373. Goldman RL, Cooperman H: Adenoma of the nipple: a benign lesion simulating carcinoma clinically and pathologically. Am J Surg. 1970;119:322-325. 374. Brownstein MH, Phelps RG, Magnin PH: Papillary adenoma of the nipple: analysis of fifteen new cases. J Am Acad Dermatol. 1985;12:707-715. 375. Perzin KH, Lattes R: Papillary adenoma of the nipple (florid papillomatosis, adenoma, adenomatosis): a clinicopathologic study. Cancer. 1972;29:996-1009. 376. Diaz NM, Palmer JO, Wick MR: Erosive adenomatosis of the nipple: Histology, immunohistology, and differential diagnosis. Mod Pathol. 1992;5:179-184. 377. Hidano A, Kobayashi T: Adnexal polyp of neonatal skin. Br J Dermatol. 1975;92: 659-662. 378. Koizumi H, Itoh E, Ohkawara A: Adnexal polyp of neonatal skin observed beyond the neonatal period. Acta Dermatol Venereol. 1998;78:391-392. 379. Ost MC, Schlussel RN: a congenital scrotal mass consistent with an adnexal polyp of neonatal skin. Urology. 2002; 59:600. 380. Wick MR, Ockner DM, Mills SE, et al: Homologous carcinomas of the breasts, skin, and salivary glands: a histologic and immunohistochemical comparison of ductal mammary carcinoma, ductal sweat gland carcinoma, and salivary duct carcinoma. Am J Clin Pathol. 1998;109:75-84.

CHAPTER 29 ■ SWEAT GLAND TUMORS

353. Mehregan AH: Proliferation of sweat ducts in certain diseases of the skin. Am J Dermatopathol. 1981;3:27-31. 354. Sakai H, Satoh K, Manabe A, et al: Eccrine squamous syringometaplasia and syringomatous hyperplasia in association with linear scleroderma. Dermatology. 2002;204:136-138. 355. Sommer B, Hagedorn M, Wood F, Heenan P: Eccrine squamous syringometaplasia in the skin of children after burns. J Cutan Pathol. 1998;25:56-58. 356. Vargas-Diez E, Valks R, Fraga J, et al: Eccrine squamous syringometaplasia in a patient with phytophotodermatosis. Int J Dermatol. 1998;37:715-717. 357. Munoz E, Valks R, Fernandez-Herrera J, Fraga J: Herpetic syringitis associated with eccrine squamous syringometaplasia in HIV-positive patients. J Cutan Pathol. 1997;24:425-428. 358. Bhawan J, Malhotra R: Syringosquamous hyperplasia and eccrine squamous syringometaplasia associated with benoxaprofen therapy. Arch Dermatol. 1987;123: 1202-1204. 359. King DT, Barr RJ: Syringometaplasia: Mucinous and squamous variants. J Cutan Pathol. 1979;6:284-291. 360. Karam A, Labat JP, Leroy JP, Guillet G: Squamous syringometaplasia associated with docetaxel. Br J Dermatol. 2002;146:524-525. 361. Valks R, Fraga J, Porras-Luque J, et al: Chemotherapy-induced eccrine squamous syringometaplasia: a distinctive eruption in patients receiving hemato-

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CHAPTER 30 Fibrous and Fibrohistiocytic Tumors Stefan Kraft and Scott R. Granter

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

TUMORS OF FIBROUS TISSUE

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Tumors of fibrous tissue are common and histologically diverse. In addition, new entities continue to be described. The behavior and overall prognosis of these lesions is highly varied, so precise classification is required. It cannot be emphasized enough that the behavior of fibrous tumors may be difficult to predict based on traditional histologic concepts. For example, the morphologic features of some tumors, such as low-grade fibromyxoid sarcoma (LGFMS) and atypical fibroxanthoma, do not reflect their biologic behavior. For this reason, the pathologist should not attempt to predict the clinical behavior of mesenchymal tumors without a firm histologic diagnosis.

BENIGN FIBROUS PROLIFERATIONS AND TUMORS

Hypertrophic Scar and Keloid CLINICAL FEATURES Wound healing may be associated with an abnormal connective tissue response and result in exuberant scar formation. Hypertrophic scars and keloids occur most commonly in children and young adults (Table 30-1). They show a strong predilection for darkly pigmented races, particularly African Americans. Keloids occur most commonly in the head and neck, upper chest, and shoulder region. Most hypertrophic scars and keloids develop soon after surgical or other traumatic injury. Keloids are raised, shiny, smooth, and well-circumscribed plaques. They tend to extend beyond the original site of injury and may attain very large size through progressive growth and thereby become unsightly. Hypertrophic scars, in contrast to keloids, do not usually extend beyond the site of original injury and tend to regress with time. HISTOPATHOLOGIC FEATURES Early scars may be fairly cellular and are composed

Table 30-1 Hypertrophic Scar and Keloid

Table 30-2 Fibroepithelial Polyp

Clinical Features Most common in children and young adults Keloids Predilection for African Americans Head and neck, upper chest, and shoulder region Raised, shiny, smooth, and wellcircumscribed plaques Extend beyond the original site of injury Tend to grow progressively Hypertrophic scar Does not extend beyond the original site of injury and tends to regress Histopathologic Features Early scars: fairly cellular, fibroblasts arranged in parallel array Sparse chronic inflammatory cells may be present Cellularity decreases and collagenization increases with age Long, slender blood vessels oriented perpendicularly to the epidermis Keloids have thick bands of “glassy” hyalinized collagen Differential Diagnosis Dermatofibroma Fibromatosis

Clinical Features Commonly involve the skin of the neck and axillary area of middle-aged and elderly adults Frequently multiple 1-15 mm in size Polypoid, soft, and attached by a thin fibrovascular stalk Often slightly hyperpigmented Histopathologic Features Polypoid with a collagenous core of loosely textured to dense sclerotic collagen Soft fibromas are larger with adipose tissue Epidermis may show features of lichen simplex chronicus or seborrheic keratosis Differential Diagnosis Seborrheic keratosis Nevus lipomatosus superficialis Angiofibroma Pedunculated nevus

perpendicularly to the epidermis are not seen in fibromatosis.

Fibroepithelial Polyp and Soft Fibroma Synonyms: acrochordon, skin tag

of plump myofibroblasts and fibroblasts arranged in parallel array (see Table 30-1). Sparse chronic inflammatory cells may be present, particularly in early scars. As the scar ages, cellularity decreases, and collagenization increases. A characteristic feature of hypertrophic scars, which often tend to be nodular, is the presence of long, slender blood vessels oriented perpendicular to the epidermis. Keloids are similar histologically to hypertrophic scars but with the addition of characteristic thick bands of “glassy” hyalinized collagen. DIFFERENTIAL DIAGNOSIS The hyalinized bands of collagen seen in keloids are distinctive, so these lesions rarely pose a diagnostic problem. Dermatofibroma is distinguished from hypertrophic scar by its storiform pattern and characteristic entrapment of collagen bundles. The epidermis is usually hyperplastic in dermatofibroma and atrophic in hypertrophic scars. Fibromatosis is distinguished from scars by increased cellularity, longer sweeping fascicles, and a more infiltrative growth pattern; furthermore, a superficial location would be exceptional, except in palmar, plantar, and penile sites. Blood vessels oriented

CLINICAL FEATURES The fibroepithelial polyp, also know as skin tag or acrochordon, is a common skin lesion. It is polypoid, soft, often slightly hyperpigmented, and attached by a thin fibrovascular stalk. Fibroepithelial polyps are most common in middle-aged and elderly adults, are frequently multiple, and range in size from 1 mm to more than 1 cm (Table 30-2). They are particularly common in the neck and axillary area and usually are removed for cosmetic reasons only. Not uncommonly, fibroepithelial polyps twist about their stalk and infarct, causing a change in color from tan to black. This change in color may alarm the patient and lead him or her to seek a clinical opinion. Fibroepithelial polyps with dense collagenous stroma are often designated fibroma. HISTOPATHOLOGIC FEATURES These lesions are digitate or polypoid with a collagenous core that varies from loosely textured to densely sclerotic collagen (see Table 30-2 and Fig. 30-1). Ectatic thinwalled vessels are common. Those polyps with a core of dense sclerotic collagen are often diagnosed as fibromas. Polyps containing significant amounts of adipose tissue are often designated soft fibromas, or even, mistakenly, nevus lipomatosus

 FIGURE 30-1 Acrochordon. Fibroepithelial polyp with squamous epithelium surrounding loose collagenous stroma.

DIFFERENTIAL DIAGNOSIS Distinction between some fibroepithelial polyps and seborrheic keratosis can be difficult. We designate clinically polypoid lesions as fibroepithelial polyps, but this is, admittedly, an arbitrary decision. Alternatively, lesions with prominent epidermal changes may be designated pedunculated seborrheic keratosis. Soft fibromas with large amounts of fat may mimic nevus lipomatosus superficialis. Broad-based, plaquelike lesions with fat extending into the dermis are more characteristic of nevus lipomatosus superficialis. In contrast to fibroepithelial polyps and soft fibroma, nevus lipomatosus superficialis is most often located on the posterior upper thigh and buttocks. Angiofibromas are distinguished by a prominent vascular component; however, a spectrum between fibroepithelial polyp and angiofibroma exists. Commonly, pedunculated melanocytic nevi are mistaken for fibroepithelial polyps by clinicians. Indeed, some fibroepithelial polyps may represent involuted nevi. Not uncommonly, a small nest of nevomelanocytes is noted within an otherwise typical fibroepithelial polyp.

Angiofibroma Angiofibromas comprise a clinically heterogeneous group of lesions with similar histopathology (Table 30-3). The three distinct clinical variants of angiofibroma are facial angiofibroma (adenoma sebaceum), fibrous papule, and pearly penile papule.

Facial Angiofibroma Synonym: adenoma sebaceum CLINICAL FEATURES Facial angiofibroma is one manifestation of tuberous sclerosis complex, an autosomal dominant neurocutaneous syndrome caused by mutations in the TSC1 (hamartin) or TSC2 (tuberin) gene. Central nervous system manifestations include mental

Table 30-3 Angiofibromas

Clinical Features Facial angiofibroma (adenoma sebaceum) Manifestation of tuberous sclerosis complex Multiple skin-colored to pink-red papules and nodules of the central face, especially the nasolabial folds Minute papules to large nodules Present at birth or in early childhood Fibrous papule Small, shiny papule Located on the face, especially the nose Occurs in adults Several millimeters in diameter Pearly penile papules Tiny papules on the glans penis Oriented circumferentially about the coronal sulcus of the glans Histopathologic Features Angiofibromas Paucicellular fibrous proliferation Collagen swirling around preexisting adnexal structures Dilated thin-walled vessels Stellate fibroblasts with “ganglion-like” appearance Multinucleated fibroblasts Differential Diagnosis Angiofibromas Dermal nevus Pleomorphic fibroma

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

superficialis. The epidermis may be unremarkable or show features of lichen simplex chronicus, the result of rubbing by the patient or friction from clothing. Many fibroepithelial polyps show epithelial changes similar to seborrheic keratosis, including acanthosis with horn cysts.

retardation, epilepsy, glial hamartomas, and sube-pendymal nodules and subependymal giant cell astrocytomas. Systemic manifestations include cardiac rhabdomyomas, angiomyolipomas of the kidney, renal cysts, and carcinomas, as well as pulmonary lymphangioleiomyomatosis and fibrous dysplasia of bone. Mucocutaneous lesions commonly seen in tuberous sclerosis include facial angiofibromas (adenoma sebaceum), ungual and periunugual fibromas, café-au-lait spots, large hypomelanotic macules (ash-leaf spots or thumbprint-shaped lesions) and confettilike macules, forehead fibrous plaques, gingival fibromas, molluscum pendulum, and connective tissue nevi (shagreen patch).1 The original term adenoma sebaceum is a misnomer. It is distributed in the “sebaceous” area of the face where the greatest concentration of sebaceous glands reside; however, the lesion is not derived from sebaceous glands and shows compression and atrophy of adnexal structures within a fibrovascular proliferation. These lesions present as multiple skincolored to pink-red papules and nodules on the cheeks, forehead, and chin and often are most dense in the nasolabial folds. They range from minute papules to large coalescent nodules (forehead fibrous plaques in infancy have been regarded as being part of this entity). They develop at birth or in early childhood and may be the first sign of disease. Clinical recognition of these lesions as a manifestation of tuberous sclerosis is important because spontaneous mutations are believed to account for approximately two-thirds of patients.

Fibrous Papule CLINICAL FEATURES Fibrous papule, a variant of angiofibroma, is a small, shiny cutaneous papule that is located on the face, most commonly on the nose of adults. It is usually only a few millimeters in diameter. Dermatologists often biopsy these lesions to exclude basal cell carcinoma. They may also be indistinguishable from small nevi.

Pearly Penile Papules CLINICAL FEATURES Pearly penile papules present as tiny papules, usually no more than a few millimeters in diameter, on the glans penis. They are often oriented circumferentially about the coronal sulcus of the glans.2 Most patients are younger than 40 years of age, and these lesions are more common in African Americans and uncircumcised men.3 No

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 30-4 Acral Fibrokeratoma and Periungual Fibroma

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 FIGURE 30-2 Fibrous papule. Ectatic vessels are surrounded by spindled and stellate fibroblasts.

association with human papilloma virus infection has been found.4 HISTOPATHOLOGIC FEATURES Histologically, these three types of lesion are dermal fibroblastic proliferations associated with variable numbers of thin-walled, slightly ectatic vessels (see Table 30-3 and Fig. 30-2). The composite fibroblasts often are multinucleated and stellate shaped, resembling ganglion cells or radiation fibroblasts. Concentric fibrosis surrounding adnexal structures is a characteristic feature. DIFFERENTIAL DIAGNOSIS Pleomorphic fibroma, a rare variant of fibroepithelial polyp, differs by its typical location on the extremities and the presence of large pleomorphic and hyperchromatic nuclei, in comparison with the more reactive-appearing fibroblasts seen in facial angiofibroma. In addition, pleomorphic fibroma lacks the rich vascular pattern seen in angiofibromas. Fibrous papules, predominantly composed of plump, rounded fibroblasts, may be mistaken for dermal nevi. Dermal nevi are distinguished from fibrous papules by nests of nevus cells. The fibroblasts in fibrous papule are not reactive for S-100 protein, allowing immunohistochemical

distinction from nevomelanocytes. Pearly penile papules are clinicopathologically distinctive and rarely pose a diagnostic problem.

Acral Fibrokeratoma and Periungual Fibroma

Clinical Features Fibrokeratoma Fingers, toes, palms and soles, feet, and legs of adults Small (<1.5 cm) nodules Slightly elevated to dome-shaped or tall protrusions Periungual fibroma Arise in the peripubertal period in patients with tuberous sclerosis Flesh-colored nodules that arise from the nail folds Few millimeters to >1 cm Histopathologic Features Fibrokeratoma Dense, irregular collagen bundles Variable numbers of fibroblasts Sparse to numerous thin-walled vessels Vessels and collagen bundles often arranged perpendicular to the epidermis Epidermis usually shows some degree of hyperkeratosis and acanthosis Periungual fibroma May be indistinguishable from fibrokeratoma, except some cases may have multinucleated giant cells and stellate cells resembling ganglion cells Differential Diagnosis Supernumerary digit Dermatofibroma Angiofibroma

Synonyms: acquired digital fibrokeratoma

tuberous sclerosis complex. Periungual fibromas are seen in approximately half of patients with this disorder.

CLINICAL FEATURES Acral fibrokeratoma occurs mostly in adults and most frequently on the fingers; however, it is also seen on the toes, palms and soles, and feet (Table 30-4).5-7 Fibrokeratomas are small (<1.5 cm) nodules that range from slightly elevated to protuberant lesions that often are exophytic with a narrow base. The overlying epidermis usually is hyperkeratotic. A traumatic etiology has been discussed, although convincing evidence is lacking. Periungual fibromas are smooth, shiny, flesh-colored nodules that arise from the nail folds (see Table 30-4). They range in size from a few millimeters to more than 1 cm. They usually present as multiple lesions in the peripubertal period. As with facial angiofibroma (adenoma sebaceum), the presence of periungual fibromas should prompt a careful family history and clinical examination for evidence of

HISTOPATHOLOGIC FEATURES Fibrokeratoma is composed of dense hyalinized and irregularly arranged collagen bundles with variable numbers of fibroblasts. Sparse to numerous thin-walled vessels may be present (see Table 30-4). Vessels and collagen bundles are often arranged perpendicular to the overlying epidermis. The overlying epidermis usually shows some degree of hyperkeratosis and acanthosis. Elastic tissue stains usually fail to show elastic fibers. Periungual fibromas also are composed of dense collagen bundles arranged in parallel array and may be associated with a variable number of blood vessels (Fig. 30-3). They may be indistinguishable from acral fibrokeratoma.8 Some cases have multinucleated giant cells and stellate cells resembling ganglion cells. Similar cells are seen in some variants of angiofibroma.

only rare scattered fibroblasts interposed between collagen bands. The clefts are randomly oriented and impart a storiform pattern at low magnification. Multiple lesions with identical histologic appearance may be seen in Cowden disease. Giant cell collagenoma is a variant with multinucleated giant cells with bizarre shapes.11

DIFFERENTIAL DIAGNOSIS Clinically, supernumerary digit may resemble fibrokeratoma, but true supernumerary digit contains a proliferation of nerve bundles as well as fibrous tissue. Periungual fibromas of tuberous sclerosis complex demonstrate concentric perivascular fibrosis and contain stellate and multinucleated fibroblasts, features generally not seen in fibrokeratoma. Epidermal acanthosis and hyperkeratosis, in contrast to fibrokeratoma, is usually absent. Other authors have not found these features helpful in distinguishing periungual fibroma from fibrokeratoma. These features are, however, seen in angiofibromas, a group of tumors within which periungual fibroma may be classified. In contrast to dermatofibroma, a well-developed storiform pattern and encapsulation of collagen is not seen in periungual fibroma and fibrokeratoma.

Storiform Collagenoma (Sclerotic Fibroma) CLINICAL FEATURES Storiform collagenoma occurs most often in young and middleaged adults (Table 30-5). These lesions usually measure less than 1 cm and present as slow-growing solitary nodules on the head and neck region, or upper extremities.9,10 Recurrence is not a feature.

HISTOPATHOLOGIC FEATURES These tumors are symmetric and well-circumscribed but unencapsulated (see Table 30-5). The tumor is composed of paucicellular hyaline collagen containing numerous cleftlike spaces (Fig. 30-4). Cellularity varies; however, most tumors contain

Table 30-5 Storiform Collagenoma

Clinical Features Young and middle-aged adults Usually <1cm Slow-growing nodule in the head and neck region and upper extremities Multiple collagenomas associated with Cowden disease Histopathologic Features Symmetric, well circumscribed but unencapsulated Paucicellular hyaline collagen with numerous cleftlike spaces Rare scattered fibroblasts between collagen bands Clefts impart a storiform pattern to the tumor Differential Diagnosis Dermatofibroma Myofibroma Keloid

Fibroma of Tendon Sheath

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

 FIGURE 30-3 Periungual fibroma. The epidermis shows acanthosis and hyperkeratosis. The underlying dermis is expanded by dense collagen associated with a few ectatic vessels.

DIFFERENTIAL DIAGNOSIS Epidermal acanthosis and the presence of inflammatory cells, including multinucleated giant cells, help to distinguish between sclerotic dermatofibroma and circumscribed storiform collagenoma. Circumscribed storiform collagenoma tends to expand and efface the overlying epidermis, in contrast to the thickened epithelium over dermatofibroma. However, it seems that occasional examples of this entity may represent an end-stage dermatofibroma or solitary myofibroma. This perspective is supported by occasional examples resembling collagenoma with small foci recognizable as dermatofibroma or solitary myofibroma. Keloids can be distinguished by the association of typical hypertrophic scar and poor circumscription. Storiform collagenoma shows more uniform hyalinization compared with keloid. Sclerosing perineuriomas (storiform perineurial fibroma), typically seen in the hands, may closely mimic storiform collagenoma but contain very delicate spindled cells with long processes and express epithelial membrane antigen (EMA).12

CLINICAL FEATURES Fibroma of tendon sheath is a tumor of unclear pathogenesis. It is seen most frequently on the hands and feet of young adults, particularly men (Table 30-6).13 Most tumors are painless, slowly growing nodules or masses on a finger, measuring less than 3 cm in diameter. Attachment to the tendon or tendon sheath can usually be demonstrated at the time of surgery.14 Up to 25% of tumors may recur after surgical excision.15 Serious functional impairment is almost never seen. HISTOPATHOLOGIC FEATURES These tumors are well-circumscribed and show variable cellularity (see Table 30-6). They are composed of uniform spindled fibroblasts and myofibroblasts with slender, tapered nuclei arranged in short fascicles. Paucicellular tumors may be markedly hyalinized and demonstrate concentric whorls of dense eosinophilic collagen. A characteristic feature is the

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from them. Distinction of some cases from hyalinized forms of nodular fasciitis may be somewhat arbitrary.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Dermatomyofibroma

770

CLINICAL FEATURES Dermatomyofibroma usually presents as a pale pink or hypopigmented plaque on the upper trunk or neck of adolescents and young adults, particularly females (Table 30-7). Lesions may resemble keloid or plaquelike dermatofibrosarcoma protuberans (DFSP), grow slowly over many years, and attain a size of up to 5 cm.17-19 Surgical excision appears curative in the small number of cases reported.

 FIGURE 30-4 Storiform collagenoma. The tumor is composed of paucicellular hyaline collagen containing numerous cleftlike spaces and only rare, scattered fibroblasts. The pattern of randomly oriented bands of collagen often creates a storiform pattern at low magnification.

presence of slitlike vascular channels that appear compressed by surrounding stroma (Fig. 30-5). The presence of multinucleated giant cells in occasional tumors suggests the existence of a morphologic spectrum with giant cell tumor of tendon sheath (GCTTS).16 Many cases show foci indistinguishable from hyalinized forms of nodular fasciitis, suggesting that at least some fibromas of tendon sheath represent old, “burnedout” fasciitis.

cells arranged in short fascicles favors fibroma of tendon sheath. These features, together with overall circumscription of the tumor, allow distinction from fibromatosis. Angioleiomyoma may resemble fibroma of tendon sheath at low-power magnification; however, the vessels of angioleiomyoma have thick walls with smooth muscle cells radiating

HISTOPATHOLOGIC FEATURES The tumor exhibits a bandlike configuration in the reticular dermis with a grenz zone sparing the superficial dermis (see Table 30-7 and Fig. 30-6). The composite lesional cells are arranged in fascicles oriented parallel to the surface. Adnexal structures tend to be spared. Prominent extension into subcutaneous tissue is usually not seen, although focal involvement of subcutaneous fat is present in some cases. The composite cells are uniformly actin-positive myofibroblasts with eosinophilic cytoplasm. Although these lesions can be cellular and mitotically active, cytologic atypia is not present. DIFFERENTIAL DIAGNOSIS Dermatofibroma usually does not appear as a plaque

DIFFERENTIAL DIAGNOSIS Cellular tumors with giant cells may be difficult, if not impossible, to distinguish from GCTTS.15 The presence of slitlike vessels and tumor

Table 30-6 Fibroma of Tendon Sheath

Clinical Features Young to middle-aged men Slow-growing, painless nodule of hands and feet 25% recur after excision Histopathologic Features Well circumscribed Variably cellular, composed of fibroblasts and myofibroblasts in short fascicles Slitlike vascular spaces Differential Diagnosis Giant cell tumor of tendon sheath Angioleiomyoma Fibromatosis

 FIGURE 30-5 Fibroma of tendon sheath. This tumor is composed of uniform spindled fibroblasts and myofibroblasts with slender, tapered nuclei in a densely collagenous stroma. The presence of slitlike vascular channels that appear compressed by surrounding stroma is characteristic.

Table 30-7 Dermatomyofibroma

clinically and displays a prominent storiform pattern of growth with “encapsulation” of individual collagen bundles. Dermatomyofibroma is distinguished from DFSP by the lack of a uniform storiform pattern and absence of extensive infiltration into fat and subcutaneous tissue. In difficult cases, CD34 negativity and smooth muscle actin positivity help to rule out DFSP.19 Cutaneous leiomyosarcomas display more pronounced cytoplasmic eosinophilia, perinuclear vacuolization, and at least focally contain enlarged, hyperchromatic cells.20 The hemorrhagic variant of dermatomyofibroma shows similarities to plaque-stage Kaposi sarcoma; however, chronic inflammatory cells and eosinophilic globules are not a typical feature, and lesional cells are negative for CD34 and HHV-8.21

Nodular Fasciitis Nodular fasciitis is a reactive myofibroblastic proliferation notorious for being misinterpreted as a sarcoma. On the other hand, sarcomas also may be misinterpreted as nodular fasciitis, resulting in patients not receiving appropriate therapy promptly. To complicate matters, this reactive proliferation shows a variety of distinct histologic patterns. CLINICAL FEATURES Most lesions are rapidly growing, often painful, subcutaneous or deep soft tissue masses, usually several centimeters in greatest dimension (Table 30-8). Comparable lesions may arise primarily in the dermis.20 Alarmed patients often present with the history of a mass growing rapidly over the course of a week to several weeks,

A

B  FIGURE 30-6 Dermatomyofibroma. (A) The tumor exhibits a plaquelike growth pattern in the reticular dermis with a grenz zone sparing the superficial dermis. (B) The tumor is composed of fascicles of spindled cells with a myoid appearance.

and some patients even testify to lesions growing “overnight.” It must be emphasized, however, that some examples of nodular fasciitis are reported to have been present for an extended period, and such history does not exclude this diagnosis. Most patients are young adults; however, the overall age range is wide. The upper limb, particularly the forearm, is the most common site of involvement. In children, most lesions are seen in the head and neck region.22,23 Cranial fasciitis, a distinctive form of nodular fasciitis seen in infants, involves the soft tissue of the scalp and may erode into underlying bone.24 Recurrence is observed in 1% to 2% of cases and is most likely a result of inadequate surgical excision of growing lesions.25 Biopsy material from recurrent tumors must be reevaluated carefully to ensure that the original lesion was diagnosed correctly. HISTOPATHOLOGIC FEATURES This process most commonly involves the fascia and subcutaneous fat, but a rare dermal variant has also been described (see Table 30-8). Lesions may be either well circumscribed or show infiltrative borders. At

low power, the cellularity varies from one area to another. Areas of low cellularity have a distinctive microcystic or myxoid background, creating a loosely textured “feathery” appearance (Fig. 30-7). Cells in both the cellular and paucicellular zones tend to be arranged in broad, sweeping, and interlacing fascicles associated with thin-walled blood vessels. A storiform pattern may be seen focally. The dominant cell types are fibroblasts and myofibroblasts with a spindled shape and vesicular nuclei and occasional prominent nucleoli. Many of these cells show abundant tapering eosinophilic cytoplasm with frequent stellate forms. Their morphology has been likened to fibroblasts grown in tissue culture. Mitoses may be abundant but are never atypical. Pleomorphism and nuclear hyperchromasia are absent. Variable numbers of acute and chronic inflammatory cells are usually seen. Multinucleated osteoclast-like giant cells are often present, particularly in children and in intravascular lesions. Long-standing examples of nodular fasciitis may show abundant hyalinized matrix, with only focal areas of more typical, cellular histology.

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

Clinical Fatures Pale pink or hypopigmented plaque Upper trunk Adolescents and young adults, usually girls and young women Histopathologic Features Fascicles oriented parallel to the skin surface Grenz zone Composite cells are myofibroblasts with eosinophilic cytoplasm Significant extension into fat and subcutaneous tissue is not seen Differential Diagnosis Dermatofibroma Dermatofibrosarcoma protuberans (plaque stage)

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Table 30-8 Nodular Fasciitis

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Clinical Features Rapidly growing and often tender Subcutaneous or deep soft-tissue masses, usually several centimeters in greatest dimension Young adults Upper limb, particularly the forearm In children, most lesions in the head and neck region Recurrence is rare Histopathologic Features May be well circumscribed or show infiltrative borders Cellularity varies within the tumor Areas of low cellularity have a distinctive myxoid, feathery background Short to broad, sweeping fascicles, focal storiform pattern “Tissue-culture” myofibroblasts with vesicular nucleus with occasional prominent nucleoli Essentially no cytologic atypia Mitoses may be abundant Inflammatory cells and multinucleated osteoclast-like giant cells may be seen Ganglion-like cells in proliferative fasciitis Differential Diagnosis Fibromatosis Sarcoma, particularly low-grade myxofibrosarcoma and fibrosarcoma

A

B

Proliferative fasciitis is a variant of nodular fasciitis that is distinguished by the presence of larger polygonal cells with abundant amphophilic or basophilic cytoplasm that imparts a resemblance to ganglion cells or even rhabdomyoblasts (Fig. 30-8). These distinctive cells, which may be abundant or rare, are superimposed on a background of typical nodular fasciitis. Proliferative fasciitis in children may display alarming cellularity and necrosis, mimicking various sarcomas.26 Intramuscular tumors with the same histology have been designated proliferative myositis.26 Ischemic fasciitis, also termed atypical decubital fibroplasia, is a nodular fasciitis-like reaction thought to be secondary to ischemia. This lesion is characterized by fibrinoid necrosis associated with a nodular or proliferative fasciitis-like fibroblastic reaction in the dermis and subcutis near bony protuberances of elderly and debilitated patients.27,28 Intravascular fasciitis is an uncommon variant that involves veins, usually in the upper extremities and the head and neck region. This subtype is characterized by multinodular growth

 FIGURE 30-7 Nodular fasciitis. (A) Spindle and stellate cells on a myxoid background with “feathery” appearance. (B) The cells are reminiscent of “tissue culture fibroblasts” and lack cytologic atypia.

 FIGURE 30-8 Proliferative fasciitis. The lesion resembles nodular fasciitis in all aspects with the additional of plump cells resembling ganglion cells.

of nodular fasciitis within vessels and may closely mimic soft tissue giant cell tumors.29 The majority of cases of nodular fasciitis show immunoreactivity for smooth muscle actin and muscle specific actin with a characteristic “tram-track” pattern; however, reactivity for desmin is usually not seen, although sometimes this may be affected by the antibody used. The immunohistochemical profile and ultrastructural characteristics support a myofibroblastic origin for nodular fasciitis.

Knuckle Pad CLINICAL FEATURES Some authors consider knuckle pads to be a form of fibromatosis. They are hyperkeratotic papules on the dorsum of the interphalangeal or metacarpophalangeal joints.30 They are usually seen in adults and rarely cause symptoms or functional impairment. Some cases may be familial or be associated with superficial fibromatosis such as Dupuytren disease. They show no apparent tendency to recur. HISTOPATHOLOGIC FEATURES Microscopically, knuckle pads are composed of a bland fibrous proliferation, usually less cellular than fibromatosis. They usually are associated with overlying epidermal acanthosis and hyperkeratosis. DIFFERENTIAL DIAGNOSIS Knuckle pad may resemble scarring fibrosis secondary to trauma but is distinguished by clinical history.

Palmar and Plantar Fibromatosis The fibromatoses are a family of fibroblastic proliferations sharing similar histology, an infiltrative pattern of growth, and a tendency to recur after excision. Tumors located at some sites show the capacity for locally aggressive and destructive growth; however, these tumors never metastasize.31,32 The clinical behavior of fibromatoses is very site dependent; however, in general, superficial fibromatoses such as palmar and plantar fibromatosis are less aggressive than deep fibromatoses such as desmoid fibromatosis. Some studies have suggested an association of superficial fibromatoses with alcoholism, tobacco use, and epilepsy, although this remains controversial. Development of palmar fibromatosis has been reported in HIV-positive patients treated with indinavir.33 CLINICAL FEATURES Palmar fibromatosis (Dupuytren contracture) is an extremely common tumor affecting mostly older adults, with a male predominance (Table 30-9). Frequently, both hands are involved. Uncommonly, both palmar and plantar fibromatosis occur in the same patient. This tumor generally begins as small nodules that progressively enlarge to form a cordlike band. Many patients eventually develop flexion contracture with significant functional impairment. Flexion causes characteristic puckering

Table 30-9 Palmar and Plantar Fibromatosis

Clinical Features Palmar fibromatosis Both hands are commonly involved Small nodule that progressively enlarges to form a cordlike band that causes puckering of overlying skin Flexion contracture and functional impairment of the hand Plantar fibromatosis Occurs in younger age groups May cause minor discomfort when walking Rarely associated with functional impairment Histopathologic Features Interlacing fascicles with wavy collagenous stroma Tumor cells are spindle shaped; tapering or vesicular nuclei Early lesions are fairly cellular, mitotically active, and composed of plumper myofibroblasts Later stage lesions are less cellular, less mitotically active, with more abundant hyalinized collagen Plantar form tends to be more cellular Differential Diagnosis Fibrosarcoma Desmoid fibromatosis

of skin overlying the tumor. Fasciectomy with surgical division of the fibrous bands or complete removal of the lesion often are performed to give functional improvement. Plantar fibromatosis (Ledderhose disease) differs from its palmar counterpart by its tendency to occur in younger age groups and is less commonly associated with functional impairment. Plantar fibromatosis may cause minor discomfort when walking but rarely causes contractures. However, there is a significant tendency for local recurrence. HISTOPATHOLOGIC FEATURES Superficial fibromatoses involve mainly fibrotendinous and subcutaneous tissue and appear to proceed through several histologic stages as the lesion ages (see Table 30-9). Early lesions tend to be more cellular, more mitotically active, and composed of plumper myofibroblasts. Later-stage lesions are much less cellular, less mitotically active, and tend to have more abundant hyalinized stromal collagen. Intermediate-stage lesions (when biopsy is commonest) contain features of both phases in alternating areas. Tumor cells are spindle shaped, often with wavy

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

DIFFERENTIAL DIAGNOSIS Because of rapid growth, high mitotic activity, and a frequently infiltrative pattern, nodular fasciitis is often mistaken for a malignant neoplasm. The low-power pattern of nodular fasciitis, with distinctive alternating cellular and paucicellular “feathery” myxoid zones, taken with the bland cytologic features, establishes the correct diagnosis. At higher power, “tissue culture” fibroblast-like cells with vesicular nuclei, absence of nuclear hyperchromasia, together with absence of atypical mitoses, help to exclude a diagnosis of sarcoma. Areas of nodular fasciitis showing storiform patterns may be indistinguishable from dermatofibroma. Nodular fasciitis is discriminated from dermatofibroma based on the other characteristic of “feathery” arrangements of uniform fibroblasts in broad, sweeping fascicles; myxoid alteration; and depth typical of nodular fasciitis. In addition, nodular fasciitis does not show interdigitation among preexisting collagen, a feature characteristic of dermatofibroma. Fibromatosis is more uniformly cellular and fascicular, is associated with more abundant dense collagen, and lacks the myxoid areas seen in nodular fasciitis. The fibroblasts in fibromatosis are more uniform and tend to have wavy nuclei. Fibrosarcoma, which is rare, is much more cellular, lacks the loose “feathery” pattern seen in nodular fasciitis, and is characterized by a herringbone fascicular pattern. Low-grade myxofibrosarcoma is occasionally misdiagnosed as nodular fasciitis. This tumor is distinguished from nodular fasciitis by characteristic curvilinear vessels and the presence of cells with atypical hyperchromatic nuclei and vacuolated cytoplasm that may resemble lipoblasts. Recurrent nodular fasciitis is rare, and pathologic material from patients with recurrent lesions must be examined critically and the original diagnosis carefully reassessed. It is the authors’ experience that a significant proportion of cases

diagnosed as recurrent nodular fasciitis are sarcomas.

773

Calcifying Aponeurotic Fibroma

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

CLINICAL FEATURES Calcifying aponeurotic fibroma is an extremely rare tumor that classically presents as a slowly growing mass in the hands or, less commonly, the feet of adolescents and young children, although older patients may also be affected (Table 30-11).39 This tumor usually is not associated with pain or functional impairment. The mass is often attached to tendons or fascia. Approximately half of the cases recur. The pathogenesis and relationship with fibromatosis are unclear.

 FIGURE 30-9 Plantar fibromatosis. The composite cells are spindle-shaped, often with wavy nuclei and are arranged in interlacing fascicles within dense very collagenous stroma.

nuclei, and are arranged in interlacing fascicles within a wavy collagenous stroma (Fig. 30-9). Histologically, the plantar form of the disease tends to be more uniformly hypercellular at all stages in the disease process. Both palmar and plantar fibromatoses are often more cellular than their deep soft tissue counterparts, a feature that often causes concern. Multinucleated giant cells are seen in some superficial fibromatoses.34 DIFFERENTIAL DIAGNOSIS The main differential diagnosis is with fibrosarcoma; however, this distinction is rarely difficult. Fibrosarcoma demonstrates a “herringbone” fascicular growth pattern, is more cellular, shows significant nuclear atypia and hyperchromasia, and has a higher mitotic rate. It should be emphasized that mitotic figures may be found in all forms of fibromatoses and that there is no “cutoff” that reliably separates fibromatoses from fibrosarcoma. Desmoid-type fibromatosis is almost invariably more deep-seated.

Penile Fibromatosis

774

CLINICAL FEATURES Penile fibromatosis (Peyronie disease) is considered by some a form of fibromatosis. Middle-aged and older men develop a slowly enlarging fibrous thickening of the penis, usually on the dorsum (Table 30-10).35 With time, pain and curvature of the penis develops, which are exacerbated by erection. The pathogenesis and relationship to other forms of fibromatosis are poorly understood; however, it seems probable that Peyronie disease has an inflammatory basis, possibly vasculitic

in nature.36 In addition, association with diabetes mellitus and venoocclusive dysfunction has been reported.37 HISTOPATHOLOGIC FEATURES The histologic pattern depends on the age of the lesion.38 Early lesions are associated with chronic inflammation, often perivascular in location (see Table 30-10).36 Older lesions tend to show less inflammation and more scarlike fibrous proliferation (hence the resemblance to fibromatosis) involving the corpus cavernosum. Calcification and metaplastic ossification are prominent features in some cases. DIFFERENTIAL DIAGNOSIS The absence of a history of trauma and progressive slow growth over years help to distinguish penile fibromatosis from a simple cicatrix. In the appropriate clinical setting, there is no real differential diagnosis.

Table 30-10 Penile Fibromatosis

Clinical Features Middle-aged and older males Slowly enlarging fibrous thickening of the penis, usually on the dorsum Pain and curvature of the penis, exacerbated by erection Histopathologic Features Chronic inflammation in early lesions Scarlike fibrous proliferation as lesion ages Calcification and metaplastic ossification in some cases Differential Diagnosis Cicatrix

HISTOPATHOLOGIC FEATURES The histologic findings are distinctive; a fibrous proliferation of spindled to epithelioid cells is present within a densely collagenous background (see Table 30-11). The more plump fibroblasts often line up in single-file array and palisade around foci of calcification (Fig. 30-10). Areas of calcification may be associated with cartilage formation, particularly in longstanding lesions. DIFFERENTIAL DIAGNOSIS Calcifying aponeurotic fibroma is distinguished from fibromatosis by the presence of rounded epithelioid fibroblasts and calcification surrounded by palisaded fibroblasts. In some cases, the presence of metaplastic cartilage is also helpful in this distinction. Fibro-osseous pseudotumor may also contain cartilage; however, fasciitis-like proliferation associated with osteoid is distinctive. The palisade of fibroblasts helps distinguish calcifying aponeurotic

Table 30-11 Calcifying Aponeurotic Fibroma

Clinical Features Usually adolescents and young children Slowly growing mass in the palm or sole Not associated with pain or functional impairment Approximately half of cases recur Histopathologic Features Fibrous proliferation of spindled to rounded fibroblasts within a densely collagenous background Plump fibroblasts palisade around foci of calcification Cartilage formation in some cases Differential Diagnosis Fibromatosis Fibro-osseous pseudotumor Calcium pyrophosphate deposition disease (pseudogout)

Table 30-13 Dermatofibroma

fibroma from calcium pyrophosphate deposition disease (pseudogout). Chondromas of soft parts lack the fibroblastic proliferation seen in calcifying aponeurotic fibroma and consist of more uniformly mature hyaline cartilage.

BENIGN AND INTERMEDIATE FIBROHISTIOCYTIC TUMORS

Dermatofibroma (Fibrous Histiocytoma) Dermatofibroma or fibrous histiocytoma (dermatofibroma will be used as a collective term for this lesion and its variants throughout this chapter) is one of the most common dermal tumors encountered in dermatopathology practice. Recognition of some variants of dermatofibroma is critical because they may mimic malignant neoplasms (Table 30-12). The pathogenesis is unknown, and it is controversial if

Table 30-12 Variants of Dermatofibroma Aneurysmal fibrous histiocytoma Hemosiderotic histiocytoma Atypical fibrous histiocytoma (“dermatofibroma with monster cells”) Epithelioid fibrous histiocytoma Cellular variant Palisading variant Clear cell variant

it is a reactive or neoplastic process. Clonal cytogenetic abnormalities have been identified in some cases of dermatofibroma.41 CLINICAL FEATURES Dermatofibroma may be seen in any age group but is especially common in young to middleaged adults (Table 30-13). Women seem to be affected more often than men. Most tumors are smaller than 1.5 cm. The overlying skin may be erythematous or hyperpigmented with the borders gradually fading to normal skin color (Fig. 30-11A). Tumors characteristically exhibit the “dimple sign”—compression of the lateral borders of the tumor causes central depression or dimpling. Dermatofibromas are most commonly seen on the legs, arms, and trunk. Clinically, tumors with extensive hyperpigmentation may be mistaken for a melanocytic lesion. Lesions sometimes occur after minor trauma such as an insect bite and may persist for many years, and some may regress spontaneously. Recurrence is infrequent after excision of the classical type, but the aneurysmal and cellular variants recur in 20% to 25% of cases, especially if marginally or incompletely excised. The aneurysmal variant often shows rapid growth and can attain large size, causing clinical concern. Clinically, aneurysmal fibrous histiocytoma often is mistaken for a melanocytic or vascular neoplasm owing to its red-brown color secondary to hemorrhage and hemosiderin

deposition. The epithelioid variant is noted for often being polypoid. Rare metastases of some variants, especially cellular and atypical fibrous histiocytoma, have been reported.42-48 HISTOPATHOLOGIC FEATURES Dermatofibroma is a remarkably heterogeneous tumor with many variants described (see Table 30-12). This tumor varies tremendously with regard to cellularity, vascularity, hemorrhage or hemosiderin deposition, degree of sclerosis (a feature of later-stage lesions), and types of composite cells (eg, giant cells, atypical cells, lipid-laden histiocytes). Attention to the characteristic growth pattern at scanning magnification is critical to recognizing variants of dermatofibroma. At low power, dermatofibromas are symmetric and fairly well circumscribed, but not encapsulated, round to lens-shaped nodules centered in the reticular dermis (Fig. 30-11B). The common denominator for this family of tumors is the presence of tightly whorled fascicles of fibroblasts arranged in a storiform or pinwheel pattern (Fig. 30-12). In addition,

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

 FIGURE 30-10 Calcifying aponeurotic fibroma. Plump epithelioid cells present within cellular fibrous stroma are arranged in single-file array, palisading around a focus of calcification.

Clinical Features Young to middle-aged adults Papule or nodule, most tumors <1.5cm Overlying skin may be erythematous or hyperpigmented, with borders gradually fading to normal skin color “Dimple sign” May persist for many years; some may regress spontaneously Recurrence is infrequent after excision, except in the cellular, atypical, and aneurysmal variants Histopathologic Features Symmetric Well circumscribed but not encapsulated Most tumors confined to dermis or minimal extension into subcutaneous tissue Tightly whorled fascicles in a storiform pattern Fibrohistiocytic cells entrap preexisiting collagen bundles Lymphocytes, xanthoma cells, histiocytes, multinucleated giant cells Touton-type giant cells may be seen in variable numbers Overlying epidermis is acanthotic with basilar hyperpigmentation Differential Diagnosis Dermatofibrosarcoma protuberans Leiomyosarcoma (for cellular variant) Vascular tumors (for aneurymal variant)

775

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 776

A

B

 FIGURE 30-11 Dermatofibroma. (A) Uniform brown papule. (B) At low power, dermatofibromas are symmetric, fairly well-circumscribed, but not encapsulated, round to lens-shaped nodules centered in the reticular dermis. Note the overlying epidermal hyperplasia.

 FIGURE 30-12 Dermatofibroma is characterized by tightly whorled fascicles of bland fibroblasts arranged in a storiform or pinwheel pattern. These cells wrap themselves around preexisting collagen bundles to encapsulate them. Note also hemosiderin deposition and scattered giant cells.

some lesions show prominent fascicular arrangements of spindle cells. The composite cells are spindled to oval with vesicular nuclei and variable amounts of amphophilic cytoplasm. Dermatofibromas infiltrate the dermis in a very characteristic manner—the cells wrap themselves around preexisting collagen bundles to encapsulate them. This entrapment of collagen is observed in its most characteristic pattern at the periphery of the tumor. In addition to the fibrohistiocytic cells, lymphocytes, xanthoma cells, histiocytes, osteoclastlike giant cells, and Touton-type giant cells may be seen in variable numbers. Frequently, the overlying epidermis is acanthotic with basilar hyperpigmentation, often suggesting a lentigo or seborrheic keratosis (Fig. 30-13). In contrast, epidermal effacement may be seen over some lesions. In some cases, a striking basaloid hyperplasia occurs that may mimic basal cell carcinoma. A narrow grenz zone is often present. Occasional mitoses may be seen. Occasional dermatofibromas extend into the superficial subcutaneous fat along with the fibrous trabecula separating fat lobules, resulting in a starburst or spoke-wheel pattern. Some of these tumors may infiltrate the most superficial and peripheral rims of fat lobules, entrapping fat in a pattern focally resembling that of DFSP. However, these lesions otherwise exhibit typical features of dermatofibromas. Some dermatofibromas are highly vascular and have been designated sclerosing hemangioma in the past. Examples with extensive hemosiderin deposition have been designated hemosiderotic histiocytoma, which may represent an early evolutionary stage of aneurysmal benign fibrous histiocytoma. Aneurysmal fibrous histiocytoma is an important variant to recognize because it is frequently misdiagnosed.49-51 Histologically, aneurysmal fibrous histiocytoma tends to be very cellular with characteristic cleftlike or gaping pseudovascular spaces, lacking an endothelial lining (Fig. 30-14). Hemorrhage into these spaces causes confusion with vascular neoplasms, particularly Kaposi sarcoma. The cleftlike spaces often have an artifactual appearance, giving the impression that the histotechnician cut the section using a dull blade. Examination of the periphery of the tumor shows features typical of dermatofibroma, with characteristic encapsulation of collagen by fibroblasts. Atypical fibrous histiocytoma (“dermatofibroma with monster cells”) denotes a variant with pleomorphic cells and

bizarre giant cells (Fig. 30-15).42,51,52 Although mainly dermal, approximately one-third of the lesions extend into the subcutis. Some cases also show worrisome features usually not seen in dermatofibroma such as unusually large size (>2 cm)

and geographic necrosis. There is a variable proportion of pleomorphic cells with plump, spindle, or polyhedral cells with large hyperchromatic, irregular or bizarre nuclei. Multinucleated giant cells are often present with bizarre nuclei and

 FIGURE 30-14 Aneurysmal fibrous histiocytoma is usually cellular with characteristic cleftlike hemorrhagic pseudovascular spaces.

DIFFERENTIAL DIAGNOSIS The cellular variant must be distinguished from DFSP and leiomyosarcoma. Fascicular growth of eosinophilic spindled cells with ovoid to cigar-shaped nuclei, perinuclear vacuoles, and smooth muscle actin and desmin expression are characteristic of leiomyosarcoma. Extensive infiltration into fat in a sievelike pattern and CD34 immunoreactivity are characteristic of DFSP. The presence of inflammatory cells, multinucleated giant cells, Toutontype giant cells, and xanthoma cells are supportive of dermatofibroma. Expression of factor XIIIa in dermatofibroma may aid in the differential diagnosis. Newer markers, such as stromelysin-3 in dermatofibroma and apolipopoprotein D, in DFSP have been proposed to be helpful by some authors but are yet to be validated.59,60 Aneurysmal fibrous histiocytoma may be confused with vascular tumors such as spindle cell hemangioma and Kaposi sarcoma, as well as with angiomatoid fibrous histiocytoma (AFH). The presence

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

 FIGURE 30-13 Dermatofibroma. A characteristic feature seen in many dermatofibromas is acanthosis with basilar hyperpigmentation of the overlying epidermis. Note the entrapment of collagen.

foamy, sometimes hemosiderin-rich cytoplasm. The background often shows classical features of dermatofibroma such as a storiform growth pattern and entrapped hyaline collagen bundles, especially at the periphery. Mitotic activity is variable, and atypical mitoses are sometimes seen. In the largest reported series, 2 of 59 patients developed metastases, although referral bias may have occurred in this study.42 Epithelioid fibrous histiocytoma is an underrecognized variant of dermatofibroma comprised largely of polygonal or rounded, often binucleated cells with abundant eosinophilic cytoplasm (Fig. 30-16).53-55 This variant is often exophytic with a collarette. The nuclei often are vesicular with small nucleoli. As with many variants of dermatofibroma, the periphery of the lesion often shows typical features of dermatofibroma. Perhaps the most problematic variant of dermatofibroma is the cellular variant (Fig. 30-17).56 This variant shows a more densely cellular fascicular growth pattern and may infiltrate fat in a limited fashion, causing confusion with DFSP or leiomyosarcoma. An admixture of inflammatory, foam cells, and giant cells often is present but sparse. Necrosis may be present, and normal mitoses are common.56 The palisading variant of fibrous histiocytoma is characterized by focally prominent nuclear palisading.57 Tumors composed predominantly of clear cells are designated clear cell dermatofibroma (Fig. 30-18).58

777

with melanocytic lesions, including epithelioid nevi, and Spitz nevus in particular. A junctional component and immunoreactivity for S-100 protein establish the diagnosis of a melanocytic tumor.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Atypical Fibroxanthoma

778

Atypical fibroxanthoma is characterized by a highly pleomorphic histologic phenotype usually associated with malignant neoplasms. Despite its seemingly malignant histologic features, atypical fibroxanthoma has little, if any, potential for metastasis and essentially is a benign tumor when strict diagnostic criteria are applied. Given the differences in behavior of atypical fibroxanthoma compared with other pleomorphic tumors, particularly melanoma, the pathologist must always approach atypical fibroxanthoma as a diagnosis of exclusion.  FIGURE 30-15 Atypical fibrous histiocytoma (“dermatofibroma with monster cells”). This variant shows scattered bizarre giant cells and cells with unusually plump nuclei superimposed on an otherwise typical dermatofibroma.

of slitlike vessels and immunoreactivity for vascular tumor markers such as CD31 favors a vascular origin. The artifact-like pseudovascular spaces are characteristic of aneurysmal fibrous histiocytoma and are not found in true vascular tumors. The presence of thickwalled muscular vessels or organizing thrombi favor spindle cell hemangioma. Examining the periphery of aneurysmal

fibrous histiocytoma shows characteristic encapsulation of collagen fibers. This feature is particularly helpful in the distinction from Kaposi sarcoma. AFH typically occurs in younger patients and has a very characteristic histologic appearance, with a thick fibrous capsule, numerous lymphoid follicles, and distinctly “histiocytoid” cells. Epithelioid fibrous histiocytoma may be confused

 FIGURE 30-16 Epithelioid fibrous histiocytoma. This variant of dermatofibroma is comprised of polygonal or rounded cells with abundant eosinophilic cytoplasm.

CLINICAL FEATURES Atypical fibroxanthoma occurs almost exclusively in the sun-damaged skin of old adults (Table 30-14). Cases associated with xeroderma pigmentosum and immunosuppression have been reported.61,62 Ultraviolet-induced p53 mutations have been identified in these lesions.63 Most tumors occur in the head and neck region, frequently are rapidly enlarging, and should be smaller than 1.5 cm in greatest dimension. Many cases of purported atypical fibroxanthoma occurring in non–sun-damaged skin in young patients probably represent atypical fibrous histiocytomas.52 Because they are not clinically distinctive, the diagnosis is rarely made clinically. Atypical fibroxanthoma may be mistaken for squamous cell carcinoma, basal cell carcinoma, and melanoma.64 Complete excision is adequate therapy. Lesions with atypical features require a more generous excision and careful follow-up. HISTOPATHOLOGIC FEATURES Atypical fibroxanthomas are relatively symmetric, well-circumscribed, exophytic tumors at scanning magnification (see Table 30-14). The bulk of the tumor is located in the dermis; however, some tumors show very superficial extension into subcutaneous fat. Tumors involving the superficial dermis may exhibit a grenz zone between the epidermis and the neoplasm or extend to the dermal–epidermal interface, often with ulceration. Intraepidermal pagetoid spread is not seen, and the presence of intraepidermal malignant cells should raise the possibility of melanoma or pleomorphic squamous

Table 30-14 Atypical Fibroxanthoma

cell carcinoma with pagetoid spread. An epidermal collarette is quite common but is a nonspecific finding. The lesional cells range from highly pleomorphic bizarre forms with marked hyperchromasia and irregular nuclear outlines to more uniform spindled cells (Fig. 30-19). Although the degree of pleomorphism varies from case to case, the degree of cytologic atypia is generally uniform throughout a given tumor.

Most cases show marked nuclear pleomorphism, prominent nucleoli, hyperchromasia, and frequent bizarre multinucleated tumor giant cells.65,66 Mitoses are often numerous and frequently atypical. Tumors cells often are arranged in a focally storiform pattern. Some tumors show a relatively monomorphic fascicular pattern that mimics leiomyosarcoma.66,67 Inflammatory cells, especially lymphocytes and histiocytes, including

 FIGURE 30-18 Clear cell dermatofibroma. This variant is composed predominantly of clear cells. The growth pattern is typical of dermatofibroma.

lipidized cells, are frequently seen within the tumor. Multinucleated giant histiocytes, including Touton-type giant cells, are also commonly noted. Importantly, however, necrosis and vascular or perineural invasion are not seen. DIFFERENTIAL DIAGNOSIS The diagnosis of atypical fibroxanthoma must be carefully approached as a diagnosis of exclusion because all other tumors considered in the differential diagnosis are metastasizing malignant neoplasms. If strict criteria are followed, atypical fibroxanthoma may be regarded as benign neoplasms cured by simple excision. Tumors with atypical features are best regarded as potentially malignant, and the clinician should be alerted to this possibility. An unequivocal diagnosis of atypical fibroxanthoma should not be rendered in cases with atypical features. Atypical features that portend potential aggressive behavior include significant extension into adipose tissue, necrosis, and vascular invasion. Cases reported as metastatic atypical fibroxanthoma have demonstrated some of these features and form the rationale for requiring strict criteria to establish a diagnosis of atypical fibroxanthoma.68 Tumors may show focal infiltration into superficial fat near the cutaneous– subcutaneous junction; however, tumors with significant extension into fat should be regarded as potentially malignant. Because the entire base of the lesion must be examined to make this determination, a diagnosis based on a poorly sampled

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

 FIGURE 30-17 Cellular dermatofibroma. This variant is hypercellular with a fascicular growth pattern.

Clinical Features Sun-damaged skin of adults Head and neck Frequently rapidly enlarging, usually <1.5 cm Mistaken for squamous cell carcinoma, basal cell carcinoma clinically Histopathologic Features Well circumscribed, symmetric at scanning magnification Located in the dermis with minimal extension in to subcutaneous tissue Marked nuclear pleomorphism, prominent nucleoli, hyperchromasia, and frequent multinucleated giant cells Mitoses are numerous and frequently atypical No necrosis or vascular invasion Differential Diagnosis Squamous cell carcinoma Melanoma Pleomorphic sarcomas Metastasis

779

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 780

A

B  FIGURE 30-19 Atypical fibroxanthoma. (A) The composite cells range from highly pleomorphic bizarre forms with marked hyperchromasia and irregular nuclear outlines. (B) Occasional cases are composed of more uniform spindled cells. Mitoses are often numerous and frequently atypical. The tumor cells are often arranged in a storiform or fascicular pattern. (Figure 30-19: Courtesy of Dr. A. Folpe, Mayo Clinic, Rochester, MN).

specimen, shave biopsy, or punch biopsy is not advised. Even if strict criteria are followed, recent case reports suggest that some atypical fibroxanthomas may have the potential to metastasize; however, this has not been our experience. In a large series of 140 atypical fibroxanthomas, nine patients developed recurrence, and none developed metastatic disease.64 Deeply invasive tumors raise the possibility of pleomorphic sarcomas including leiomyosarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor, extraosseous osteosarcoma and pleomorphic rhabdomyosarcoma. Immunohistochemical studies may be helpful in the differential diagnosis. These studies should never be used to “rule-in” a diagnosis of atypical

fibroxanthoma; rather, they are used to rule out other tumors.66 This approach is based on the fact that atypical fibroxanthoma is positive only for highly nonspecific markers, such as vimentin, α1-antitrypsin, and α1-antichymotrypsin. Recently, additional markers said to be helpful to “rule in” atypical fibroxanthoma, such as CD99, CD10, calponin and (probably most widely used) procollagen-1 70 have been proposed to be useful in conjunction with markers to rule out other malignant neoplasms, but they require further validation. More specific immunohistochemical markers such as desmin, S-100, HMB45, MelanA/MART-1, and a panel of keratins should be used to exclude other pleomorphic tumors. Reactivity with keratins suggest spindle cell squamous cell carcinoma,

perhaps the commonest simulant of atypical fibroxanthoma. Because atypical fibroxanthoma arises in severely sundamaged skin, the presence of actinic keratosis or squamous cell carcinoma in situ in the same biopsy should not reflexively lead to a diagnosis of pleomorphic squamous cell carcinoma but nevertheless should be sought carefully. Keratin immunoreactivity is helpful in this situation. It is not surprising that atypical fibroxanthoma may coexist with other tumors related to sun exposure, especially basal cell carcinoma and squamous cell carcinoma. Pleomorphic or spindle cell melanoma must also be considered in the differential diagnosis of atypical fibroxanthoma. The epidermis should be examined for atypical intraepidermal malignant melanocytes and precursor lesions. Immunoreactivity for S-100 protein and HMB45 or Melan-A/MART-1 suggest melanoma; however, it should be kept in mind that HMB-45 and Melan-A/MART-1 results are often negative in spindle cell or pleomorphic melanomas. It should be noted that scattered Langerhans cells and histiocytes immunoreactive for S-100 protein are commonly present within atypical fibroxanthoma and must be distinguished from immunoreactivity in tumor cells.70,71 Spindle cell variants of angiosarcoma may also rarely simulate atypical fibroxanthoma. In most cases, careful histologic evaluation reveals more typical areas of angiosarcoma, with dissecting vascular channels lined by hyperchromatic cells. Demonstration of CD31 expression is diagnostic of spindled forms of angiosarcoma, although as with S-100 protein, care must be taken not to mistake CD31-positive intralesional macrophages for reactive tumor cells.72

Giant Cell Tumor of Tendon Sheath CLINICAL FEATURES GCTTS is usually located on the fingers and much less commonly on the toes of young adults (Table 30-15).73 There is a female predominance. GCTTS presents as a slowly growing, painless mass, usually smaller than 3 cm. Tumors may erode adjacent bone. Approximately 10% of cases recur after excision.74 Extremely rare examples of malignant GCTTS have been documented.75 Diffuse type giant cell tumor (pigmented villonodular tenosynovitis) tends to be more aggressive. Because of its deeper location involving the synovium of large joints, this form is usually not encountered by dermatopathologists.

Table 30-15 Giant Cell Tumor of Tendon Sheath

HISTOPATHOLOGIC FEATURES GCTTS is usually multilobulated. Lobules are sometimes separated by synovial-lined spaces (see Table 30-15). The tumor is composed, in variable proportion, of sheets of histiocytoid mononuclear cells, osteoclast-like multinucleate giant cells, xanthoma cells, chronic inflammatory cells, hemosiderin-laden macrophages, and collagenized stroma (Fig. 30-20). The degree of cellularity and collagenization varies and is probably related to age of the lesion. As lesions age, they tend to become less cellular, and the stroma becomes more hyalinized. Multinucleated cells may be difficult to find and are entirely absent in some tumors. Mitotic figures are frequently present and may be numerous on occasion. DIFFERENTIAL DIAGNOSIS Hyalinized examples of GCTTS may resemble fibroma of tendon sheath, and distinction may be difficult.16 The presence of cleftlike vascular spaces and the absence of giant cells favors fibroma of tendon sheath. GCTTS with prominent fascicular arrangements of spindle cells may closely resemble dermatofibroma. However, the other features typical of GCTTS and the location facilitate the distinction of GCTTS from dermatofibroma. Occasional epithelioid sarcomas may contain multinucleated giant cells. The presence of a monomorphic population of epithelioid cells with characteristic necrosis surrounded by a palisade of tumor cells and cytologic atypia helps distinguish epithelioid sarcoma from GCTTS. In

 FIGURE 30-20 Giant cell tumor of tendon sheath. The tumor is composed predominantly of sheets of histiocytoid mononuclear cells and osteoclast-like multinucleate giant cells within variable amounts of collagenous stroma. In addition, xanthoma cells, chronic inflammatory cells, and hemosiderin-laden macrophages may be present.

difficult cases, keratin immunoreactivity helps confirm a diagnosis of epithelioid sarcoma. Highly cellular examples of GCTTS, particularly those with few giant cells, may be mistaken for round cell malignant neoplasms, including lymphoma. This is particularly true in thick sections. In contrast to giant cell tumor of the tendon sheath, giant cell tumor of soft tissues (soft tissue giant cell tumor of low malignant potential),76-78 the soft tissue counterpart of giant cell tumor of bone, has significant capacity for local recurrences, but only rarely metastasizes, usually to lymph nodes. However, recently, metastases to the parotid and the lung have been reported.79,80 It usually presents in the skin or subcutis of young to middle-aged adults and, in contrast to giant cell tumor of the tendon sheath, often shows a multinodular growth pattern. The tumor nodules of giant cell tumor of soft tissues consist of a mixture of osteoclastic giant cells, bland mononuclear cells, and short fascicles of bland spindled cells. Mitotic figures are usually easily identified, but atypical forms are not. Other commonly present features include a peripheral shell of woven bone and cystic change, reminiscent of aneurysmal bone cyst. Vascular involvement may be present. Giant cell tumor of the tendon sheath differs from giant cell tumor of soft tissues by virtue of its usual location near joint

spaces or bursae; a uninodular rather than multinodular growth pattern; prominent stromal hyalinization; and its generally more mixed population of small synoviocyte-like cells, siderophages, foamy histiocytes, and lymphocytes. Metaplastic bone production is not seen in giant cell tumor of the tendon sheath.

FIBROUS AND FIBROHISTIOCYTIC TUMORS OF CHILDHOOD

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

Clinical Features Predilection for young women Fingers, much less commonly in the toes Slowly growing painless mass, <3cm May recur after excision Histopathologic Features Multilobulated Varying proportions of histiocytoid mononuclear cells, osteoclast-like multinucleated giant cells, xanthoma cells, chronic inflammatory cells, hemosiderin-laden macrophages, collagenized stroma Multinucleated cells may be difficult to find Mitotic figures may be present Differential Diagnosis Fibroma of tendon sheath Dermatofibroma Epithelioid sarcoma Giant cell tumor of soft tissues

Infantile Digital Fibromatosis Synonyms: inclusion body fibromatosis, recurring digital fibrous tumor of childhood Infantile digital fibromatosis of childhood is a distinctive myofibroblastic proliferation occurring mainly in the fingers and toes of infants and young children. A perplexing feature of this tumor is sparing of the thumb and great toe in all cases. The pathognomonic histologic finding is the presence of cytoplasmic eosinophilic inclusion bodies. CLINICAL FEATURES Infantile digital fibromatosis occurs nearly exclusively in young children and infants (Table 30-16). Most occur in children under 1 year of age, and one-third are present at birth. Approximately one-third of patients have multiple tumors that may affect both

781

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 30-16 Infantile Digital Fibromatosis

782

Clinical Features Asymptomatic dermal or subcutaneous nodule, <2 cm Involvement of fingers and toes, especially lateral aspect Sparing of the great toe and thumb More than half recur after excision Spontaneous regression in most cases Rare cases in adults and at extradigital sites Histopathologic Features Poorly circumscribed Sweeping fascicles of (myo)fibroblasts Pathognomonic eosinophilic inclusions, stain with trichrome and PTAH (phosphotungstic acid-hematoxylin) Differential Diagnosis Dermal scar Dermatofibroma

hands and feet, and these may be asynchronous. Most tumors are smaller than 2 cm, asymptomatic, and tend to be located on the lateral aspect of the digit.81,82 Rare tumors with identical pathologic features have been observed in adults. In this population, the lesion tends to occur in nondigital locations.83,84 Because recurrence is common after excision and most of these lesions regress eventually without therapy, only clinical follow-up of these lesions is warranted unless functional compromise or symptoms dictate otherwise.85 HISTOPATHOLOGIC FEATURES The tumor is poorly circumscribed and composed of interlacing bundles of fibroblasts and myofibroblasts in variably collagenous stroma (see Table 30-16). Lesions may be located primarily in the dermis or extend deeply into the subcutaneous tissue, even to periosteum. Nuclei are uniform, spindled, and somewhat wavy. The pathognomonic intracytoplasmic eosinophilic (often orange-red) inclusions vary from a fraction of the size of a red blood cell to several times larger and are frequently located next to the nucleus (Fig. 30-21). The inclusions may be rare or numerous. Staining with trichrome or phosphotungstic acid-hematoxylin (PTAH) is helpful to identify inclusions in cases in which they are difficult to locate on routine hematoxylin and eosin (H&E) staining. The inclusions have been shown to be composed of actin filaments by immunoelectron microscopy.86 DIFFERENTIAL DIAGNOSIS Because of the unique clinical setting and pathognomonic

 FIGURE 30-21 Infantile digital fibromatosis. Note the interlacing bundles of fibroblasts and myofibroblasts within collagenous stroma and with diagnostic small, eosinophilic inclusions. The nuclei are uniform, spindled, and somewhat wavy. The pathognomonic intracytoplasmic eosinophilic inclusions are usually appreciated in standard hematoxylin and eosin–stained sections.

inclusions, the diagnosis of infantile digital fibromatosis is rarely a challenge. As mentioned, PTAH and trichrome stains help to highlight the inclusions in cases in which they are difficult to find. It is interesting to note that comparable inclusions are now being recognized in other types of myofibroblastic or myoid lesions.87

Infantile Myofibromatosis and Solitary Myofibroma Infantile myofibromatosis is a disease of infants and young children with a predilection for boys. Some cases appear to be inherited, mostly in an autosomal dominant pattern.88-90 The disease may be limited to a single lesion, or multifocal lesions involving bones and viscera, particularly the lungs and gastrointestinal tract, may be present. Early literature emphasized cases with systemic involvement, giving the false impression that this was the most common form of the disease. Larger series have concluded that the solitary tumors predominate.91,92 Immunohistochemical and ultrastructural evidence suggest that these tumors are myofibroblastic in origin.91,93 Adults may be affected by tumors that are histologically similar to infantile myofibromatosis; however, multiple lesions are rare in this population.92,93 For this reason, the tumors are termed solitary myofibromas in adults.

CLINICAL FEATURES Skin and soft tissue lesions tend to be smaller than 3 to 4 cm and often present in the perinatal period as small subcutaneous or soft tissue nodules or a poorly defined swelling (Table 30-17). The head, neck, and trunk are the most common sites of skin and soft tissue involvement. Because lesions may recur after surgical excision and most lesions eventually show spontaneous regression if left untreated, close clinical follow-up after diagnosis is a reasonable clinical approach. Children with multiple lesions often show involvement of bones. Patients with visceral involvement, particularly lung and gastrointestinal tract, have a worse prognosis, with a potentially fatal outcome.94 The adult solitary myofibroma usually presents as a solitary subcutaneous nodule or mass in a wide variety of sites, but a head and neck location is most common. Visceral involvement is not seen in adults. Recurrence is rare.95 HISTOPATHOLOGIC FEATURES The tumors are well circumscribed but unencapsulated and are composed of two distinct elements that are present in varying proportions (see Table 30-17 and Fig. 30-22). First, broad, sweeping fascicles or whorled nodules of myoid-appearing spindle cells with bland nuclei and abundant eosinophilic cytoplasm resembling myofibroblasts are present. The second component

Table 30-17 Infantile Myofibromatosis and Solitary Myofibroma

is characterized by more cellular areas of primitive small round to spindled cells with scant cytoplasm. This primitive cellular component is often associated with a hemangiopericytoma-like pattern of branching vessels (Fig. 30-23). A distinctly zonal appearance is seen in most myofibromas, with the myoid zones typically present at the periphery of the lesion and the primitive zones more centrally located. Several features may lead to a mistaken diagnosis of malignancy; necrosis, vascular invasion, and mitoses may be present. The spindled cells usually stain with actin. Solitary myofibroma of adults is histologically similar to the infantile form, except that there is often only a small component of primitive cells with a hemangiopericytoma-like vascular pattern.96 Stromal hyalinization, sometimes with a pseudochondroid appearance, is quite common. The distinctive zonal architecture of childhood myofibromas is seen less often in adult cases. DIFFERENTIAL DIAGNOSIS A careful search for the more differentiated spindle cell fascicles will prevent confusion with “infantile hemangiopericytoma” in cases in which the slitlike vascular pattern is prominent. Probably most, if not all,

 FIGURE 30-22 Myofibroma(tosis). These tumors, especially in children, show distinct zonation, usually with a peripheral rim of distinctly myoid-appearing spindled cells, and a central region of less mature, hemangiopericytoma-like cells.

cases of “infantile hemangiopericytoma” represent cellular variants of infantile myofibromatosis in which the hemangiopericytoma pattern predominates.95 The biphasic pattern also allows differentiation from fibromatosis. Fibrous hamartoma of infancy contains fascicles of myofibroblasts that are similar to those seen in infantile myofibromatosis. The former is distinguished by the presence

of distinctive whorled organoid nests of primitive spindled cells in myxoid stroma as well as areas of disorderly fibrosis and mature adipose tissue. Most important is the recognition that mitoses, necrosis, and vascular invasion may be observed in infantile myofibromatosis and are not indicative of a malignant neoplasm. Vascular invasion is also a feature in up to one-third of adult lesions.

 FIGURE 30-23 Myofibroma(tosis). The primitive cellular component often is associated with a hemangiopericytoma-like pattern of branching vessels.

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

Clinical Features Mainly infants and young children Predilection for boys Subcutaneous or soft tissue nodule, <3-4 cm Head and neck and trunk are the most common sites Lesions may recur after surgical excision Many lesions show spontaneous regression Minority of patients have bone or visceral involvement Histopathologic Features Circumscribed but unencapsulated Sweeping fascicles or whorls of spindled cells with bland nuclei and abundant eosinophilic cytoplasm More cellular zones of smaller round to spindled cells with scant cytoplasm associated with hemangiopericytoma-like vascular pattern Necrosis, vascular invasion, and mitoses may be present Differential Diagnosis “Infantile hemangiopericytoma” Fibromatosis Fibrous hamartoma of infancy

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Juvenile Hyaline Fibromatosis

784

Juvenile hyaline fibromatosis is an extremely rare disease that affects young children and is characterized by the deposition of an amorphous, hyaline material. Siblings are often affected, and the disease shows an autosomal recessive pattern of inheritance. This disorder may also be associated with impaired intellect, gingival hypertrophy, flexural contractures, and bone lesions.97 It represents an inherited abnormality of collagen metabolism rather than a neoplastic process. The gene for this disease is located on chromosome 4q21 and encodes capillary morphogenesis protein 2 (CMG2), which is involved in basement membrane assembly.98 Recently, mutations in this gene have been described in juvenile hyaline fibromatosis and infantile systemic hyalinosis, a related and more severe disorder with hyaline deposits in visceral organs.99,100 CLINICAL FEATURES The onset of this disease is usually before 5 years of age; however, new lesions may continue to develop during adulthood (Table 30-18). Patients develop multiple exophytic lesions ranging from small papules measuring several millimeters to large masses many centimeters in diameter. The lesions have a predilection for the head, neck, and upper trunk. They are slow growing and usually asymptomatic. However, some patients develop multiple disfiguring nodules that require multiple surgical procedures over many years.101,102 HISTOPATHOLOGIC FEATURES The tumors are poorly circumscribed and show variable but usually low cellularity. Separating

Table 30-18 Juvenile Hyaline Fibromatosis

Clinical Features Onset in first 5 years of life Siblings may be affected Lesions often are multiple Size ranges from small papules to large masses May be associated with gingival hypertrophy, flexion contractures, bone lesions, impaired intellect Histopathologic Features Bands of homogeneous “glassy” hyaline material Bland fibroblasts, cellularity varies Differential Diagnosis Keloid Infantile myofibromatosis

 FIGURE 30-24 Juvenile hyaline fibromatosis. This unusual and rare lesion is characterized by paucicellular ribbons of glassy hyaline eosinophilic material.

strands of bland appearing fibroblasts are ribbons of glassy hyaline eosinophilic material (Fig. 30-24). Early lesions appear more cellular (see Table 30-18).97 Fibroblasts are sometimes surrounded by prominent clear halos caused by retraction artifact. The bands of homogeneous eosinophilic material, the defining feature of this disorder, stain with periodic acid-Schiff (PAS) and Alcian blue stains.97 DIFFERENTIAL DIAGNOSIS The diagnosis is not difficult if the pathologist is cognizant of this entity. The presence of affected siblings is suggestive of this diagnosis. The broad bands of hyaline eosinophilic material are distinctive but could be confused with the bands of collagen seen in keloidal scars. The bands of amorphous hyaline material lack the fibrillar appearance of keloidal collagen. Infantile myofibromatosis could be confused clinically; however, the latter is usually more cellular; often has a hemangiopericytoma-like vascular pattern; and, most importantly, lacks hyaline material. Nodular fasciitis also may show keloidal hyalinization as a pattern of regression but the typical “feathery” appearance of the cellular component allows ready distinction.

Fibrous Hamartoma of Infancy CLINICAL FEATURES Fibrous hamartoma of infancy is a distinctive fibrous proliferation that occurs most often in children younger than 2 years of age and shows a predilection for boys (Table 30-19).103,104

Approximately 15% of the tumors are present at birth. The patient presents with an ill-defined subcutaneous mass usually in the shoulder, upper arm, or axillary region. Less common sites include extremities, pubic area, and scrotum.105 Most tumors are smaller than 5 cm, may develop slowly or rapidly, and may be mobile or adherent to muscle or fascia.103 These tumors are not prone to spontaneous regression if followed clinically or recurrence after surgical excision.106,107 HISTOPATHOLOGIC FEATURES Tumors are situated in the deep dermis, are unencapsulated

Table 30-19 Fibrous Hamartoma of Infancy

Clinical Features Children <2 years of age with a predilection for boys 15% of tumors are present at birth Slowly or rapidly growing ill-defined subcutaneous mass Shoulder, upper arm, or axillary region Usually no spontaneous regression No recurrence after surgical excision Histopathologic Features Fascicles of eosinophilic spindle cells Organoid nests of primitive appearing round to spindle cells within a myxoid matrix, mature fat dispersed in varying amounts Scarlike fibrous tissue Differential Diagnosis Infantile myofibromatosis Connective tissue nevus

Table 30-20 Giant Cell Fibroblastoma

 FIGURE 30-25 Fibrous hamartoma of infancy. Note the fascicles of palely eosinophilic spindle cells, organoid nests of primitive cells within a myxoid background, and fat.

but relatively circumscribed, and are composed of four distinctive elements (see Table 30-19 and Fig. 30-25): 1. Fascicles of pale eosinophilic spindle cells of varying width 2. Organoid nests of primitive appearing, round to spindled cells within a myxoid background. The myxoid matrix is Alcian blue positive, and staining is abolished with hyaluronidase pretreatment. 3. Mature fat dispersed in varying amounts 4. Scarlike fibrous tissue These four elements may be present in varying proportions. The spindle cells appear to be composed of actin-positive myofibroblasts and fibroblasts.107 DIFFERENTIAL DIAGNOSIS In most cases, the findings are so distinctive that differentiation from other tumors is not difficult. However, in cases with only a minor component of the primitive myxoid foci, diagnosis may be challenging. Careful search for and identification of this element allow distinction from infantile myofibromatosis and connective tissue nevus. In addition, the hemangiopericytoma-like vascular pattern seen in myofibromatosis is not seen in fibrous hamartoma. The plexiform growth pattern of the spindled component of fibrous hamartoma may suggest plexiform fibrohistiocytic tumor. Unlike plexiform fibrohistiocytic tumor,

however, nodules of rounded cells and osteoclast-like giant cells are not present. A case of fibrous hamartoma with only a minor component of primitive myxoid zones might closely simulate infantile forms of fibromatosis (so-called lipofibromatosis).108

Giant Cell Fibroblastoma Giant cell fibroblastoma is a rare tumor of children that shares some pathologic features with, and is closely related to, DFSP. Tumors showing elements resembling both giant cell fibroblastoma and DFSP have been documented.109 Giant cell fibroblastoma may recur with histologic features of DFSP.110 In addition, DFSP may recur with a histologic phenotype similar to giant cell fibroblastoma.111 Both tumors are reactive for CD34. Finally, abnormalities involving chromosome 17 and 22 have been documented in both of these tumors, leading to the expression of a fusion gene consisting of the platelet-derived growth factor (PDGF) B-chain gene (PDFGB) and the collagen gene COL1A1.112-114 A recent report suggests that cytogenetic and molecular differences between both tumors may not lie in the type of translocation (unbalanced versus balanced, linear versus supernumary ring chromosome) but rather genomic gains resulting in increased copy numbers of the resulting PDFGB-COL1A1 gene in dermatofibrosarcoma.115 Evidence points to a fibroblastic origin for giant cell fibroblastoma.116

CLINICAL FEATURES This tumor occurs mainly, but not exclusively, in young children, particularly boys (Table 30-20).117 Cases in adulthood are distinctly rare. There is a predilection for the trunk, groin, and lower extremities. Most lesions are a few centimeters in size and asymptomatic. These tumors are situated in the dermis or superficial subcutaneous tissue. The overlying skin is usually unremarkable. Between 30% and 50% of cases recur after surgical excision. For this reason, wide local excision is advocated, if clinically feasible. Metastases have not been recorded. HISTOPATHOLOGIC FEATURES The principal histologic hallmark of this tumor is the presence of irregular pseudovascular spaces lined by multinucleated, often floret-like giant cells (see Table 30-20 and Fig. 30-26). The cells lining the pseudovascular spaces are not immunoreactive for specific endothelial markers, such as CD31, but do express CD34.118 The pseudovascular spaces are frequently separated by hypocellular hyalinized ribbons of collagenous tissue arranged in a parallel array. The bulk of the tumor is composed of diffusely infiltrative sheets of fibroblastic spindle cells in a matrix that is often myxoid. Such cellular areas usually involve the subcutaneous adipose tissue. Some cases show hypercellular areas with a storiform pattern resembling DFSP. Transition between cellular and myxoid areas may be gradual or abrupt. Giant cells, similar to

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

Clinical Features Young children, particularly boys Asymptomatic subcutaneous lesions of the trunk, groin, and lower extremities 30%-50% of cases recur after surgical excision Histopathologic Features Irregular pseudovascular spaces lined by multinucleated giant cells Hypocellular hyalinized ribbons of collagenous tissue Diffuse spindle cells Storiform pattern resembling dermatofibrosarcoma protuberans in some cases Differential Diagnosis Vascular tumor or hemangioma Dermatofibrosarcoma protuberans Giant cell angiofibroma

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stimulation of the PDGF receptor PDGFR by PDGFB appears to play a role in tumor cell proliferation. Interestingly the tyrosine kinase inhibitor imatinibe mesylate appears to inhibit these signals and has been used successfully in various studies, leading to its approval for the treatment of unresectable or metastatic dermatofibrosarcoma.125

786

CLINICAL FEATURES DFSP affects individuals over a wide age range, from children to the elderly, but occurs most commonly in young and middle-aged adults (Table 30-21). The tumor presents as a slowly enlarging plaque and subsequent nodule that is frequently present for many years before diagnosis (Fig. 30-27A). After long periods of stable size or slow growth, tumors may enlarge rapidly. The most commonly affected sites are the trunk and proximal extremities. The extent of tumor is frequently underestimated. Tumors with uninvolved surgical margins of 3 cm or greater have a lower recurrence rate (20%) than tumors with narrower

A

Table 30-21 Dermatofibrosarcoma Protuberans B  FIGURE 30-26 Giant cell fibroblastoma. (A) Scanning magnification shows pseudovascular spaces separated by ribbons of fibrous tissue consisting of fibroblastic spindle cells, which diffusely infiltrate subcutaneous tissue. (B) High power view a multinucleated floret-like giant cell.

those lining the pseudovascular spaces, are seen in variable numbers in both myxoid and cellular areas of the tumor. DIFFERENTIAL DIAGNOSIS The differential diagnosis is not difficult if the angiectoid spaces are recognized as pseudovascular; otherwise, confusion with vascular neoplasms is possible. Because the tumor cells are immunoreactive for CD34, a marker for endothelial cells, there is further potential for confusion with vascular tumors. As already noted, cellular tumors with a storiform architectural pattern share more than a superficial resemblance to DFSP. Giant cells, pseudovascular spaces, and the young age of the patient should allow distinction. Another morphologically similar but rare lesion is giant cell angiofibroma (giant cell–rich solitary fibrous tumor) that, in contrast, occurs mainly around

the orbit, is well circumscribed, and shows areas identical to ordinary solitary fibrous tumor.119,120

FIBROUS AND FIBROHISTIOCYTIC TUMORS OF INTERMEDIATE MALIGNANCY

Dermatofibrosarcoma Protuberans DFSP is increasingly being accepted as a tumor of the fibrohistiocytic lineage. Cytogenetic analyses have identified abnormalities shared with giant cell fibroblastoma, most frequently ring chromosomes derived from chromosomes 17 and 22 or a linear t(17;22).121-123 These cytogenetic abnormalities lead to the expression of a fusion gene consisting of the PDGF B-chain gene (PDFGB) and the collagen gene COL1A1.114,124 Autocrine

Clinical Features Most common in young and middle-aged adults Slowly enlarging nodule or plaque Trunk and proximal extremities Tumors may enlarge rapidly Recurrence rate (20%) depends on wide local excision with generous free margins Occasional tumors metastasize Histopathologic Features Diffuse infiltration of subcutaneous tissue with entrapment of fat creating a sievelike pattern Uniform population of cells with spindled nuclei, scant cytoplasm Whorled or storiform pattern Inflammatory cells and xanthoma cells are absent or sparse Mitotic rate is usually <5 mitoses per 10 high-power fields Variants: myxoid change, fibrosarcoma-like areas, giant cell fibroblastoma-like foci, dendritic melanin-containing cells, myoid nodules Differential Diagnosis Cellular dermatofibroma Neurofibroma Pleomorphic sarcoma Myxoid liposarcoma Myxofibrosarcoma

A

B  FIGURE 30-27 Dermatofibrosarcoma protuberans. (A) Plaque composed of three reddish brown coalescent papules. (B) At scanning magnification, diffuse infiltration of subcutaneous tissue with entrapment of fat by tumor cells results in a sievelike or “Swiss cheese” pattern. The tumor is composed of a uniform population of small oval or spindled cells arranged in a whorled or storiform pattern.

margins.126 Although it has been difficult to estimate the incidence of metastatic disease, occasional tumors metastasize.127 Metastases seem to occur almost exclusively in recurrent lesions that have undergone fibrosarcomatous transformation. The overall incidence of metastases appears to be less than 0.5%. HISTOPATHOLOGIC FEATURES The histopathology of DFSP is remarkably similar from case to case (see Table 30-21). Tumors tend to be localized to the reticular dermis and subcutis, usually sparing

the papillary dermis. The epidermis frequently is unremarkable, but ulceration may occur. Epidermal hyperplasia with basilar hyperpigmentation, as one observes in dermatofibroma, may be seen occasionally, particularly with tumors involving the superficial dermis. At scanning magnification, there is diffuse infiltration of subcutaneous tissue with entrapment of fat by tumor cells, resulting in a sievelike or honeycomb pattern (Fig. 30-27B). The tumor is composed of a remarkably uniform population of cells with relatively small oval or

DIFFERENTIAL DIAGNOSIS For small biopsy specimens, the main differential diagnosis is cellular dermatofibroma. Hyperplastic pigmented epidermal rete, inflammatory cell infiltrates, foam cells, and entrapment of collagen all favor dermatofibroma. Less cellular DFSPs can be very difficult to distinguish from superficially biopsied dermatofibromas in which the characteristic infiltration of fat is not appreciated. Fortunately, the clinical appearance of dermatofibroma, that is, a small firm hyperpigmented nodule, is quite different from the gross appearance of DFSP. Thus, clinical information may be helpful in difficult cases. For equivocal tumors in which the base of the lesion is not visualized, it is prudent to request reexcision so that the entire lesion may be examined. Nearly all cases of DFSP are immunoreactive for CD34, an attribute helpful in distinguishing DFSP from dermatofibroma.136 It should be recognized that cellular dermatofibromas may contain a reactive collar of CD34-positive cells, and care should be taken not to misdiagnose such cases as DFSP. DFSP may mimic neurofibroma, particularly in small biopsies. Careful search for more cellular areas with a storiform pattern usually leads to the correct diagnosis. Immunostaining for

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

spindled nuclei and scant pale cytoplasm, arranged in a whorled or storiform pattern. In general, this storiform pattern is maintained throughout the tumor. DFSP usually have prominent cellularity, and this cellularity usually is greatest near the center of the lesion. Multinucleate cells, xanthoma cells, and inflammatory cells are generally sparse or absent. The mitotic rate is usually less than 5 mitoses per 10 high-power fields.128 Although most DFSP are remarkably similar histologically, some tumors display heterogeneity, including extensive myxoid change, hyalinization, fibrosarcoma-like areas (Fig. 30-28), and giant cell fibroblastoma-like foci.129,130 “High-grade” change in DFSP usually shows fibrosarcoma-like histology, with long fascicles of hyperchromatic, relatively monomorphic spindled cells, although occasional cases may show pleomorphic sarcomalike changes. Although it has been thought that tumors with a significant amount of fibrosarcoma-like areas have a worse prognosis,131 this does not appear to be true for lesions that have received appropriate surgical therapy.132 DFSP containing dendritic melanin-containing cells have been termed pigmented DFSP or Bednar tumor (Fig. 30-29).133,134 Nodular myoid differentiation, most notably in the fibrosarcomatous variant, may occur.135

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a primary granulomatous process. This tumor is considered to be a low-grade neoplasm based on frequent and, in some cases, persistent recurrence, as well as the potential for metastasis. Ultrastructural and immunohistochemical studies favor a myofibroblastic origin for this tumor.137

788

 FIGURE 30-28 Dermatofibrosarcoma protuberans (DFSP). This DFSP shows areas identical to fibrosarcoma. Tumors with a significant degree of fibrosarcoma-like areas may have a worse prognosis.

S-100 protein is very helpful because DFSP, unlike virtually all neurofibromas, is not immunoreactive with this marker. Pleomorphic sarcomas may also have a prominent storiform pattern. Although focal pleomorphism may occur in DFSP, marked pleomorphism favors a pleomorphic sarcoma. DFSP with extensive myxoid change may mimic myxoid liposarcoma; however, “chicken wire” vasculature and the lipoblasts are diagnostic of liposarcoma. Extensive sampling

of DFSP with myxoid change almost always reveals areas with more typical histologic features. Scattered cells with marked pleomorphism, pseudolipoblasts, and characteristic arcuate vessels distinguish myxofibrosarcoma from myxoid DFSP.

Plexiform Fibrohistiocytic Tumor Plexiform fibrohistiocytic tumor is a distinctive tumor that is easily mistaken for

 FIGURE 30-29 Pigmented dermatofibrosarcoma protuberans (Bednar tumor). This tumor has dendritic melanin-containing cells. Otherwise, the tumor has typical features of dermatofibrosarcoma protuberans.

CLINICAL FEATURES This tumor occurs primarily in children and young adults and is more common in girls and young women (Table 30-22).138,139 In the largest series reported, the median age was 14.5 years.138 The tumor is an ill-defined, slow-growing nodule or mass, usually between 1 and 3 cm, but ranges up to 6 cm in diameter.138 The tumor is located in the upper extremity in nearly two-thirds of patients, with a predilection for the shoulder and forearm. Up to 37.5% recur after excision.138 In addition, metastases to local lymph nodes and lung metastases have been reported.138-140 Occasionally, tumors regress spontaneously.137 HISTOPATHOLOGIC FEATURES The tumor is composed of two elements in varying proportions: fascicles of fibroblastic cells and well-delineated, often nodular aggregates of histiocyte-like cells (see Table 30-22 and Fig. 30-30). The fascicles of fibroblastic cells are arranged in a

Table 30-22 Plexiform Fibrohistiocytic Tumor

Clinical Features Mainly children and young adults; more common in girls and young women Ill-defined, slow-growing nodule or mass, usually between 1 and 3 cm Upper extremity in nearly two-thirds of patients, particularly the shoulder and forearm 38% recur after excision; rare nodal or lung metastases Histopathologic Features Fascicles of fibroblastic cells arranged in a complex plexiform pattern Aggregates of histiocyte-like cells, often with osteoclast-like multinucleated cells and associated lymphocytes Hemorrhage common in histiocytic nodules Pleomorphism is usually not present, and mitoses are rare Differential Diagnosis Infectious process Primary granulomatous disease Fibromatosis Fibrous hamartoma of infancy Giant cell tumor of tendon sheath Giant cell tumor of soft tissues

plexiform fibrohistiocytic tumor. Location on the fingers and the relative lack of inflammatory and spindle cell components help to distinguish GCTTS from plexiform fibrohistiocytic tumor. Soft tissue giant cell tumors may closely simulate the histiocytic or osteoclastic nodules of plexiform fibrohistiocytic tumor, but they often have a shell of metaplastic bone and lack a fibroblastic component.76 Marked cytologic atypia is seen in giant cell–rich variants of pleomorphic sarcomas such as soft tissue osteosarcomas and leiomyosarcomas.

A

Angiomatoid Fibrous Histiocytoma

 FIGURE 30-30 Plexiform fibrohistiocytic tumor. (A) Scanning magnification shows fascicles of fibroblastic cells are arranged in a complex plexiform pattern. (B) High-power view shows aggregates of histiocyte-like cells associated with osteoclast-like multinucleated forms surrounded by fibrous tissue.

complex plexiform pattern, may form thin or broad bands, and tend to trap adipose tissue between them. Dispersed throughout this background are nodular aggregates of histiocyte-like cells, frequently associated with osteoclast-like multinucleated forms. A lymphocytic infiltrate is often seen, usually associated with the histiocytic foci. The transition between the fibroblastic fascicles and aggregates of histiocyte-like cells may be abrupt in some foci and gradual in others. Extravasation of red blood cells and hemosiderin deposition is common in the nodular histiocytic areas. Although all tumors have a mixture of both elements, some tumors are composed almost exclusively of the fibroblastic pattern. Rare tumors may be predominantly composed of the histiocytic component.137 Significant pleomorphism is usually not present, and mitoses are infrequent. However, vascular invasion is evident in some cases. The spindled and mononuclear cells usually express actin, and the osteoclast-like giant cells are immunoreactive for CD68.138

DIFFERENTIAL DIAGNOSIS Plexiform fibrohistiocytic tumor must be distinguished from an infectious process and primary granulomatous disease such as sarcoidosis. Confusion is most likely to occur in the rare tumors with a predominantly histiocytic pattern. The presence of central necrosis within histiocytic nodules is strongly suggestive of an infectious etiology. A conspicuous fibroblastic component with a plexiform growth pattern is present in most tumors and allows easy distinction from an infectious process. Whenever there is any doubt regarding the diagnosis, special stains for organisms should be examined and tissue submitted for culture. Predominantly fibroblastic tumors could be confused with fibromatosis; however, close inspection will show at least a few histiocytic nodules. This tumor must be distinguished from fibrous hamartoma of infancy, another tumor with a predilection for the shoulder area. The distinctive myxoid areas with an organoid arrangement that characterize fibrous hamartoma of infancy are not seen in

Table 30-23 Angiomatoid Fibrous Histiocytoma

Clinical Features Median age, 14 years Slowly enlarging deep dermal of subcutaneous growth Constitutional symptoms Local recurrence rate of 12% and metastasis rate of 1%-5% Histopathologic Features Well-circumscribed multiple nodules and sheets of uniform epithelioid to spindled cells Cells show abundant eosinophilic cytoplasm and uniform vesicular nuclei Dense collagenous stroma, often with hemosiderin Usually shows pseudocapsule and cuff of chronic inflammatory cells, sometimes with germinal centers Hemorrhagic spaces lined by neoplastic cells Differential Diagnosis Vascular tumors Aneurysmal and hemosiderotic variants of dermatofibroma Lymph node metastasis

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

B

AFH (see Table 30-23), previously known as angiomatoid malignant fibrous histiocytoma (MFH), was originally described by Enzinger, in 1979, as a “distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm.”141 Although AFH was originally regarded as a variant of MFH, subsequent study has proven the generally indolent behavior of this tumor. Two large studies have shown AFH to have a local recurrence rate of only 12% and a metastatic rate of 1% to 5%.142,143 For these reasons, the World Health Organization has reclassified AFH as a fibrohistiocytic tumor of intermediate malignancy rather than as a fully malignant sarcoma. The behavior of tumors that occur in the head or neck appears

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to be somewhat worse, probably as a consequence of difficulties in achieving complete excision.

790

CLINICAL FEATURES AFH typically presents as slowly growing deep dermal or subcutaneous growths in young patients (median age, 14 years). Constitutional symptoms are seen in a significant subset of patients and appear to be a result of the elaboration of cytokines (eg, interleukin-6) by the neoplastic cells144 ; these symptoms vanish with resection of the tumor. In early case reports, tumor cells were shown to carry a t(16p11;12q13) leading to expression of a FUS-ATF1 fusion protein, and a t(22q12;12q13) leading to expression of an EWSR-ATF1 fusion protein.145-147 However, more recent studies in which nine and 14 cases were analyzed showed EWSRCREB1 to be the predominant fusion protein, with occasional tumors showing EWSR-ATF1 fusion proteins.148,149 Interestingly, the fusion proteins have been reported in clear cell sarcoma of the gastrointestinal tract and soft tissue, respectively, which are morphologically and clinically distinct from AFH. HISTOPATHOLOGIC FEATURES AFH usually is well circumscribed and composed of multiple nodules and sheets of uniform epithelioid to spindled cells with abundant eosinophilic cytoplasm and uniform ovoid vesicular nuclei.141-144,150,151 These nodules tend to be distributed in a densely collagenous stroma often containing hemosiderin pigment. The tumor is frequently surrounded by a pseudocapsule, and a cuff of chronic inflammatory cells that may be dense and associated with germinal center formation is present at the periphery of the tumor. The presence of hemorrhagic spaces lined by neoplastic cells may suggest a vascular neoplasm (Fig. 30-31). A variety of growth patterns, including sheets, meningiomalike whorls, and short fascicles are typically seen in AFH, often within a given patient. Although AFH is typically cytologically bland, occasional cases may show striking pleomorphism, which has not been shown to have clinical significance. The cells of AFH have a unique immunophenotype, with coexpression of desmin and CD68 in more than 60% of cases, usually in the absence of other myoid markers such as smooth muscle actins.143,151 Vascular markers (eg, CD31) are negative, aiding in the distinction of this tumor from vascular neoplasms. Morphology and immunohistochemistry suggest that AFH shows myofibroblastic differentiation.151

A

B  FIGURE 30-31 Angiomatoid fibrous histiocytoma. (A) At low magnifications, this tumor shows large hemorrhagic spaces that may suggest a vascular neoplasm. (B) Higher magnification shows this tumor is composed of sheets of uniform epithelioid to spindled cells with abundant eosinophilic cytoplasm and uniform ovoid vesicular nuclei. These cells are not immunoreactive for endothelial cell makers.

DIFFERENTIAL DIAGNOSIS The angiomatoid and cystic features of AFH may suggest an epithelioid vascular tumor. The absence of vascular lumina formation and the presence of histiocytoid cells with solid and whorled growth should allow this distinction without great difficulty. The absence of expression of CD31, CD34, or factor VIII-related antigen in AFH also points away from a truly vascular tumor. Aneurysmal and hemosiderotic variants of dermatofibroma show prominent pseudovascular change, hemorrhage, and hemosiderin staining and may be mistaken for AFH. Careful examination of aneurysmal fibrous histiocytomas shows the characteristic infiltration of spindled cells among preexisting collagen bundles, as well as a more polymorphous cell population, with siderophages and foamy macrophages. The characteristic cell of aneurysmal fibrous histiocytoma is also a spindled cell rather than the distinctly

histiocytoid cell of AFH. Dermatofibromas lack a dense pseudocapsule. The dense capsule and the surrounding lymphoid infiltrate seen in AFH may closely simulate a metastasis to a lymph node. Careful evaluation invariably reveals the absence of normal anatomic landmarks, such as a subcapsular sinus or afferent lymphatics.

Solitary Fibrous Tumor Solitary fibrous tumor is a fibroblastic and myofibroblastic lesion that classically presents in the pleura, although it is increasingly being described in extrapleural locations such as soft tissues.152,153 A limited number of cases have been recently documented in the skin (Table 30-24).154-160 CLINICAL FEATURES Solitary fibrous tumor in the skin shows a predilection for the head or neck region. Generally, it occurs mostly in middle-aged and elderly

Table 30-24 Solitary Fibrous Tumor

patients with no gender predilection. Local recurrence and metastasis have been reported for primary tumors from other organs, and approximately 5% to 10% show an aggressive behavior.161,162 The reported cases of cutaneous solitary fibrous tumor showed a benign course, although local recurrences have been documented.155,160 HISTOPATHOLOGIC FEATURES There is a broad range of morphologic appearances and patterns. The tumor is usually well-circumscribed and characterized by alternating hyper- and hypocellular areas. Frequently, there is a prominent vascular network, often arranged in a branching hemangiopericytoma-like pattern. Other features are perivascular hyalinization and a background of abundant, thick, hyalinized collagen (Fig. 30-32). The cells typically permeate between collagen bundles and are spindled or more plump with minimal cytologic atypia and pale vesicular chromatin with inconspicuous nucleoli. Adipocytes and myxoid change may be present. Mitoses are usually rare. In rare cases, lesions may show pronounced atypia, necrosis, and high mitotic activity. Tumor cells are immunoreactive for CD34, vimentin, and CD99.160,163 They usually are negative for smooth muscle actin and EMA, and, except in rare cases, are negative for S-100 and keratin.

 FIGURE 30-32 Solitary fibrous tumor. Alternating hyper- and hypocellular areas are present, with a prominent vascular network on a background of thick hyalinized collagen.

DIFFERENTIAL DIAGNOSIS Dermatofibroma is usually less circumscribed and shows more polymorphism. CD34 negativity may aid in the differential diagnosis. DFSP lacks a prominent vascular pattern and is not well circumscribed. However, the immunoprofile does not allow a clear distinction because both lesions are CD34 positive and DFSP can occasionally be CD99 positive. Cytogenetic analysis may be helpful because whereas DFSP shows characteristic abnormalities (t(17;22) or ring chromosomes derived from 17 and 22 leading to expression of a PDGFBCOL1A1 fusion gene), solitary fibrous tumor lacks a distinct cytogenetic profile.

MALIGNANT FIBROUS AND FIBROHISTIOCYTIC TUMORS

“Malignant Fibrous Histiocytoma” (Undifferentiated Pleomorphic Sarcoma) Originally, the “MFH” category of soft tissue sarcomas contained five subcategories, including pleomorphic, angiomatoid, myxoid, inflammatory, and giant cell variants. Once the most commonly diagnosed malignant soft tissue tumor, the pleomorphic variant of “MFH” has been critically reevaluated.164-166 Using ultrastructural and immunohistochemical techniques, it has been shown that tumors once designated as the pleomorphic

variant of “MFH” are not histiocytic in nature and actually represent a diverse group of tumors that have in common marked cytologic pleomorphism. The criteria used to diagnose “MFH,” including cytologic pleomorphism, multinucleated giant cells, and storiform cellular pattern, are not reproducible, and this diagnosis became a “wastebasket” for pleomorphic tumors. If pleomorphic tumors are thoroughly sampled and examined, most can be precisely diagnosed. Although many turn out to be sarcomas, such as pleomorphic variants of rhabdomyosarcoma, leiomyosarcoma, or liposarcoma, a smaller number of cases represent carcinomas, melanomas, or lymphomas. Admittedly, some pleomorphic tumors defy precise categorization. We diagnose such tumors as highgrade pleomorphic sarcoma, not otherwise specified. Only if the pathologist strives for precise categorization of pleomorphic tumors will relevant clinical correlation be possible. In the skin, pleomorphic sarcomas are rare and often represent extensions of deeper lesions. In addition, cutaneous pleomorphic sarcomatous lesions are often spindle cell variants of melanomas or carcinomas. The classification of the giant cell variant of MFH is fraught with similar problems. This variant is similar to pleomorphic MFH with numerous osteoclast-like giant cells. Approximately half of these cases

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

Clinical Features Most common in pleura and soft tissues Rare in skin, with predilection of head and neck region Middle-aged and elderly patients Local recurrence described in skin tumors; 5%-10% of soft tissue and pleural tumors show aggressive behavior Histopathologic Features Broad range of morphologic patterns Usually well-circumscribed with alternating hyper- and hypocellular areas Frequently prominent vascular network with branching hemangiopericytoma-like pattern Perivascular hyalinization and background of abundant, thick, hyalinized collagen Typically spindled or plump cells with minimal atypia, permeating between collagen bundles Occasionally adipocytic and myxoid areas Differential Diagnosis Dermatofibroma Dermatofibrosarcoma protuberans

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are associated with osteoid production.167 Such tumors might be more logically designated soft tissue osteosarcomas. Some also represent leimyosarcomas rich in giant cells, and others, which show less pleomorphism and more benign clinical behavior, have been reclassified as giant cell tumors of soft tissue (as discussed previously). Two tumors originally categorized in the “MFH” family, myxofibrosarcoma (“myxoid MFH”) and AFH (“angiomatoid MFH”) appear to be distinct clinicopathologic entities and are often superficially located, thereby coming to the attention of dermatopathologists. As discussed above, AFH has been reclassified as a fibrohistiocytic tumor of intermediate malignancy. Myxofibrosarcoma is discussed below.

Myxofibrosarcoma

HISTOPATHOLOGIC FEATURES Myxofibrosarcoma demonstrates a broad histologic spectrum, from low-grade tumors that must be distinguished from a benign myxoma to high-grade sarcomas (see Table 30-25). Myxofibrosarcoma is characterized by myxoid hypocellular areas composed of acid mucopolysaccharide (mainly hyaluronic acid), often with a multinodular growth pattern (Fig. 30-33). Superficially located myxofibrosarcomas often display diffuse infiltration along preexisting fibrous septae and may extend for some distance beyond their grossly apparent borders. This growth pattern accounts in a large part for the high rate of local recurrences seen with these tumors.172 Characteristic arcuate or curvilinear, thick-walled vessels are seen in these myxoid areas. The neoplastic cells often appear to radiate from these blood vessels in a “Christmas tree” pattern. The cells within the myxoid

areas are spindled and stellate and have atypical hyperchromatic nuclei. “Pseudolipoblasts” are frequently seen in the myxoid areas. These hyperchromatic cells with bubbly cytoplasm that indent the nucleus share more than a passing resemblance to true lipoblasts; however, they contain acid mucin rather than lipid. Furthermore, they are generally smaller than lipoblasts and tend to have non-indented, often central nuclei. The myxoid zones often show transition to more cellular areas and even to highgrade pleomorphic sarcoma. The grading and prognosis of myxofibrosarcoma is dependent on the relative percentage of the hypocellular, myxoid zones, with purely myxoid lesions having the best prognosis. Prognosis is also negatively affected by the presence of necrosis and large size of the lesion.171 A rare epithelioid variant with exhibits hypercellular areas between areas of conventional myxofibrosarcoma.

CLINICAL FEATURES Myxofibrosarcoma usually is located in the extremities of elderly adults but may also be seen in younger patients (Table 30-25).168 There is good correlation between histologic grade and prognosis; low-grade tumors have little metastatic potential.169,170 Overall survival is 60% to 70% for all grades. Recurrence is common, with 57% within 5 years, as shown in a recent large study.171

Table 30-25 Myxofibrosarcoma

Clinical Features Usually located in the extremities of elderly adults Often located in subcutaneous tissue or deep dermis Correlation between histologic grade and prognosis; low-grade tumors have little metastatic potential Overall survival, 60%-70% Histopathologic Features Myxoid hypocellular areas composed of acid mucopolysaccharide Arcuate vessels in myxoid areas Cells within the myxoid areas are spindled and stellate with atypical nuclei Mucin-containing “pseudolipoblasts” Abrupt transition to more cellular or high-grade pleomorphic areas Differential Diagnosis Nodular fasciitis Benign myxomas Superficial angiomyxoma Myxoid liposarcoma Low-grade fibromyxoid sarcoma

A

B  FIGURE 30-33 Myxofibrosarcoma. (A) Note the myxoid stroma and characteristic arcuate or curvilinear blood vessels. (B) Scattered bizarre pleomorphic cells are present in a myxoid background.

In these hypercellular areas, the tumor cells show epithelioid morphology with round nuclei, vesicular chromatin, prominent nucleoli, and moderate amounts of eosinophilic cytoplasm. This variant shows more aggressive behavior than usual myxofibrosarcoma.173

and smaller than the adult form, and usually arises in the extremities.176 The prognosis of infantile fibrosarcoma is much better than that of the adult form. A 35% 5-year survival has been reported in high-grade adult fibrosarcomas.177 The outcome of patients treated with radical surgery appears superior to local excision.178 The infantile form has a much more optimistic outlook, with a 5-year survival of at least 85%.179

DIFFERENTIAL DIAGNOSIS Fibrosarcoma should be approached as a diagnosis of exclusion. Fibrosarcoma should not be immunoreactive for keratins, desmin, S-100 protein, CD34, and EMA. Distinction between low-grade fibrosarcoma and fibromatosis may occasionally be difficult. Fibromatosis lacks the hyperchromasia, nuclear irregularity, and herringbone pattern seen at least focally in conventional fibrosarcomas. There is significant overlap between the mitotic rates of fibrosarcomas and fibromatoses, and the

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

DIFFERENTIAL DIAGNOSIS At the low-grade end of the spectrum, myxofibrosarcoma must be distinguished from myxomas and reactive proliferations, including nodular fasciitis. At the other end of the spectrum, pleomorphic malignant tumors must be considered. Nodular fasciitis and benign myxomas lack significant nuclear atypia and do not display a well-developed vasculature. Superficial angiomyxoma also lacks pleomorphism and arcuate vessels, and approximately one-third of cases are associated with an epithelial cyst. Pseudolipoblasts may suggest myxoid liposarcoma; however, myxoid liposarcoma lacks significant nuclear atypia and has a characteristic “chicken wire” vascular pattern, different from the thickwalled vasculature of myxofibrosarcoma. LGFMS is principally a fibrous tumor with characteristic “abrupt” transition to myxoid nodules, is composed of uniform fibroblasts without significant atypia arranged in a whorled fashion, and lacks arborizing thick-walled vessels. Focal myxoid change may also be seen in essentially any pleomorphic sarcoma. Careful histologic evaluation and appropriate immunostains (eg, actin, S-100 protein) should allow this distinction without great difficulty in most cases.

Clinical Features Adult form: deep-seated, slow-growing mass in the thigh or trunk Infantile form: children younger than 2 years of age, often congenital, superficially located Prognosis of infantile fibrosarcoma is much better than for the adult form Histopathologic Features Uniform spindled cells arranged in herringbone fascicles Nuclei are slender with uniform chromatin and small, inconspicuous nucleoli Cytoplasmic borders not distinct High-grade tumors may have marked nuclear pleomorphism Hemangiopericytoma-like vascular spaces common in infantile tumors Differential Diagnosis Fibromatosis Nodular fasciitis Malignant peripheral nerve sheath tumor Monophasic synovial sarcoma

HISTOPATHOLOGIC FEATURES Adult fibrosarcoma tends to be larger and more deeply located than the infantile form (see Table 30-26). The histopathologic characteristics of the adult and infantile forms of fibrosarcoma are similar. The tumor is composed of strikingly uniform, spindled cells, arranged in herringbone fascicles (Fig. 30-34). The nuclei are slender, with uniform chromatin and small, inconspicuous nucleoli. Cytoplasmic borders are indistinct. Some tumors have variable amounts of dense wirelike collagen. Marked nuclear pleomorphism with clumped chromatin and prominent nucleoli may be seen in some high-grade tumors, making distinction from other high-grade sarcomas difficult. Some tumors are composed of more rounded cells, a feature common in the infantile form. Hemangiopericytoma-like branching vascular spaces are seen in many infantile fibrosarcomas. Immunoreactivity for actin is common in the infantile (but not adult) type.

Table 30-26 Fibrosarcoma

FIBROSARCOMA A 1936 report from the Mayo Clinic classified 65% of soft tissue sarcomas as fibrosarcoma.174 Using current routine diagnostic techniques, including electron microscopy and immunohistochemical studies, it is now clear that many tumors formerly designated fibrosarcoma were actually malignant peripheral nerve sheath tumors, monophasic synovial sarcomas, fibromatosis, and nodular fasciitis, among others. It is now realized that this once frequently diagnosed tumor is very uncommon. CLINICAL FEATURES Two clinically distinct forms of fibrosarcoma are recognized, an adult form and a juvenile form (Table 30-26). Fibrosarcoma in adults usually presents in young and middle-aged adults as a deep-seated, slow-growing, and sometimes painful mass in the thigh or trunk.175 In contrast, infantile fibrosarcoma often affects children younger than 2 years of age, is often congenital, tends to be more superficially located

 FIGURE 30-34 Fibrosarcoma. This tumor is composed of strikingly uniform, spindled cells arranged in herringbone fascicles.

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mitotic rate is not a helpful feature in distinguishing these entities. Before sophisticated diagnostic techniques were developed, some cases of malignant peripheral nerve sheath tumor were interpreted as fibrosarcoma. Tumors arising from neurofibromas and large nerves are most likely neural. Although a herringbone pattern may be seen focally in malignant peripheral nerve sheath tumors, other histologic patterns are usually present, such as myxoid zones and perivascular whorling. Immunoreactivity for S-100 protein is observed in approximately half of malignant peripheral nerve sheath tumors. Ultrastructural examination may be helpful in malignant peripheral nerve sheath tumors that are not immunoreactive for S-100 protein. Leiomyosarcoma is characterized by right angle fascicles composed of plumper spindle cells with cigar-shaped nuclei and is usually positive for desmin and caldesmon. A hemangiopericytoma-like vascular pattern may occur in fibrosarcoma, particularly in the infantile form, and cause confusion with monophasic synovial sarcoma. Immunoreactivity for EMA and keratin distinguish monophasic synovial sarcoma from fibrosarcoma. Cytogenetic analysis may also be helpful in this distinction since synovial sarcoma is associated with an X;18 translocation producing a SYTSSX fusion. Infantile fibrosarcoma shows trisomies of chromosomes 8, 11, 17, 20, and a 12;15 translocation producing a ETV6-NTRK3 fusion gene has been described.180-182 Adult fibrosarcoma shows complex cytogenetic abnormalities.

Low-Grade Fibromyxoid Sarcoma LGFMS is a distinctive variant of fibrosarcoma characterized by an admixture of heavily collagenized and myxoid zones,

A

794

deceptively bland spindled cells with a whorling growth pattern, and arcades of curvilinear blood vessels (Table 30-27). The great majority of LGFMS occur in deep soft tissue, and this lesion is only infrequently encountered by dermatopathologists. CLINICAL FEATURES LGFMSs are rare sarcomas, with fewer than 150 reported cases.183-187 It is difficult, however, to estimate the exact incidence of LGFMS because many tumors go unrecognized. LGFMS occurs equally in men and women and typically involves the proximal extremities of young adults. However, patients of any age may be involved, and up to 19% of cases occur in patients younger than 18 years of age.186 Our understanding of the behavior of LGFMS has evolved and, although early series suggested that LGFMS were paradoxically aggressive sarcomas, these were retrospective studies of patients originally diagnosed with and treated for a benign lesion.183-185 A more recent large series of prospectively diagnosed LGFMS showed recurrences, metastases, and death from disease in only 9%, 6%, and 2% of patients, respectively.186 These results suggest that the prognosis of LGFMS is roughly similar to that of other low-grade sarcomas. However, LGFMS may metastasize many years after initial diagnosis, and indefinite clinical follow-up is indicated for patients with this disease. HISTOPATHOLOGIC FEATURES LGFMS shows an admixture of heavily collagenized, hypocellular zones and more cellular myxoid nodules. Short fascicular and characteristic whorling growth patterns are seen, with the latter pattern often most apparent at the transition from collagenous to myxoid areas

Table 30-27 Low-Grade Fibromyxoid Sarcoma

Clinical Features Most common in young adults Wide variety of locations, mainly axial Size: few centimeters to 15 cm Recurrence after excision is common Risk of metastasis similar to other low-grade sacromas May metastasize many years after initial diagnosis Histopathologic Features Remarkably bland and uniform fibroblasts Paucicellular Whorled growth pattern Background varies from collagenous to myxoid Mitotic rate usually is low and pleomorphism is only slight Differential Diagnosis Easily mistaken for a benign tumor or reactive process Fibromatosis Low-grade myxofibrosarcoma

(Fig. 30-35). The vasculature of LGFMS consists of both small arcades of “curvilinear” small arteries and arteriole-sized vessels with perivascular sclerosis. The cells of LGFMS are very bland, with only scattered hyperchromatic cells. Approximately 40% of otherwise typical LGFMS show the focal presence of poorly formed collagen rosettes, consisting of a central core of hyalinized collagen surrounded by a cuff of epithelioid fibroblasts. In that subset of LGFMS, where collagen rosettes are particularly prominent and well-formed, the term hyalinizing spindle cell tumor with giant rosettes has been applied.187 Both conventional LGFMS and hyalinizing spindle

B

 FIGURE 30-35 Low-grade fibromyxoid sarcoma (LGFMS). (A) This tumor shows transition from myxoid areas to more fibrous areas. (B) Note the characteristic swirling growth pattern. Cellularity is often low, and the tumor is composed of remarkably bland and uniform fibroblasts.

cell tumor with giant rosettes share a t(7q34;16p11), leading to a FUS-CREB3L2 fusion gene.188,189 Immunohistochemically, LGFMS typically express only vimentin, which is consistent with fibroblastic differentiation. Myofibroblastic differentiation, as reflected by focal smooth muscle actin expression, may on occasion be seen. LGFMS almost never expresses desmin, S-100 protein, cytokeratins, EMA, or CD34.

MISCELLANEOUS TUMORS

Epithelioid Sarcoma Epithelioid sarcoma is a distinctive neoplasm of uncertain pathogenesis. Recognition of this tumor is critical because it may be mistaken for a benign granulomatous process or infection. Even when this tumor appears localized clinically, early multifocal locoregional spread often is present, making surgical control a challenge. Patients often have multiple recurrences, and 5-year survival has been reported at approximately 50%.190 A recent study found 5-year and 10-year disease-free survival rates of 34% and 17%, respectively.191 Prognosis correlates with tumor size, recurrence, and extent of tumor necrosis.190-192 Men tend to fare worse than women, and tumors in the distal extremities tend to do better than proximal and more centrally located tumors.190 CLINICAL FEATURES Tumors are most commonly located in the distal extremities, particularly the hand and fingers, of young adult men (Table 30-28).190

Clinical Features Most commonly located in the extremities, particularly in the hand and fingers Young adults males more often than females Tend to be slow growing and multifocal Propensity for multiple recurrences Metastases develop in 50%, usually to lymph nodes and lung Poor long-term prognosis Histopathologic Features Spindled to round cells with abundant eosinophilic cytoplasm Palisade around areas of necrosis Some tumors show a marked chronic inflammatory infiltrate Immunoreactivity for keratins, vimentin, and epithelial membrane antigen Differential Diagnosis Primary necrobiotic granulomatous processes (granuloma annulare, necrobiosis lipoidica, rheumatoid nodule) Granulomatous infection Giant cell tumor of tendon sheath Epithelioid angiosarcoma and epithelioid hemangioendothelioma Squamous cell carcinoma Melanoma Synovial sarcoma

Ulceration of the skin overlying superficial tumors is common. Deep-seated tumors tend to be slow growing and show a multifocal growth pattern of local spread. Most tumors are a few centimeters in size at the time of presentation. Despite the initial clinical appearance of a single localized mass, pathologic examination often documents multifocal spread along tendons, nerves, and fascial structures in a serpiginous fashion. The characteristic early multifocal spread of this tumor and propensity for multiple recurrences demand early radical surgery. Metastases, usually to lymph nodes and lung, develop in at least 50% of patients. HISTOPATHOLOGIC FEATURES Epithelioid sarcomas frequently are multifocal with a plexiform and diffusely infiltrative pattern (see Table 30-28). They are composed of spindled to round cells with abundant eosinophilic cytoplasm and relatively uniform medium-sized nuclei. The spindled and epithelioid areas tend to gradually merge and have similar nuclear and cytoplasmic characteristics. A characteristic finding in approximately 40% to 50% of cases is tumor cells arranged in a palisade around areas of

necrosis (Fig. 30-36). This feature may lead to confusion with a granulomatous or necrobiotic processes. Some tumors show a marked chronic inflammatory infiltrate, further contributing to this confusion. Cellular discohesion, producing a pseudovascular pattern, is also a common finding. Epithelioid sarcoma has a propensity for neural and tendon sheath invasion. The tumor is immunoreactive for keratins, vimentin, and EMA. Approximately 50% of cases are CD34 positive. Immunoreactivity for keratins varies from focal to diffuse, but is present invariably. DIFFERENTIAL DIAGNOSIS Distinguishing epithelioid sarcoma from necrobiotic granulomatous processes, such as granuloma annulare, necrobiosis lipoidica, and rheumatoid nodule, and infection may be difficult, particularly in small biopsies. Keratin immunoreactivity distinguishes epithelioid sarcoma from any of these granulomatous diseases. CD34 positivity is also not a feature of granulomatous diseases. Tumors that are discohesive, form cleftlike pseudovascular spaces, and show intracytoplasmic vacuole formation may be mistaken for an epithelioid vascular neoplasm. Expression of specific vascular markers, such as CD31 or Fli-1 protein, establish the diagnosis of a vascular neoplasm. It should be noted that epithelioid angiosarcoma and epithelioid hemangioendothelioma also are quite frequently immunoreactive for keratin and that both true vascular tumors and epithelioid sarcomas express CD34. The presence of overlying squamous cell carcinoma in situ, dyskeratosis, intercellular bridges, and squamous pearls all help distinguish squamous cell carcinoma from epithelioid sarcoma. Melanoma is distinguished by the presence of melanin, associated melanoma in situ, or other precursor melanocytic lesions. In problematic cases, the immunohistochemical profile of melanoma allows distinction from epithelioid sarcoma; melanomas are, in general, nonreactive for keratins; immunoreactive for S-100 protein; and, at least when epithelioid, frequently express MART-1 or HMB45. Although both epithelioid sarcoma and synovial sarcoma show epithelial differentiation and express cytokeratin, they otherwise share almost no clinical or pathologic features and are therefore easily distinguished.

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

DIFFERENTIAL DIAGNOSIS LGFMS epitomizes the “pseudobenign” sarcoma. In our experience, it is most often mistaken for a fibroma, a fibromatosis, a fibrotic neurofibroma, or a myxoma. Unlike LGFMS, fibromas are uniformly hypocellular and collagenous tumors that lack myxoid nodules and a whorling growth pattern. Fibromatoses show long, sweeping fascicles of entirely banal-appearing myofibroblastic or fibroblastic cells and have characteristic thin-walled, dilated blood vessels. Neurofibromas display “shredded carrot”-like collagen and are composed of generally bland-appearing cells with wavy nuclei. S-100 protein is invariably positive in neurofibromas but not in LGFMS. Myxomas are uniformly myxoid lesions that lack a well-developed vasculature and show cystic change. The similarly named myxofibrosarcoma is also more uniformly myxoid than is LGFMS, contains arborizing thick-walled vessels, and displays greater cytologic atypia.

Table 30-28 Epithelioid Sarcoma

Superficial Angiomyxoma and Cutaneous Myxoma CLINICAL FEATURES Superficial angiomyxoma is a slow-growing dermal or

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Table 30-29 Superficial Angiomyxoma and Cutaneous Myxoma

796

Clinical Features May be associated with the Carney complex Head and neck region of adults Slow-growing dermal or subcutaneous nodule, <3 to 4 cm May recur after surgical resection Histopathologic Features Poorly circumscribed, paucicellular Myxoid matrix with widely scattered bland stellate and spindle fibroblasts Thin-walled blood vessels, lymphocytes, and neutrophils in varying numbers Mitoses may be seen Frequent association with epithelial proliferation, particularly cysts Differential Diagnosis Low-grade myxofibrosarcoma Myxoid liposarcoma Aggressive angiomyxoma

A

B  FIGURE 30-36 Epithelioid sarcoma. (A) This tumor shows tumor cells arranged in a palisade around areas of necrosis. This feature frequently leads to confusion with granulomatous processes. (B) High magnification shows the neoplastic cells are round to spindled with abundant eosinophilic cytoplasm and relatively uniform nuclei.

subcutaneous nodule occurring most commonly in the head and neck region of adults (Table 30-29).193 Most tumors are smaller than 3 to 4 cm and may recur occur surgical resection.194 Cutaneous myxomas identical to superficial angiomyxoma may be associated with the Carney complex, an autosomal dominant disorder with multiple manifestations.195 The complex has three major components: myxomatous masses (cardiac myxomas, cutaneous myxomas, myxoid fibroadenomas of the breast), spotty pigmentation of the skin (lentigines, blue nevi), and endocrine disorders (primary pigmented nodular adrenocortical disease, large cell calcifying Sertoli cell tumor of the testes, and pituitary adenomas).195-197 Psammomatous melanotic schwannomas have been described in patients with Carney complex.198 The presence of angiomyxoma

in the external ear seems pathognomonic of Carney complex.199 HISTOPATHOLOGIC FEATURES These tumors are poorly circumscribed, sometimes multinodular, paucicellular lesions involving the dermis and superficial subcutaneous tissue (see Table 30-29). Embedded in the myxoid matrix are scattered stellate and spindled fibroblasts with bland nuclei (Fig. 30-37). Thin-walled blood vessels, lymphocytes, and neutrophils are often present in varying numbers. Lesions are frequently associated with epithelial proliferation (particularly follicular), most often in the form of cysts, basaloid buds, and pseudoepitheliomatous hyperplasia. Occasional mitoses may be seen; however, significant nuclear atypia is not present.

DIFFERENTIAL DIAGNOSIS Distinction between angiomyxomas and cutaneous myxomas associated with the Carney complex may not be possible. Cutaneous myxomas may be the first presentation of this syndrome, and the clinician should be alerted to this possibility. The bland fibroblasts and lack of curvilinear vascular pattern allow myxoma to be distinguished from low-grade myxofibrosarcoma. Although myxoid liposarcoma is composed of very bland cells, the characteristic “chicken wire” vascular pattern and presence of occasional lipoblasts establishes this diagnosis. Aggressive angiomyxoma is distinguished by a more infiltrative and less nodular growth pattern associated with thickened vessels and a generally deeper location. The typical sites for aggressive angiomyxoma in the vulva, perineum, and scrotum would be somewhat more unusual for angiomyxoma and myxoma. Because of its capacity for local destructive growth, distinguishing aggressive angiomyxoma from superficial angiomyxoma is critical.

QUICK REFERENCE GUIDE TO FIBROUS AND FIBROHISTIOCYTIC TUMORS

Tumors with Storiform Pattern Confined to dermis with overlying epithelial hyperplasia = dermatofibroma Less uniform storiform pattern mixed with fascicles parallel to epidermis = dermatomyofibroma

Dense fibrous tissue with lobules of orderly bands of collagen parallel to the epidermis separated by blood vessels = hypertrophic scar Features of hypertrophic scar with thick bands of glassy collagen = keloid Tumor of hand or feet in young patient composed of spindled to epithelioid cells, with palisading around foci of calcification = calcifying aponeurotic fibroma Exophytic lesion on hand with irregular thick bundles of collagen and variable numbers of blood vessels = acral fibrokeratoma and periungual fibroma

 FIGURE 30-37 Superficial angiomyxoma. Typical cytologically bland tumor with thin-walled vessels.

Extensive infiltration of fat and CD34+ = dermatofibrosarcoma protuberans

teristic eosinophilic inclusions = infantile digital fibromatosis

Marked atypia, sun-damaged skin, minimal infiltration of fat = atypical fibroxanthoma

Biphasic tumor composed of sweeping or whorled fascicles of myofibroblasts alternating with hemangiopericytomalike areas = infantile myofibromatosis

Marked atypia, significant infiltration subcutaneous fat = pleomorphic sarcoma, sarcomatoid carcinoma, melanoma Storiform pattern produced by cleftlike spaces in paucicellular hyaline nodule = storiform collagenoma

Tumors with a Prominent Myxoid Component Curvilinear vessels, atypical cells, pseudolipoblasts = myxofibrosarcoma Tissue culture fibroblasts within tumor with myxoid feathery zones alternating with hypercellular zones = nodular fasciitis Myxoid tumor in child with giant cells lining pseudovascular spaces, CD34+ = giant cell fibroblastoma Paucicellular nodule with very bland stellate and spindled cells, inflammatory cells and thin-walled blood vessels = myxoma, angiomyxoma Paucicellular tumor with myxoid areas admixed with whorled collagenous component, very bland cells = lowgrade fibromyxoid sarcoma

Fibrous and Fibrohistiocytic Tumors in Children Tumor of finger or toes composed of myofibroblasts in fascicles, charac-

Paucicellular nodules composed of ribbons of PAS+ glassy hyaline eosinophilic material = juvenile hyaline fibromatosis Biphasic tumor composed of anastomosing bands of fibrous tissue and nodular aggregates of histiocyte-like cells resembling granulomas, creating a plexiform pattern = plexiform fibrohistiocytic tumor Myxoid tumor with giant cells lining pseudovascular spaces, CD34+ = giant cell fibroblastoma Tumor of hand or feet composed of spindled to epithelioid cells, with palisading around foci of calcification cells = calcifying aponeurotic fibroma Tumor composed of fascicles of eosinophilic spindle cells, distinctive organoid nests within a myxoid background, mature fat dispersed and fibrous tissue = fibrous hamartoma of infancy

Tumors Composed of Fibrous Tissue Tumor composed of cellular “herringbone” fascicles with atypia, necrosis, high cellularity, necrosis and mitoses = fibrosarcoma Paucicellular tumor with dense hyalinized collagen and spindled or wavy nuclei = fibromatosis, knuckle pad, Peyronie disease

Central face in child with stigmata of tuberous sclerosis = facial angiofibroma Shiny papule on face, especially nose with clinical appearance often mistaken for basal cell carcinoma = fibrous papule Tiny papules on the glans penis = pearly penile papules

Tumors of Digits Tumor in young child composed of myofibroblasts in fascicles, characteristic eosinophilic inclusions = infantile digital fibromatosis Exophytic lesion on hand with irregular thick bundles of collagen and variable numbers of blood vessels = acral fibrokeratoma and periungual fibroma Nodule over knuckles composed of bland fibrous tissue often with overlying epithelial hyperplasia = knuckle pad

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

Angiofibromas

Lobulated tumor with giant cells, mononuclear cells, xanthoma cells, hemosiderin-laden macrophages, and collagenized stroma = giant cell tumor of tendon sheath Paucicellular tumor with slitlike vascular spaces and rare, if any, giant cells = fibroma of tendon sheath Tumor composed of keratin positive spindled and epithelioid cells with palisading around areas of necrosis = epithelioid sarcoma

REFERENCES 1. Schwartz RA, Fernandez G, Kotulska K, et al: Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007; 57:189-202. 2. Ackerman AB, Kornberg R: Pearly penile papules. Acral angiofibromas. Arch Dermatol. 1973;108:673-675. 3. Rehbein HM: Pearly penile papules: incidence. Cutis. 1977;19(1):54-57.

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133. Dupree WB, Langloss JM, Weiss SW: Pigmented dermatofibrosarcoma protuberans (Bednar tumor). Am J Surg Pathol. 1985;9:630-639. 134. Fletcher CDM, Theaker JM, Flanagan A, et al: Pigmented dermatofibrosarcoma protuberans (Bednar tumor): melanocytic colonization or neuroectodermal differentiation? A clinicopathologic and immunohistochemical study. Histopathology. 1988;13:631-643. 135. Calonje E, Fletcher CDM: Myoid differentiation in dermatofibrosarcoma protuberans and its fibrosarcomatous variant: clinicopathologic analysis of 5 cases. J Cutan Pathol. 1996;23:30-36. 136. Weiss SW, Nickoloff BJ: CD34 is expressed by a distinctive cell population in peripheral nerve, nerve sheath tumors, and related lesions. Am J Surg Pathol. 1993;17:1039-1045. 137. Hollowood K, Holley MP, Fletcher CD: Plexiform fibrohistiocytic tumour: clinicopathological, immunohistochemical and ultrastructural analysis in favour of a myofibroblastic lesion. Histopathology. 1992;19:503-513. 138. Enzinger FM, Zhang RY: Plexiform fibrohistiocytic tumor presenting in children and young adults: an analysis of 65 cases. Am J Surg Pathol. 1988; 12:818-826. 139. Remstein ED, Arndt CAS, Nascimento AG: Plexiform fibrohistiocytic tumor: clinicopathologic analysis of 22 cases. Am J Surg Pathol. 1999;23:662-670. 140. Salomao DR, Nascimento AG: Plexiform fibrohistiocytic tumor with lung metastasis. Am J Surg Pathol. 1997;21:469-476. 141. Enzinger FM: Angiomatoid malignant fibrous histiocytoma: a distinctive fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm. Cancer. 1979;44:2157-2196. 142. Costa MJ, Weiss SW: Angiomatoid malignant fibrous histiocytoma: a follow-up study of 108 cases with evaluation of possible histologic predictors of outcome. Am J Surg Pathol. 1990;14: 1126-1132. 143. Fanburg-Smith JC, Miettinen M: Angiomatoid malignant fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype. Hum. Pathol. 1999;30: 1336-1343. 144. Davies KA, Cope AP, Schofield JB, et al: A rare mediastinal tumour presenting with systemic effects due to IL-6 and tumour necrosis factor (TNF) production. Clin Exp Immunol. 1995;99:117-123. 145. Waters BL, Panagopoulos I, Allen EF: Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11. Cancer Genet. Cytogenet. 2000;121:109116. 146. Raddaoui E, Donner LR, Panagopoulos I: Fusion of the FUS and ATF-1 genes in a large, deep-seated angiomatoid fibrous histiocytoma. Diagn. Mol Pathol. 2002;11:157-162. 147. Hallor KH, Mertens F, Jin Y, et al: Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer. 2005;44:97-102.

148. Antonescu CR, Dal Cin P, Nafa K, et al: EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer. 2007;46:1051-1060. 149. Rossi S, Szuhai K, Ijszenga M, et al: EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma. Clin. Cancer Res. 2007;13:73227328. 150. Pettinato G, Manivel JC, DeRosa G, et al: Angiomatoid malignant fibrous histiocytoma: cytologic, immunohistochemical, ultrastructural and flow cytometric study of 20 cases. Mod Pathol. 1990;3:479-487. 151. Fletcher CDM: Angiomatoid “malignant fibrous histiocytoma”: an immunohistochemical study indicative of myoid differentiation. Hum Pathol. 1991;22:563568. 152. Goodlad, JR, Fletcher CD: Solitary fibrous tumor arising at unusual sites: analysis of a series. Histopathology. 1991;19:515-522. 153. Nielsen GP, O’Connell JX, Dickersin JR, et al: Solitary fibrous tumor of soft tissue: a report of 15 cases, including 5 malignant examples with light microscopic, immunohistochemical, and ultrastructural data. Mod Pathol. 1997; 10:1028-1037. 154. Okamura JM, Barr RJ, Battifora H: Solitary fibrous tumor of the skin. Am J Dermatopathol. 1997;19:515-518. 155. Cowper SE, Kilpatrick T, Proper T, et al: Solitary fibrous tumor of the skin. Am J Dermatopathol. 1999;21:213-219. 156. Smith KJ, Skelton HG: Solitary fibrous tumor. Am J Dermatopathol. 2001;23:8182. 157. Sigel JE, Goldblum JR: Solitary fibrous tumor of the skin. Am J Dermatopathol. 2001;23:275-278. 158. Hardisoon D, Cuevas-Santos J, Contreras F: Solitary fibrous tumor of the skin. J Am Acad Dermatol. 2002;46(suppl):S37-S40. 159. Chang SE, Bae GY, Choi JH, et al: Cutaneous solitary fibrous tumor with myxoid stroma. Br J Dermatol. 2002; 147:1267-1269. 160. Erdag G, Qureshi HS, Patterson JW, et al: Solitary fibrous tumors of the skin: a clinicapathologic study of 10 cases and review of the literature. J Cutan Pathol. 2007;34:844-850. 161. Vallat-Decouvelaere AV, Dry SM, Fletcher CD: Atypical and malignant solitary fibrous tumors in extrathoracic locations: evidence of their comparability to intra-thoracic tumors. Am J Surg Pathol. 1998;22:1501-1511. 162. Gold JS, Antonescu CR, Hajdu C, et al: Clinicopathologic correlates of solitary fibrous tumors. Cancer. 2002;94:10571068. 163. Westra WH, Gerald WI, Rosai J: Solitary fibrous tumor. Consistent CD34 immunoreactivity and occurrence in the orbit. Am J Surg Pathol. 1994;18:992-998. 164. Fletcher CDM: Pleomorphic malignant fibrous histiocytoma: fact or fiction? A critical reappraisal based on 152 cases. Am J Surg Pathol. 1992;16:213-228. 165. Weiss SW, Goldblum JR: Enzinger and Weiss’s Soft Tissue Tumors. St. Louis: Mosby; 2001. 166. Fletcher CDM: Diagnostic Histopathology of Tumors. New York: Churchill Livingstone;2007.

178. Bizer LJ: Fibrosarcoma: report of 64 cases. Am J Surg. 1971;121:586-687. 179. Pritchard DJ, Soule EH, Taylor WF, et al: Fibrosarcoma, a clinicopathologic and statistical study of 199 tumors of the soft tissues of the extremities and trunk. Cancer. 1974;33:888-897. 180. Dal Cin P, Brock P, Casteels-Van Daele M, et al: Cytogenetic characterization of congenital or infantile fibrosarcoma. Eur J Pediatr. 1991;150:579-581. 181. Schofield DE, Fletcher JA, Grier HE, et al: Fibrosarcoma in infants and children: application of new techniques. Am J Surg Pathol. 1994;18:14-24. 182. Bourgeois JM, Knezevich SR, Mathers JA, et al: Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol. 2000;24:937-946. 183. Evans HL: Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol. 1987;88: 616619. 184. Evans HL: Low-grade fibromyxoid sarcoma. A report of 12 cases. Am J Surg Pathol. 1993;17:595-600. 185. Goodlad JR, Mentzel T, Fletcher CDM: Low-grade fibromyxoid sarcoma: clinicopathologic analysis of eleven new cases in support of a distinct entity. Histopathology. 1995;26:229-237. 186. Folpe AL, Lane KL, Paull G, et al: Lowgrade 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. 187. Lane KL, Shannon RJ, Weiss SW: Hyalinizing spindle cell tumor with giant rosettes: a distinctive tumor closely resembling low-grade fibromyxoid sarcoma. Am J Surg Pathol. 1997;21(12):1481-1488. 188. Reid R, de Silva MV, Paterson L, et al: Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16) (q34;p11) translocation. Am J Surg Pathol. 2003;27:1229-1236.

189. Panagopoulos I, Storlazzi CT, Fletcher CD, et al: The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer. 2004;40:218-228. 190. Chase DR, Enzinger FM: Epithelioid sarcoma. Diagnosis, prognostic indicators and treatment. Am J Surg Pathol. 1985; 9:241-263. 191. de Visscher SA, van Ginkel RJ, Wobbes T, et al: Epithelioid sarcoma: still an only surgically curable disease. Cancer. 2006;107:606-612. 192. Evans HL, Baer SC: Epithelioid sarcoma: a clinicopathologic and prognostic study of 26 cases. Semin Diagn Pathol. 1993;10:286-291. 193. Allen PW, Dymock RB, MacCormack WB: Superficial angiomyxomas with and without epithelial components. Report of 30 tumors in 28 patients. Am J Surg Pathol. 1988;12:519-530. 194. Guerin D, Calonje E, McCormick D: Superficial angiomyxoma: clinicopathological analysis of 26 cases of a distinctive cutaneous tumour with a tendency for recurrence (abstract). J Pathol. 1995; 176(suppl):51A. 195. Carney JA, Hruska LS, Beauchamp GD, et al: Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Mayo Clin. Proc. 1986;61:165-172. 196. Carney JA: Differences between nonfamilial and familial cardiac myxoma. Am J Surg Pathol. 1985;9:53-55. 197. Carney JA, Toorkey BC: Myxoid fibroadenoma and allied conditions (myxomatosis) of the breast: a heritable disorder with special associations including cardiac and cutaneous myxomas. Am J Surg Pathol. 1992;15:713-721. 198. Carney JA: Psammomatous melanotic schwannoma: a distinctive heritable tumor with special associations including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol. 1990;14: 206-222. 199. Ferreiro JA, Carney JA: Myxomas of the external ear and their significance. Am J Surg Pathol. 1994;18(3):274-280.

CHAPTER 30 ■ FIBROUS AND FIBROHISTIOCYTIC TUMORS

167. Guccion JG, Enzinger FM: Malignant giant cell tumor of soft parts. An analysis of 32 cases. Cancer. 1979;29:1518-1529. 168. Mentzel T, Calonje E, Wadden C, et al: Myxofibrosarcoma: clinicopathologic analysis of 75 cases with emphasis on low-grade variant. Am J Surg Pathol. 1996;20(4):391-405. 169. Merck C, Angervall L, Kindblom L-G, et al: Myxofibrosarcoma. A malignant soft tissue tumour of fibroblastic-histiocytic origin. A clinicopathologic and prognostic study of 110 cases using multivariate analysis. Acta Pathol. Microbiol. Immunol Scand. 1983;A91(suppl 282):1-40. 170. Weiss SW, Enzinger FM: Myxoid variant of malignant fibrous histiocytoma. Cancer. 1977;39:1672-1685. 171. Huang, HJ, Lal P, Qin J et al: Low-grade myxofibrosarcoma: a clinicopathologic analysis of 49 cases treated at a single institution with simultaneous assessment of the efficacy of 3-tier and 4-tier grading systems. Hum Pathol. 2004;35: 612-621. 172. Fanburg-Smith JC, Spiro J, Katapwam SV, et al: Infiltrative subcutaneous malignant fibrous histiocytoma: a comparative study with deep malignant fibrous histiocytoma and an observation of biologic behavior. Ann Diagn Pathol. 1999;3:1-10. 173. Nascimento AF, Bertoni F, Fletcher CD: Epithelioid variant of myxofibrosarcoma: expanding the clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases. Am J Surg Pathol. 2007;31:99-105. 174. Meyerding HW, Broders AC, Hargrave RL: Clinical aspects of fibrosarcoma of the soft tissues of the extremities. Surg Gynecol Obstet. 1936;62:1010. 175. Scott SM, Reiman HM, Pritchard DJ, et al: Soft tissue fibrosarcoma. A clinicopathologic study of 132 cases. Cancer. 1989;24:925-931. 176. Chung EB, Enzinger FM: Infantile fibrosarcoma. Cancer. 1976;38:729-739. 177. MacKenzie DH: Fibrosarcoma: a dangerous diagnosis. A review of 2056 cases of fibrosarcoma of soft tissues. Br J Surg. 1964;51:607-613.

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CHAPTER 31 Vascular Tumors and Vascular Malformations

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Michel Wassef Steven J. Hunt Daniel J. Santa Cruz Raymond L. Barnhill

The nomenclature of vascular lesions is at best confusing and in some instances is entirely incoherent. Thus, the same terminology may be used to describe unrelated clinical entities, and there are examples of a variety of different terms being applied to a single condition. To illustrate this point, cavernous hemangioma has been used to designate both a venous malformation (VM) and a hemangioma of infancy. In fact, the latter two entities are characterized by completely different clinical features, natural histories, and managements. Because the pathogenesis of many lesions is still poorly understood, many classifications have been proposed. However, no single classification to date is entirely satisfactory.1-4 This chapter adheres to the classification scheme recommended by the International Society for the Study of Vascular Anomalies (ISSVA), which is based on the distinction between proliferative lesions (vascular tumors and reactive proliferative lesions) and vascular malformations (Table 31-1). Vascular malformations may be further classified as to the type or caliber of predominant vascular channel present (eg, capillaries, veins, arteries, lymphatics, or glomus vessels). With this conceptual basis, this chapter will discuss (1) benign vascular

tumors (ie, different types of hemangiomas) and proliferative vascular lesions of reactive or indeterminate nature, (2) vascular tumors of low grade or borderline malignancy, (3) malignant vascular tumors, and (4) vascular malformations and acquired nonproliferative vascular lesions. In addition, the chapter attempts to clarify the nomenclature and to maintain a balanced perspective in discussing each entity without trying to resolve all of the controversial issues of nomenclature and pathogenesis. The vast majority of vascular channels, except small lymphatics, sinuses, and sinusoids, are lined by endothelial cells with a peripheral layer of pericytes or smooth muscle cells. Similarly, most vascular tumors are composed of endothelial cells associated with pericytes, smooth muscle cells, or both. Endothelial cells express the so called vascular markers CD31, CD34, von Willebrand factor, and Ulex europaeus lectin-1. Von Willebrand factor is often referred to in the literature as factor VIII-related antigen. Pericytes and smooth muscle cells contain contractile proteins (smooth muscle actin and αsmooth muscle actin). Lymphatic endothelial cells express lymphatic vascular endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin, which is recognized by D2-40 antibody. Activated blood endothelial cells may, however, weakly express these two markers.5 Small lymphatics lack pericytes, and larger ones demonstrate irregular media made of smooth muscle cells. There is undoubtedly considerable heterogeneity of endothelial and smooth muscle cell phenotypes and functions in normal vessels that remain poorly understood. It is certain that there are specialized functions of endothelial cells, including antigen presentation, secretion of cytokines, and so on, beyond the simple and obvious properties of maintenance of blood or lymph circulation. Finally, although well-defined clinicopathologic entities can be recognized,

Table 31-1 SSVA Classification Scheme for Vascular Anomalies VASCULAR ANOMALIES

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VASCULAR TUMORS

VASCULAR MALFORMATIONS

Benign: Hemangioma Intermediate or borderline: Hemangioendothelioma Malignant: Angiosarcoma

Low flow: Capillary Venous Lymphatic High flow: Arteriovenous

there is frequent morphologic overlap of some lesions, and diagnosis may be difficult or impossible on small biopsy specimens.

BENIGN VASCULAR TUMORS

Infantile Hemangioma Synonyms: Hemangioma of infancy, juvenile hemangioma, strawberry hemangioma, capillary cellular or hypercellular hemangioma Infantile hemangioma (IH) is the most frequent tumor of infancy (Table 31-2).2-4,6-8 Infantile hemangioma most commonly presents in the first few weeks of life as a solitary localized tumor in the skin. However, lesions involving multiple sites may occur. The incidence at birth is 1% to 2% and increases to 12% by age 1 year. Whites are most commonly affected relative to other racial groups, and girls outnumber boys by a ratio of 3:1. Infantile hemangioma is typified by a fairly predictable natural history in the great majority of cases, which includes rapid proliferation and enlargement in the first 8 to 12 months of life (the proliferative phase) and regression over a period of 1 to 5 years (the involutional phase). More than 50% of patients have complete regression of IH by age 5 years and 70% to 90% by age 7 years, and there is continued involution in the remainder of patients up to an age of about 10 to 12 years. Approximately 90% of IH are associated with no adverse effects in children and do not necessitate any treatment. The remaining 10% require intervention, often because of local destructive effects or impingement on a vital structure such as an airway or the eye. In addition, large or multiple IH may result in shunting of blood and high-output cardiac failure. Contrary to what was thought until recently, IH is not associated with entrapment of platelets, thrombocytopenic coagulopathy, and potentially life-threatening hemorrhages (ie, Kasabach-Merritt syndrome [KMS] or Kasabach-Merritt phenomenon; see Tufted Angioma and Kaposiform Hemangioendothelioma).9-11 The pathogenesis of IH is poorly understood. There is an association with very low birth weight (<1 kg) and chorionic villous sampling.12,13 In rare kindreds, an autosomal dominant form of IH has been identified, with linkage to 5q in three families.14 IH has been shown to be a clonal proliferation of endothelial cells.15 There are many disparate hypotheses with regard to the pathogenesis of IH, including development from sequestrated

Table 31-2 Infantile Hemangioma

primitive angioblasts or from a somatic mutation of stem cells; manifestation of a field defect; origin from engrafted cells of placental origin; and imbalance between angiogenic and angiostatic factors, possibly due to mutation in cytokine regulatory pathways.16,17

HISTOPATHOLOGIC FEATURES In the initial proliferative phase, IH is characterized by a dense cellular proliferation of uniform capillaries composed of endothelial cells with an antiluminal row of actin-positive pericytes grouped in lobules occupying the dermis and frequently the subcutaneous fat.2,4,6,7 Mast cells are frequent, and the vascular lobules are generally associated with afferent or efferent vessels with distinct muscular media (Fig. 31-1 and Table 31-2). Vascular lumina may be difficult to discern, but the highly organized architecture of IH can be highlighted with reticulin stains. The mitotic rate of endothelial cells and pericytes is usually significant at this stage. IH vessels may penetrate the perineurium or endoneurium of small nerves; in this setting, this feature is not indicative of malignancy.18 With time, the lobular character of the tumor becomes more

evident, the degree of cellularity diminishes, and the vascular lumina are readily identified (Fig. 31-2). At this stage, IH with dilated capillaries is sometimes improperly designated as cavernous hemangioma. With involution, the vascular lobules are gradually replaced by fibrous tissue or fat, with hyalinization of the rare persisting capillaries (Fig. 31-3). Apoptosis has been demonstrated in involuting IH.19 The endothelial cells of IH express common endothelial markers (CD31, CD34, von Willebrand factor and Ulex europaeus lectin-1). Moreover, in all stages of the lesion, they present a unique immunophenotype with expression of the erythrocyte-type glucose transporter molecule isoform 1 (GLUT-1), merosin (α-laminin), Lewis Y antigen, and FcγRII. This phenotype is shared by the endothelial cells of the placenta and with respect to GLUT-1 and merosin by those of blood–tissue barriers.20 DIFFERENTIAL DIAGNOSIS Infantile hemangioma must be differentiated from congenital hemangioma, kaposiform hemangioendothelioma, tufted angioma (TA), pyogenic granuloma (PG), and vascular malformations. Congenital hemangiomas (CHs) are fully developed at birth and are made up of lobular aggregates of capillaries with more irregular and branching lumina. The lobules often contain stellate, thin-walled, larger vessels, and the endothelial cells often manifest dark, round, hobnail nuclei protruding into the lumina. In the noninvoluting type of congenital hemangioma, eosinophilic hyaline

 FIGURE 31-1 Infantile hemangioma. Note the strikingly cellular nature of the lesion with only rare vascular lumina.

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Clinical Features Incidence at birth, 1%-2% and 12% by 1 year Most develop in the first month of life or in the first year Females outnumber males by a ratio of 3:1 Whites are most commonly affected racial group Head and neck most common sites but may occur anywhere Present initially as pink or pale macular lesions that usually become red to purple nodules Involution occurs with the development of whitish streaks Natural History Rapid proliferation and enlargement in the first 8-12 months of life Regression of the lesion over 1-5 years or longer Occasional lesions may be life threatening Impingement on vital structures such as an airway Ulceration, infection, visceral location, hemorrhage, congestive heart failure Histopathologic Features Proliferative phase Highly cellular lobules separated by fibrous septa Thick-walled afferent or efferent vessels Lobules contain uniform endothelial cells with an admixture of pericytes and mast cells Mitoses are common Inconspicuous vascular lumina With time, the lobules become less cellular and vascular lumina become more prominent Involuting phase Vascular lobules composed almost entirely of microvessels Gradual replacement of lobules by fibrous or fatty stroma All phases: expression of GLUT-1 in endothelial cells Differential Diagnosis Congenital hemangioma Kaposiform hemangioendothelioma Tufted angioma Pyogenic granuloma Nonvascular tumors Vascular malformations

CLINICAL FEATURES IH often presents in the first weeks to first year of life, usually involving the head and neck and showing considerable variation in size. Before the development of the tumor, a pink macule or area of pale skin may herald its future development. With growth, these lesions become red to purplish papules or nodules that often have a rubbery texture. Some may occupy large areas, greatly distorting the normal anatomy and threatening vital structures. Some may exhibit ulceration. Involution is heralded by blanching, and the lesion may disappear without any residual scar. Large lesions may regress with distended redundant skin.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

is fully developed at birth and does not exhibit postnatal growth. At least two subgroups of CH are recognized: rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH).21-24 There is an equal gender ratio of CH in contrast to the female preponderance of IH.21,22,24

 FIGURE 31-3 Infantile hemangioma. With involution, the vascular lobules are gradually replaced by fibrous tissue or fat, with hyalinization of the rare persisting capillaries.

804

globules may be seen in the cytoplasm of some endothelial cells. Kaposiform hemangioendothelioma (KHE) differs from IH by showing dense spindle cell sheets or nodules, which contain slitlike vascular channels resembling Kaposi sarcoma (KS). TA differs by the small size of discrete cellular nodules with cannonball-like appearance in the dermis, the presence of crescentic slitlike vessels at the periphery of the tufts, and the absence of afferent thick-walled vessels. PG is often ulcerated with edema and inflammation.

 FIGURE 31-2 Infantile hemangioma. The lobular character of the hemangioma is more evident in this field. The degree of cellularity is not as conspicuous, and vascular lumina are easily detected.

The capillaries are more branching and the lobules often less well delineated. Vascular malformations lack the welldefined lobular architecture and cellularity of IH. They are often poorly delineated and dominated by ectatic vascular channels with thin or thick walls or both.

Congenital Hemangioma CH, or congenital nonprogressive hemangioma, designates a vascular tumor of intrauterine onset, which contrary to IH,

CLINICAL FEATURES RICH presents as raised violaceous tumors with central depression, ulceration, or scarring often with coarse telangiectasias and a pale peripheral rim. These lesions are usually localized to the head and neck and extremities and range from one to 15 cm in diameter.24,25 They are warm on palpation. On magnetic resonance imaging (MRI), the lesions occupy the dermis and subcutis and sometimes extend into the underlying muscles. They contain large and irregular high-flow vessels with arterial aneurysms on ultrasonography and MRI.24-26 Such lesions commonly involute rapidly in 6 to 14 months. NICH presents at birth as round to oval plaquelike or slightly raised lesions of pink to purple color often with telangiectasias. They are also warm on palpation and contain high-flow vessels. They lack the central depression or scar of RICH. NICH persists indefinitely with some alteration in color or size over time. Some CH exhibit characteristics of both RICH and NICH. For example, some CH may suggest RICH at birth because of rapid involution that is ultimately incomplete and eventuates in a stable persistent process consistent with NICH.25 HISTOPATHOLOGIC FEATURES RICH are characterized by a proliferation of capillaries grouped in lobules of variable sizes. Their lumina are small and round or irregular; however, a larger thin-walled vascular channel is often seen in the center of the lobules. The lobules are separated by fibrous tissue containing large tortuous vessels with irregular contours composed of thin-walled (veins or lymphatics) and thick-walled (arterial) channels (Fig. 31-4).24,25 The centers of such lesions contain areas of fibrous tissue devoid of capillary lobules suggesting lesional involution. Thrombi, hemosiderin deposits, and calcifications may be present.24,25 NICH generally shows larger lobules of capillaries with irregular lumina. Endothelial cells have lymphocyte-like, dark, round nuclei protruding into the lumen with a hobnail pattern (Fig. 31-5). Mild anisocaryosis is frequent. The cytoplasms focally contain eosinophilic hyaline inclusions similar to those observed in papillary

less cellular than NICH and do not demonstrate hobnail nuclei and hyaline eosinophilic inclusions. The feeding and draining vessels of IH lobules have a high media-to-lumina ratio, contrasting with the intralobular thin-walled stellate vessels of CH.22,24 Contrary to RICH and NICH, IH express GLUT-1 in almost all instances.20

Tufted Angioma

A

B

 FIGURE 31-5 Congenital hemangioma. (A) Noninvoluting congenital hemangioma generally demonstrates larger lobules of capillaries with irregular lumina. (B) Endothelial cells (inset) have lymphocyte-like, dark, round nuclei protruding into the lumen with a hobnail pattern.

and glomeruloid hemangiomas (GHs). The complex branching and folding of lobular vessels sometimes results in a papillary appearance. Perilobular fibrosis and interlobular vascular networks are less developed than in RICH.22,24,25 Some of the vascular lobules of NICH protrude into large veins or lymphatic-like vessels.22 Except for a single case of RICH, neither RICH nor NICH express GLUT-1, the specific marker of infancy hemangioma.22-24 Actin-positive smooth muscle

cells may ensheath individual capillaries as in IH but more characteristically form a poorly organized network about the capillaries DIFFERENTIAL DIAGNOSIS Intrauterine onset and lack of postnatal progression allow distinction of CH from the more common IH and from PG. During its proliferative phase, IH lacks the interlobular fibrous tissue and large tortuous vessels of RICH. Involuting IH are generally

CLINICAL FEATURES Classically, TA presents as slowly enlarging dull red or brown plaques or macules typically on the neck and upper trunk of children and young adults.27,28 More than half of the cases reported have developed during the first five years of life, and a few cases have presented at birth. Lesions have been associated with hyperhidrosis29 and KMS (discussed with kaposiform hemangioendothelioma).10,37 TAs often have superficial and deep components. Occasionally, the superficial component may appear more brightly red. TA may slowly enlarge over the course of years and may attain considerable size. Some lesions regress, especially those with congenital onset.38,39 TA generally occurs sporadically. However, there have been two reports of familial lesions with an autosomal dominant inheritance.40 Cases of eruptive TA appearing in a patient with Crohn disease or soon after liver transplantation have been documented. Surprisingly, the lesions were self-limited, involuting

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-4 Congenital hemangioma. The lobules are separated by fibrous tissue containing large tortuous vessels with irregular contours made up of thin-walled (veins or lymphatics) and thick-walled (arterial) channels.

Synonyms: Angioblastoma (Nakagawa), progressive capillary hemangioma, acquired tufted angioma, and tufted hemangioma This entity was first reported by Wilson Jones in 1976, and the description of additional patients have better defined its clinicopathologic phenotype.27-29 TA is generally considered to be a distinct clinicopathologic entity. However, a number of clinical and morphologic observations, such as its common association with the KMS, its morphologic overlap or association in the same patient, and the common expression of lymphatic markers,10,30-35 suggest that TA may be a minor form of kaposiform hemangioendothelioma or represents part of the spectrum of a single vascular condition.32,33,36 The relationship between TA and PG (lobular capillary hemangioma) has also merited discussion because of morphologic resemblance (eg, lesions reported as dermal PGs have been purported to be TA). Furthermore, peripheral satellite nodules suggesting PGs have been associated with TA.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 806

 FIGURE 31-6 Tufted angioma. Small circumscribed, cellular, capillary tufts are dispersed as “cannonballs” throughout the dermis.

spontaneously over several months. TA of the oral mucosa has been reported recently.41,42 Some of these eruptive cases or oral lesions may actually be better classified as PG. HISTOPATHOLOGIC FEATURES The hallmark of this hemangioma is the presence of small circumscribed, cellular, capillary tufts dispersed as “cannonballs” throughout the dermis (Fig. 31-6).27-29 The tufts tend to be larger in the middle and lower dermis and may extend into the subcutis. Crescentic cleftlike vessels are generally found at the

periphery of some of the capillary tufts (Fig. 31-7). The degree of cellularity within tufts is often so dense that capillary lumina may not be readily evident. Reticulin stains will reveal a rich network of reticulin that ensheathes individual endothelial cells. In some cases, spindled endothelial cells may be present. Dilated lymphatic-like vessels, reminiscent of a lymphatic malformation (LM), may also be present in the dermis. Mitotic figures may be seen, but cellular atypia is absent. Immunoreactivity for von Willebrand factor and Ulex europaeus lectin is best seen

 FIGURE 31-7 Tufted angioma. Crescentic cleftlike vessels are generally found at the periphery of some of the capillary tufts.

in endothelial cells of larger, well-formed vascular channels. Ulex europaeus lectin also outlines the capillaries of the vascular tufts. D2-40, a marker of lymphatic endothelial cells, is expressed in a proportion of TA cells.35 Crystalline lamellae in endothelial cells have been identified by electron microscopy in some but not all cases of TA. They are not specific for TA because they have also been seen in infantile hemangioma (IHs) and in fetal skin apparently as an aspect of immature endothelial cells. Proliferation of eccrine glands near capillary tufts has been reported in four children with angioblastoma and mucinous replacement of some capillary tufts in one patient. Further review of cases of TA might serve to clarify whether these are true differential features. At present, the literature seems to favor the point of view that TA and angioblastoma are synonymous. DIFFERENTIAL DIAGNOSIS Although the progressive nature of TA may invoke consideration of a low-grade angiosarcoma or KS, the clinicopathologic features and particularly the early onset of most cases allow distinction. The most common differential diagnosis is with PG and some reported TA might actually be PG.41,43 TA generally presents as a macule, patch, or plaque of up to several centimeters rather than as a small, easily bleeding papule or nodule and lacks ulceration, edema, inflammation, and a collarette. TA also lacks intralobular open stellate vessels. The scattered nature and crescentic peripheral vessels of TA tufts are fairly characteristic. GH may also be similar to TA, but the systemic manifestations of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome and the characteristic intracytoplasmic periodic acid-Schiff (PAS)–positive eosinophilic bodies allow distinction. In contrast to TA, reactive angioendotheliomatosis (RAE) demonstrates varied clinical presentations and rather heterogeneous vascular lobules. Distinction from cutaneous kaposiform hemangioendothelioma may be difficult, especially on small biopsies. KHE is composed of larger, often interconnecting, lobules or sheets of vascular elements commonly with an infiltrative pattern. The spindling of tumor cells is more pronounced and diffuse. D2-40 staining is also more diffuse. However, the histologic features of TA and kaposiform hemangioendothelioma may be present in the same lesion simultaneously or in successive biopsies.32,33

Papillary Hemangioma Papillary hemangioma (PH) is a recently described vascular tumor of the head and neck area.44 CLINICAL FEATURES The lesion presents as a bluish papule of 3 to 20 mm in diameter. The ages of patients have ranged from 2 to 77 years, but the majority have been older than age 55 years. Only one patient among the 11 reported cases manifested lesional recurrence 10 years after diagnosis.

DIFFERENTIAL DIAGNOSIS PH must be differentiated from NICH, GH, intravascular papillary endothelial hyperplasia (IPEH),

Spindle Cell Hemangioma In 1986, Weiss and Enzinger delineated the features of this unique vascular lesion and coined the name spindle cell hemangioendothelioma.47 It was first considered to be a low-grade angiosarcoma, with features of both a “cavernous” vascular malformation and KS. However, because of the failure to observe metastases among these lesions, with the exception of a single case of presumptive radiation-induced malignant transformation, in 1996 Perkins and Weiss suggested that this entity was most likely benign and more appropriately termed spindle cell hemangioma (SCH).48 Some authors have also maintained that

 FIGURE 31-8 Papillary hemangioma. Note the papillary architecture and protrusion of capillary lobules into large, thin-walled vessels with prominent lumina.

Table 31-3 Spindle Cell Hemangioma

Clinical Features Men = women Any age, often in the third and fourth decades of life Favors the extremities, particularly distal Solitary or multiple, circumscribed, red to red-brown nodules Gradually increase in size or number Association with large vessels; many cases entirely or partially intravascular Cystic hemorrhagic cavities, occasionally with a phlebolith Associations with Maffucci disease, varicose veins, and congenital lymphedema Histopathologic Features Cavernous, thin-walled blood vessels Organizing thrombi and phleboliths Solid, cellular areas of spindled cells Network of slitlike spaces Short fascicles Plumper, more epithelioid cells, occasionally vacuolated Relative lack of cytologic atypia and mitotic activity Differential Diagnosis Kaposi sarcoma Nodular venous and malformation

SCH may be a nonneoplastic, reactive vascular proliferation, associated with malformed blood vessels and repeated cycles of recanalization after thrombosis.48,49 CLINICAL FEATURES SCH occurs in individuals at any age and in both genders (Table 31-3).48 Lesions have arisen as early as the perinatal period, but nearly half of cases have presented during the third and fourth decades of life. SCH has a predilection for the extremities, particularly distally, often involving the hands and feet. Typically arising in the dermis or subcutaneous tissue, SCH presents as either solitary or multiple, asymptomatic nodules that gradually increase in size or number over a period of months or years and often eventuate in extensive disease. When the lesions are multiple, they usually occur in the same general area; however, bilateral lesions of the hands have been described, and rare patients may have multiple lesions on diverse sites, including the trunk, oral cavity, and genitalia.48-51 SCH has developed in Maffucci syndrome and rarely in Klippel-Trenaunay syndrome, early-onset varicose veins, and congenital lymphedema of Milroy disease.47,50,52,53 Two cases of SCH have arisen as multiple lesions associated

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

HISTOPATHOLOGIC FEATURES All reported lesions were remarkably similar to noninvoluting congenital hemangioma as evidenced by papillary architecture and protrusion of capillary lobules into large, thin-walled vessels with prominent lumina. The papillae exhibit a fibrous core that contains bland capillaries. The outer surfaces of the aforementioned capillaries are lined by endothelial cells containing intracytoplasmic eosinophilic, PAS-positive hyaline globules (Fig. 31-8). These hyaline globules contain α1-antitrypsin and lambda immunoglobulin light chains. One case reported as a GH, unassociated with POEMS syndrome, has been reclassified as PH.44,45 Another closely related variant previously reported as endovascular PH of the lip shows some resemblance to PH, but intracellular hyaline globules were not evident.46

and endovascular papillary angioendothelioma. PH differs from NICH because it is an acquired lesion. Furthermore, the papillary architecture appears more diffuse and the intracytoplasmic hyaline globules more numerous and localized at the outer surface of the papillae in PH compared with NICH. Contrary to GH, PH reported thus far has never affected patients with POEMS syndrome. The capillary loops of GH are smaller and arranged in a more organoid glomeruloid fashion. IPEH is characterized by thin, elongated papillae demonstrating fibrin in the early stage of development and in later stages shows acellular hyaline collagen. These papillae are lined by bland endothelial cells that do not contain hyaline globules.44 In endovascular papillary angioendothelioma (Dabska tumor), the papillations are lined by columnarappearing endothelial cells.

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with epithelioid hemangioendothelioma (EHE).54 One patient with Maffucci syndrome presented with multiple lesions of SCH on the arm and chest and high-grade angiosarcoma of the abdominal wall. Grossly, the tumors may be several millimeters to centimeters in diameter and generally appear as small, circumscribed, red to red-brown nodules that on sectioning show variably sized cystic, hemorrhagic spaces. On occasion, a phlebolith may be present and “pop out” from these cavities. More than half of cases of SCH are entirely or partially intravascular, being associated with large vessels and often thick-walled veins.48 Local recurrence frequently occurs after simple excision, and multiple recurrences may occur in individual patients. Although several patients have developed extensive local disease, none have developed visceral metastasis or died despite having received only conservative surgical therapy. HISTOPATHOLOGIC FEATURES SCH is characterized by a nodular appearance with two distinctive components: (1) thinwalled, “cavernous” blood vessels that are separated by thin fibrous septa and are sometimes filled with organizing thrombi and phleboliths (Fig. 31-9) and (2) solid, cellular areas composed predominantly of spindle cells (see Table 31-3 and Fig. 31-10). The proportion of cavernous spaces to areas of spindle cells is variable.47,50,52,53 The spindle cells may form a network of slitlike spaces or may form short fascicles between the dilated “cavernous” vessels. Small aggregates of plump, epithelioid cells are commonly interspersed among the spindle cells. Isolated or focally numerous intracytoplasmic clear vacuoles are often present, usually in association with the epithelioid areas. On occasion, these vacuolated cells may line vascular spaces. Cytologic atypia and mitotic activity are inconspicuous. The large, thick-walled veins containing SCH have abnormalities of the muscular wall and intima, which are apparent on multiple sectioning.48 Von Willebrand factor, CD31, Ulex europaeus lectin, and CD34 are expressed by most of the endothelial lining cells and by the occasional plump cells, but rarely, if ever, by the spindle cells. Because of the histologic similarities to KS, these tumors have been examined for HIV-1 antibody titers and for human herpesvirus-8 (HHV-8) expression with negative results.51,55 DIFFERENTIAL DIAGNOSIS The most problematic entity in the differential diagnosis is KS. In particular, the solid, cellular areas

 FIGURE 31-9 Spindle cell hemangioma. The lesion contains cavernous vascular channels.

 FIGURE 31-10 Spindle cell hemangioma. A solid area composed of spindle cells.

of spindle cells in SCH bear a resemblance to KS but differ by containing an admixture of plump endothelial cells with clear to vacuolated cytoplasm. Ectatic, irregular vascular spaces are a component of plaquestage KS, but cavernous spaces containing thrombi and phleboliths are usually not. KS-associated herpesvirus (HHV-8) is not found in SCH.55

This hemangioma, with its characteristic histologic appearance of small dermal blood vessels, was first described by Hunt and coworkers in 1991.56 A very similar, if not identical, appearing angioma arising in young women under the hormonal influence of pregnancy or hormonal contraceptives has been referred to as microcapillary angioma.

Microvenular Hemangioma

CLINICAL FEATURES Microvenular hemangiomas (MVHs) typically occur as solitary asymptomatic, small, enlarging, purple

Synonym: Microcapillary angioma

Table 31-4 Microvenular Hemangioma

to red plaques or nodules usually on the extremities of young to middle-aged adults (Table 31-4). The patients range in age from 9 to 64 years (mean, 28 years) and present with lesions as large as 1 to 2 cm.56,57 The natural history of MVH is usually brief as most lesions involute during a few weeks to months but some have persisted as long as 4 years. Clinically, MVH is generally viewed as a benign vascular tumor, however but the differential diagnosis may included KS. MVH has been reported in association with the Wiskott-Aldrich syndrome,58 and acute myelogenous leukemia,59 and the POEMS syndrome.60 In this last case, MVH cells expressed HHV-8.

DIFFERENTIAL DIAGNOSIS MVH has a distinctive histologic appearance, allowing little difficulty in diagnosis, although there may be some resemblance to stasis change, reactive angiogenesis in scars, early KS, and the vascular proliferations in some lesions previously included under the term sclerosing hemangioma (vessel-rich dermatofibroma). The venular differentiation may be similar to that sometimes seen in the late stages of TA and targetoid hemosiderotic hemangioma (THH).

 FIGURE 31-11 Microvenular hemangioma. Typical infiltrative growth pattern of venules throughout the dermis.

Stasis change is clinically distinct from MVH, typically present on the distal lower extremities of an individual with chronic venous insufficiency. Immature scars, in contrast to MVH, show irregularly arranged fibroblastic and vascular proliferations often associated with erythrocyte extravasation, hemosiderin deposition, and an inflammatory infiltrate that may contain a few plasma cells. Early KS can be excluded by clinical setting and the absence of angulated, irregular vascular spaces enveloping preexisting dermal blood vessels, plasma cells, hyaline (eosinophilic) globules, and a spindle cell component.

Verrucous Hemangioma Verrucous hemangioma (VH) is a vascular lesion of elusive classification, occurring as solitary or multiple keratotic lesions on the extremities. It demonstrates clinical features of a vascular malformation as evidenced by presence at birth or appearance in childhood, proportionate growth and indefinite persistence, and histologic features suggesting a vascular tumor because it is composed of small thickwalled, vascular channels, more or less grouped in lobules, with focal expression of GLUT-1.61,62 It is discussed in the malformation section.

Targetoid Hemosiderotic Hemangioma Synonym: Hobnail hemangioma THH is a benign, possibly reactive, vascular lesion first described in 1988.63 More than 100 cases have been reported. THH is one of the histologic simulants of KS, and knowledge of its clinicopathologic features is crucial to the avoidance of misdiagnosis. THH endothelial cells express vascular endothelial growth factor receptor (VEGFR)-3 in a proportion of cases64 and the D2-40,65 which indicates a lymphatic phenotype. CLINICAL FEATURES THH typically presents as a solitary, annular, violaceous to purple papule 2 to 3 mm in diameter, with both a surrounding pale rim and a more peripheral ecchymotic ring resulting in a targetlike appearance (Table 31-5).63 This ring expands peripherally and then eventually disappears. Late lesions may show only a purple-brown, slightly elevated papule. This latter lesional alteration appears to be secondary to trauma or thrombosis and may not be a constant feature. Neither gender appears to be favored, the age range is 5 to 72 years,

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Clinical Features Young to middle-age adults Extremities most common site Small, purple to red plaques or nodules Histopathologic Features Irregular branching, small blood vessels Inconspicuous lumina Variable degree of desmoplasia Scant or absent inflammatory infiltrate Differential Diagnosis Stasis change Scar Early Kaposis sarcoma Sclerosing hemangioma or dermatofibroma

HISTOPATHOLOGIC FEATURES MVH is composed of irregularly branching, small blood vessels, often with the appearance of collapsed venules56,57 (Table 31-4 and Fig. 31-11). Lumina are generally inconspicuous (narrow to absent). Endothelial cells may at times be a little plump, but no cellular atypia is present. Some examples of MVH have prominent epithelioid cells resembling those of epithelioid hemangioma (EH). Tufted aggregates of vessels can be seen in the deep dermis. These structures closely resemble those of PG and TA. Examples of PG merging with MVH have also been observed. There is a background of dermal desmoplasia with variably thickened dermal collagen. Inflammation and hemosiderin are generally scant or absent. Plasma cells and eosinophils are usually not observed. Immunohistochemically, the endothelial cells express von Willebrand factor weakly and Ulex europaeus lectin 1 strongly. The peripheral cells stain with smooth muscle–specific actin.

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Table 31-5 Targetoid Hemosiderotic Hemangioma

810

Clinical Features Wide age distribution; childhood to elderly Diverse sites Annular target-like lesion: central violaceous papule surrounded by a pale rim and a more peripheral expanding ecchymotic ring Histopathologic Features Early Lesions Widely dilated, irregular, thin-walled vascular lumina in the superficial dermis Endothelial cells flat to epithelioid Intraluminal papillary projections usually lined by a single layer of epithelioid endothelial cells Narrower, more angulated and inconspicuous vessels “dissecting” collagen bundles of the deeper reticular dermis Dermal edema, red blood cell extravasation, hemosiderin, little lymphocytic inflammation Later lesions Collapsed lumina Extravascular spindle cells Narrow, angulated, thin-walled vessels crisscross the dermis in “dissection” of collagen Variable hemosiderin deposition Expression of D2-40 in endothelial cells Differential Diagnosis Early Kaposi sarcoma Lymphangioma-like Kaposi’s sarcoma Acquired progressive lymphangioma Retiform hemangioendothelioma

and the median age is in the early fourth decade of life.63,64,66-68 THH occurs in diverse sites, favoring the proximal upper and lower extremities (particularly the thigh) and the trunk. Some cases have shown cyclic changes in clinical appearance, sometimes during the menstrual cycle.66,69 THH is benign, may be removed by local excision or excisional biopsy, and typically does not recur. HISTOPATHOLOGIC FEATURES The histology of THH varies according to the age of the individual lesion. The earliest finding is a proliferation of widely dilated and irregular, thin-walled vascular lumina in the superficial dermis63 (see Table 31-5 and Fig. 31-12). The endothelial cells are flat or conspicuously epithelioid. Intraluminal papillary projections lined by a single layer of epithelioid, and endothelial cells in “hobnail” fashion are often seen protruding into vascular lumina (Fig. 31-13). These plump endothelial cells

 FIGURE 31-12 Targetoid hemosiderotic hemangioma (hobnail hemangioma). Full-thickness dermal involvement with rounded vascular lumina in the superficial to mid-dermis, an anatomosing configuration in the mid- to deep dermis, and “hobnailing” of the endothelium protruding into the vascular lumina.

may occasionally pile up and even obliterate vascular lumina. Intraluminal fibrin thrombi may be present. Vessels deeper in the reticular dermis have an inconspicuous endothelial cell lining and become angulated and irregular, appearing to dissect collagen bundles. The vessels tend to be oriented around adnexal structures such as eccrine coils. Other features of THH are dermal edema; variable, often intense red blood cell extravasation; hemosiderin deposition; and an inconspicuous to mild, predominantly lymphocytic, inflammatory infiltrate. Overall, on low-power magnification, THH gives a stratified or biphasic appearance with ectatic vessels containing epithelioid endothelial cells at the top and angulated, inconspicuous vessels at the bottom. Mature lesions show most vascular lumina to be collapsed and increased cellularity of extravascular tissue. Spindle cells appear in close approximation to the vascular proliferation. Late lesions demonstrate collapsed, anastomosing, thin-walled vessels criss-crossing the dermis. Foci of elongated arborizing vessels within THH are said to resemble acquired progressive

lymphangioma (APL) and retiform hemangioendothelioma (RH).64,66 Immunohistochemically, the endothelial cells of the typical THH express CD31 and D2-40 but react variably with CD34, von Willebrand factor, Ulex europaeus lectin 1, and VEGFR-3. They do not express HHV-8.70 Franke et al.65 have shown a continuity in vessels lined by endothelial cells of blood and lymphatic phenotypes, suggesting the existence of microshunts between blood and lymphatic vessels. DIFFERENTIAL DIAGNOSIS THH appears histologically as an atypical vascular lesion with resemblance to APL, patchstage KS, and lymphangiosarcoma. The clinical setting is helpful in differentiating these lesions because THH occurs as a solitary small lesion in healthy individuals. Outside of Africa, KS is seen classically in elderly individuals and secondary to AIDS. Lesions of KS are typically multiple and of variable size. APL is clinically distinct from THH and occurs as welldemarcated dermal plaques that are larger in size than THH and often reach considerable proportions.

on the characteristics of the cases, this process is considered neoplastic rather than a malformation.

THH shares histologic features with patches of KS. These similarities include angulated vascular lumina dissecting collagen bundles; erythrocyte extravasation; hemosiderin deposition; and, in late lesions, the presence of spindle cells. Differential features are present, however, and in particular, whereas the scanning magnification appearance of THH shows stratification, and KS tends to be “bottom heavy.” The papillary intraluminal projections and epithelioid endothelial cells of early lesions of THH are not features of KS. THH typically lacks plasma cells and is more apt to show significant erythrocyte extravasation and hemosiderin. Apoptotic endothelial cells may be seen in early KS but do not seem to be a feature of THH. Despite all of these features, the overlap in morphologic features of THH and KS may be so great that clinicopathologic correlation is necessary to separate the lesions. Immunohistochemistry may be of help because, contrary to KS, HHV-8 is not demonstrated in THH.70 The lymphangioma-like variant of KS and lesions of APL may also be confused histologically with THH, particularly mature lesions of THH. The clinical setting is important for the discrimination of these entities. Patients with lymphangioma-like KS have extensive, clinically typical KS. Histologically, APL lacks hemosiderin and extravasated erythrocytes and clinically is quite different, being a much more extensive process

than THH. RH share with THH the slitlike vessels and the hobnail appearance of endothelial cells. THH are, however, generally smaller and superficial lesions, with less fibrosis and less relatively sparse lymphocytic infiltrates and regularly express D2-40. The characteristic biphasic appearance of THH with superficial dilated vessels and deep slitlike component is not a feature of RH. In late lesions, THH needs to be differentiated from the vessel-rich variant of dermatofibroma, the so-called sclerosing hemangioma.

Multifocal Lymphangioendotheliomatosis or Cutaneovisceral Angiomatosis with Thrombocytopenia Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT)71 or cutaneovisceral angiomatosis with thrombocytopenia (CAT)72 is a rare recently described entity presenting in newborns and children as several to hundreds of red to brown macules or papules on the skin and gastrointestinal (GI) mucosa associated with severe GI bleeding. These lesions are accompanied by moderate thrombocytopenia (10,000 to 66,000/mm3) without consumption of coagulation factors. Some patients also have involvement of the lung, muscle, bone, bone marrow, synovium, or spleen or have retinal or vitreous hemorrhages or brainstem calcifications. Based

DIFFERENTIAL DIAGNOSIS MLT or CAT must be differentiated from APL and intravascular papillary angioendothelioma. Contrasting with MLT or CAT, the latter two conditions are generally solitary, are not reported in the GI tract, and are not associated with GI bleeding or thrombocytopenia. Compared with MLT or CAT, endothelial hyperplasia and papillation is rare and focal in APL and much more pronounced in intravascular papillary angioendothelioma, in which hobnailed or matchstick endothelial cells are numerous with moderate atypia.

BENIGN VASCULAR LESIONS OF INDETERMINATE OR REACTIVE NATURE

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-13 Targetoid hemosiderotic hemangioma (hobnail hemangioma). Deep portion of the process with angulated vessels lined by thin endothelial cells that dissect collagen. Intraluminal papillary projections lined by a single layer of epithelioid and endothelial cells in “hobnail” fashion are often seen protruding into the vascular lumina.

HISTOPATHOLOGIC FEATURES Cutaneous, GI, synovial and lung specimens show thin-walled, dilated channels with variable degrees of endothelial hyperplasia, occasional hobnailed nuclei, and focal intraluminal pseudopapillary or papillary projections. In areas of endothelial hyperplasia and within the papillae, PAS-positive intracellular cytoplasmic globules or interstitial deposits may be found. In rare cases, endothelial hyperplasia virtually occludes some vascular lumina. Vascular lumina have been variably described as empty or containing blood cells. Endothelial cells express CD31, CD34, LYVE-1, fascin with variable intensity, and only rare and focal staining with D2-40. Thus, controversy exists as to the classification of these lesions as either of lymphatic71 or blood vessel derivation.72

Epithelioid Hemangioma (Angiolymphoid Hyperplasia with Eosinophilia) Synonyms: angiolymphoid hyperplasia with eosinophilia, atypical PG, inflammatory angiomatous nodules with abnormal blood vessels, PG, papular angioplasia, atypical vascular proliferation with inflammation, intravenous atypical vascular proliferation, nodular angioblastic hyperplasia with eosinophilia and lymphofolliculosis, histiocytoid hemangioma EH is an entity that has evolved since the 1960s and has carried various designations since that time.73-75 Moreover, EH had been confused with Kimura disease, a condition that differs clinically

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and histopathologically from EH and is now viewed as a separate entity. With respect to the pathogenesis, whether EH is a reactive vascular proliferation versus a primary benign vascular tumor has not been resolved. HHV-8 has not implicated in the pathogenesis of EH.76

812

CLINICAL FEATURES EH presents as single or multiple pink to red-brown papules or plaques in the head and neck region of young to middle-aged adults, especially women, although some reports have noted a male predominance (Table 31-6).73-75 The most common sites are the ear, forehead, and scalp. Uncommonly, the trunk, extremities, hands, oral mucosa, and penis may be involved. Disseminated lesions have also been reported.77 Most lesions of EH are intradermal, but deeper extension into the subcutaneous tissue may occur, and the condition may occasionally arise as primary subcutaneous nodules. Peripheral blood eosinophilia is present in a minority of cases. Lesions of EH are usually asymptomatic, but on occasion, there may be tenderness, pulsation, pruritus, or bleeding, either spontaneously or after minor trauma. HISTOPATHOLOGIC FEATURES EH shows blood vessel proliferation and inflammation (Table 31-6 and Fig. 31-14).73-75 The vessels vary in diameter and are lined by prominent epithelioid endothelial cells, a feature that is characteristic of EH and

Table 31-6 Epithelioid Hemangioma

Clinical Features Young to middle-aged adults Head and neck region favored, especially auricle and periauricular skin Single or multiple, pink to red-brown papules or plaques Peripheral blood eosinophilia, on occasion Histopathologic Features Proliferation of blood vessels of variable diameter Prominent endothelial cells Enlarged, cuboidal or hobnail shape Abundant eosinophilic to amphophilic cytoplasm and large vesicular nuclei (“histiocytic” appearance) Cytoplasmic vacuoles of variable size Diffuse to nodular lymphocytic infiltrate Lymphoid follicles Variable numbers of eosinophils Differential Diagnosis Kimura disease Epithelioid hemangioendothelioma Epithelioid angiosarcoma

 FIGURE 31-14 Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia). Low-power view of the vascular proliferation with peripheral rim of lymphocytes.

defines the entity. The endothelial cells are enlarged, cuboidal to tombstone in shape, with abundant eosinophilic to amphophilic cytoplasms and large vesicular

nuclei (Fig. 31-15). Cytoplasmic vacuoles may be present and, when large, may distort the nucleus and protrude into the vascular lumina. These endothelial cells

 FIGURE 31-15 Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia). The endothelial cells are enlarged, cuboidal to epithelioid cells with a “tombstone” appearance, abundant eosinophilic to amphophilic cytoplasms, and large vesicular nuclei.

DIFFERENTIAL DIAGNOSIS Clinical and pathologic features differentiate EH from Kimura disease. In essence, Kimura disease lacks the characteristic epithelioid endothelial cell of EH and is usually noted in young Asian males. Large subcutaneous masses typically develop in the parotid and submandibular regions. Commonly, the patient has associated manifestations, such as lymphadenopathy, blood eosinophilia, and increased

serum levels of immunoglobulin (IgE). Distinctive histologic features of Kimura disease include a florid lymphocytic infiltrate with prominent lymphoid follicles, germinal center vascularization, germinal center necrosis, sclerosis, and marked eosinophilia with or without eosinophil abscess formation. Warthin-Finkeldey type polycaryon are frequently observed. There also are germinal center deposits of IgE and frequent involvement of the skeletal muscle, salivary glands, and regional lymph nodes. Kimura disease is considered to be the result of an immunologic reaction of an allergic or autoimmune nature. Juvenile temporal arteritis recently has been speculated to be an accessory lesion of Kimura disease.83 EHE is an angiocentric tumor often suggesting metastatic carcinoma that also may be mistaken for EH. Vascular differentiation in EHE is more primitive than that seen in EH and occurs primarily at the cellular level with the formation of vacuoles and intracellular lumina. These lesions are often desmoplastic, relatively noninflammatory, and frequently associated with a chondromyxoid matrix. Compared with EH, angiosarcoma generally has conspicuous cytologic atypia, frequent mitotic figures, and piling up of cells and lacks the inflammatory infiltrate of EH, although rare angiosarcomas may display substantial infiltrates. Solid areas of EH may resemble epithelioid angiosarcoma and even more so EHE. However, epithelioid angiosarcoma is generally a highly malignant-appearing tumor that is more apt to be mistaken for poorly differentiated carcinoma than a lesion of EH.

Pyogenic Granuloma (Lobular Capillary Hemangioma) Synonyms: Granuloma pyogenicum, granuloma gravidarum, botryomycoma This common vascular lesion was once considered to be secondary to pyogenic infection or arising as exuberant granulation tissue in response to trauma. At present, PG is considered to be a specific form of vascular lesion is often designated lobular capillary hemangioma because of its lobular architecture at scanning power magnification.84-86 However, the latter designation is misleading because it appears valid for many vascular tumors, including IH, congenital hemangioma, TA, PH, and reactive vascular conditions composed of capillaries grouped in a lobular fashion.87 Moreover, the neoplastic nature of PG is clearly questionable. As a result, the authors prefer to restrict the term hemangioma to vascular tumors proper and thus favor

the use of the somewhat outdated but universally understood term PG. CLINICAL FEATURES PG typically appears as a solitary, rapidly growing, dark red, exophytic, raised to polypoid, vascular lesion that frequently has superficial ulceration (Fig. 31-16A and Table 31-7). Many PG arise spontaneously without a known cause, but others are associated with trauma, cast immobilization,88 pregnancy,89 antiretroviral therapy,90 and so on. The most common sites for PG are the fingers, face, and oral cavity. In the oral cavity, lesions may be seen on the gingiva, lips, and tongue. The term granuloma gravidarum or pregnancy tumor applies to a PG arising on the gingival surface during pregnancy. Whereas oral mucosal PG favor female patients (2:1), cutaneous lesions affect both genders equally.91 PG may develop on capillary malformations (CMs; port wine stains [PWSs]) and arteriovenous malformations (AVMs). Retinoids; isotretinoin; etretinate; and topical use of tretinoin, tazarotene, and a combination of retinoic acid and minoxidil has also been implicated in development of PG-like lesions.92 The phenomenon of satellite lesions arising after surgical removal, laser excision, or trauma to a PG is well known. Satellite lesions usually occur on the trunk, particularly on the upper back of individuals younger than 25 years of age. A rare, eruptive, disseminated, self-limited form with lesions that may number in the hundreds has been described. In most cases, they have appeared spontaneously, although they have also arisen after a second-degree burn and after the removal of an ocular neoplasm. Underlying malignancy has been documented in some patients with disseminated PGs, but causation has not been established. The notion of a circulating angiogenic factor being involved in the pathogenesis is certainly intriguing but is still entirely speculative. The rapid growth of PG may result from decreased apoptosis associated with increased expression of the Bcl-2 family of apoptotic-regulatory proteins.93 In one study, PGs from pregnant women showed no immunoreactivity for estrogen and progesterone receptor proteins.89 Also, epidemiologic data are against a hormonal influence for cutaneous PG. HISTOPATHOLOGIC FEATURES PG evolve through three more or less distinct phases (see Table 31-7). In the early phase, there is a compact vascular proliferation of solid, largely collapsed vascular structures (Figs. 31-16 to 31-18). The histology appears abnormal with endothelial cells

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

express common endothelial markers (CD31, CD34, von Willebrand factor) and may express simple epithelial keratins such as K19 and K7 focally. Thick-walled vessels with muscular media may be surrounded by or infiltrated by myxoid or mucoid material. There is an accompanying diffuse to nodular lymphocytic infiltrate possibly with lymphoid follicles and germinal center formation. Variable numbers of eosinophils are almost always present. There is zonation of the inflammatory infiltrate toward the periphery of the lesion. Occasional thrombi may be seen, and mitotic activity is generally inconspicuous to absent. Multinucleated cells disposed in a perivascular and interstitial distribution may be noted.78 Subcutaneous lesions, particularly those associated with arteriovenous fistulas, tend to show prominent endothelial cell proliferation, sometimes forming solid intraluminal masses. Such solid proliferations of endothelial cells may obscure the true vascular nature of the lesion and occasionally lead to confusion in diagnosis. However, vascular organization is generally present at the periphery of the lesion, suggesting a “maturation” of the lesion.79 Lesions with confluent proliferation of epithelioid endothelial cells have recently been reported under the term cutaneous epithelioid angiomatous nodules and appear to be related to EH.80 The latter proliferative lesions involve the superficial dermis, nasal submucosa, or subcutis.81 They are characterized by small, welldefined unilobular aggregates of epithelioid endothelial cells with intracytoplasmic vacuoles, minimal vascular lumen formation, and inflammatory infiltrates composed of lymphocytes and eosinophils. Mitoses up to 5 to 10 high-power fields (hpf) may be present without atypical mitoses or nuclear atypia. Subcutaneous masses developing after trauma and demonstrating thickened small to medium-sized arteries, myxoid degeneration, and capillary vascular proliferation have been designated traumatic pseudoaneurysm and are theorized to be a precursor of EH.82

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A

B

 FIGURE 31-16 Pyogenic granuloma (lobular capillary hemangioma). (A) Red polypoid tumor with subtle wafer-like collarette of scale. (B) The lesion is dome shaped, has epidermal collarettes at the base, and exhibits a well-developed lobular architecture. In the early phase, there is a compact vascular proliferation of solid, largely collapsed vascular structures. The endothelial cells are arranged in solid aggregates with prominent nuclei and numerous mitotic figures.

arranged seemingly in solid sheets with prominent nuclei and numerous mitotic figures. Later, there is a frank evolution into vascular structures with a multilobular arrangement and regular-appearing lumina with larger intralobular thinwalled stellate vessels. In the final stage,

Table 31-7 Pyogenic Granuloma

Clinical Features Etiology: idiopathic, posttraumatic, pregnancy-, retinoid-, or antiretroviral therapy-related Many sites but most common are fingers, face, mouth Rapidly growing, red papule or polyp, frequently ulcerated Satellite lesions occasionally arise after trauma or removal Rare eruptive, disseminated form Rare, wholly intradermal, subcutaneous, or intravenous forms Histopathologic Features Proliferation of capillaries with loose lobular arrangement Cytologically bland endothelial cells with variable number of mitoses Epidermal flattening and peripheral collarette Frequent superficial ulceration with secondary edema, hemorrhage, fibrin, necrosis, and acute inflammation Differential Diagnosis Capillary hemangioma Bacillary angiomatosis Acquired tufted angioma Stellate central lobular vessels with progressive venulization

there is a progressive transformation of some vessels into veins. Initially, one or two such veins dominate each lobule, but later, there is extensive “venulization” of the entire lesion. Intra- and interlobular fibrosis ensues, and the lesion becomes progressively avascular and fibrotic. Rare examples may resemble a VM, but the typical lobular configuration of PG is distinctive. The typical PG contains variably cellular but cytologically bland lobular capillary proliferation with variable mitotic activity.

The overlying epidermis is flattened, forms a peripheral collarette, and frequently shows erosion. Edema, hemorrhage, fibrin, necrosis, and acute inflammation are frequent. Extramedullary hematopoiesis was reported in one case.94 PGs have also occurred intravenously and in subcutaneous tissue. Intravenous PG extend into the vascular lumina as polypoid lesions that connect with the wall of the vein by a fibrovascular stalk. Immunohistochemically, the endothelial cells of the well-formed capillaries

 FIGURE 31-17 Pyogenic granuloma (lobular capillary hemangioma). With time, the vascular structures show less cellular multilobular arrangements and regular-appearing lumina with larger intralobular thin-walled stellate vessels.

Table 31-8 Glomeruloid Hemangioma

express von Willebrand factor, Ulex europaeus lectin, CD31, and CD34. The endothelial cells of the more compact, cellular areas show similar results, although in one study, the staining for von Willebrand factor was equivocal. A concentrically arranged perivascular spindle cell proliferation marks with vimentin, muscle-specific actin, and collagen type IV and is considered to be pericytes. The immunopathologic and ultrastructural features of localized and disseminated PGs have been reported to be virtually identical. DIFFERENTIAL DIAGNOSIS The differential diagnosis of PG is as varied as its clinical presentations and evolutionary stages. It may be confused clinically with amelanotic melanoma and eccrine poroma. Histologically, PG has features that link it with tufted hemangioma; however, TA lacks the nodular, sometimes exophytic character and intralobular open stellate vessels of PG. On occasion, the endothelial cells may be prominent and plump, and a differential diagnosis with EH is required. The dermal form is sometimes confused with a glomus tumor but lacks cuboidal glomus cells.

Glomeruloid “Hemangioma” This rare vascular lesion derives its name from its distinctive histologic resemblance to renal glomeruli and occurs in the setting of POEMS syndrome, a multisystem

disorder consisting of polyneuropathy, organomegaly, endocrinopathy, M-protein development, and particular skin alterations.95,96 The authors have seen a case associated with multiple myeloma. The cutaneous manifestations include hyperpigmentation, hypertrichosis, hyperhidrosis, scleroderma-like skin thickening, and hemangiomas. Many patients with POEMS syndrome show overlapping features with multicentric Castleman disease and its characteristic angiofollicular lymphoid hyperplasia of lymph nodes. The glomeruloid “hemangioma” is considered to be a reactive endothelial proliferation with a similar pathogenesis as RAE and the result of circulating angiogenic factors from activated lymphocytes. These patients with RAE have circulating cryoproteins that, when in contact with endothelium of peripheral microvessels, stimulate their proliferation with widespread inspissated cryoproteins within vascular lumina. CLINICAL FEATURES GHs appear to be more common in Japanese patients than in other ethnic groups (Table 31-8). Only a few cases have been reported in whites. GHs often present in the fifth to sixth decades of life without predilection for either gender. Patients with POEMS syndrome and hemangiomas have multiple, punctuate to several-millimetersized, red or violaceous papules favoring the trunk and proximal limbs. Most of the hemangiomas are actually cherry-like

angiomas rather than GHs, which are actually fairly rare. HISTOPATHOLOGIC FEATURES A precursor stage of immature vascular tissue has been suggested.97 Typical GHs are characterized by ectatic vascular spaces that surround intraluminal conglomerates of blood-filled capillaries. The microvessels within latter glomerulus-like structures are lined by flat endothelial cells.95,96,98 (see Table 31-8 and Fig. 31-19). However, an occasional endothelial cell may be plump with pale cytoplasm, clear vacuoles, or eosinophilic globules. Some GHs may exhibit striking numbers of eosinophilic droplets. Similar cells, which may be immature endothelial cells, are interspersed as stromal cells between the capillary loops. The eosinophilic globules, which are PAS positive and diastase resistant, show polytypic immunoglobulin staining and presumably represent circulatory-derived immunoglobulins and other proteinaceous material. Mitoses are inconspicuous, numbering less than 1 per 10 hpf. Little, if any, inflammation is present. Irregular lumina associated with capillaries and sinusoid-like spaces have been described within the glomeruloid structures in GH. In contrast to the immunophenotype of the endothelia of the vascular ectasia and capillaries (expression of CD31, CD34, von Willebrand factor, and Ulex europaeus lectin 1), the endothelial cells of the sinusoid-like

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-18 Pyogenic granuloma (lobular capillary hemangioma). In the final stage, some vessels progressively transform into veins. Initially, one or two such veins dominate each lobule, but later extensive “venulization” of the entire lesion takes place.

Clinical Features Japanese >other populations Fifth to sixth decades of life Multiple, punctate to a few millimeters, eythematous or violaceous papules Most common sites: trunk and proximal limbs Histopathologic Features Conglomerates of capillaries within ectatic spaces, giving a glomerulus-like appearance Generally bland endothelial cells Occasional plump endothelial and stromal cells with pale cytoplasm, clear vacuoles, or eosinophilic globules Little to absent inflammation Differential Diagnosis Acquired tufted angioma Intravascular pyogenic granuloma Intravascular papillary endothelial hyperplasia Reactive angioendotheliomatosis Endovascular papillary angioendothelioma (Dabska tumor)

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A

816

B

 FIGURE 31-19 Glomeruloid hemangioma. (A) Vascular channels throughout the dermis show the typical intravascular proliferation of endothelium reminiscent of renal glomeruli. (B) Typical glomeruloid proliferation of blood vessels.

spaces are reported to be positive for CD31 and CD68 but negative for CD34, von Willebrand factor, and Ulex europaeus lectin 1.99 Cells containing the PAS-positive eosinophilic globules are also CD68 positive. The cherry-type angioma of POEMS syndrome may demonstrate rare, miniature glomeruloid tufts. The endothelial cells are positive for both von Willebrand factor and Ulex europaeus lectin 1. Many of the plump “stromal” cells are also positive for von Willebrand factor. DIFFERENTIAL DIAGNOSIS TA is frequently associated with peripheral vascular clefts; however, there is no actual intravascular angiomatous proliferation, and TAs are devoid of eosinophilic globules. The lesions develop in children and young adults as slowly growing macules and plaques that are larger than the small papules of GH. PG may rarely occur intravascularly but does not show the glomeruloid appearance of GH. IPEH differs from GH by having fibrous cores lined by plump endothelial cells and largely represents the organization of thrombotic matrix. RAE shows dilated vessels that contain proliferations of endothelial cells that often fill lumina; have associated fibrin thrombi; and appear swollen or, at times, display mild cytologic atypia. In contrast to GH, endovascular papillary angioendothelioma (Dabska tumor) shows intraluminal papillations lined by endothelium displaying some degree of pleomorphism and a hobnail or matchstick appearance. The vascular channels of endovascular papillary angioendothelioma are more primitive, and endothelial cells may appear to float free as single cells or clumps within vascular lumina. The hemorrhage and

necrosis of more cellular lesions are not features of GH.

Intravascular Papillary Endothelial Hyperplasia Synonyms: Masson tumor, intravascular angiomatosis, vegetant intravascular hemangioendothelioma In 1923, Masson first described as vegetant intravascular hemangioendothelioma, an unusual angiosarcoma-like proliferation in organizing thrombi of hemorrhoidal veins.100-102 However, the phenomenon received little attention until the past two to three decades, when the clinical and pathologic features of IPEH became better defined. CLINICAL FEATURES IPEH occurs in patients of all ages (Table 31-9).100-102 The typical presentation is that of a slowly enlarging, often tender, blue to red, deep dermal to subcutaneous swelling or mass. IPEH occurs at diverse sites and has a predilection for the head and neck and the extremities, particularly the fingers. Most lesions have been present for more than 1 year, and rare lesions may be present for as long as 21 years. In native blood vessels, IPEH occurs within arterial thromboemboli and venous thrombi, particularly those of hemorrhoids. In the skin, IPEH occurs as a pure form without any apparent prior lesion or, more commonly, as a focal change within a preexisting PG. IPEH may arise within VMs and in LMs (cystic hygromas). IPEH has also been identified in unusual sites such as the paranasal sinus, oral mucosa, tongue, and eyelid. IPEH arising on the palm in the setting of lymphedema after surgery and radiation therapy for breast

cancer, thereby mimicking Stewart-Treves syndrome, has been reported.103 IPEH appearing as violaceous papules and nodules on the lower extremities may clinically mimic KS. HISTOPATHOLOGIC FEATURES IPEH shows conspicuous intravascular papillary structures composed of cores of fibrous tissue and lined by endothelial cells that are generally flattened in appearance (see Table 31-9 and Fig. 31-20). However, at times, endothelial cells may be plump with slightly enlarged nuclei, endothelial

Table 31-9 Intravascular Papillary Endothelial Hyperplasia

Clinical Features All ages Diverse sites; head, extremities, fingers most common Predilection for hemorrhoidal veins Slowly enlarging swelling, often tender and blue to red Dermal to subcutaneous location Arises in skin in the absence of, or more commonly within, a preexisting vascular lesion Histopathologic Features Intravascular papillary endothelial-lined structures with fibrous cores Generally flattened endothelial cells Underlying organizing, thrombotic matrix Vascular lumina variably filled by the process Mitotic figures absent or rare Differential Diagnosis Angiosarcoma Glomeruloid hemangioma Endovascular papillary angioendolioma (Dabska tumor)

lymphoma, is an aggressive lymphoma that is generally associated with progressive clinical manifestations leading to death.108 Therefore, the reader is referred to Chapter 34. RAE is a benign process often associated with an underlying chronic infection, such as subacute bacterial endocarditis, and various other etiologic factors such as hypoxia or ischemia with diffuse dermal angiomatosis, a purported variant of RAE. Finally, two cases of intravascular disseminated angiosarcoma have been reported and were considered by the authors to be true malignant angioendotheliomatosis.109

 FIGURE 31-20 Intravascular papillary endothelial hyperplasia. Papillary fronds with thin endothelial cells and collagenous cores.

proliferation may be conspicuous on occasion, and IPEH may virtually fill the lumina of some blood vessels. Mitotic figures are generally absent or rare. A characteristic feature in most cases is the presence of an underlying thrombotic matrix that appears to be undergoing organization. The papillary projections result from the endothelialization of fragmented thrombotic material and the ingrowth of anastomosing capillaries. Immunohistochemically, IPEH shows a pattern of reactivity similar to that of organizing thrombi. von Willebrand factor is only seen in advanced lesions. DIFFERENTIAL DIAGNOSIS The juxtaposition or fusion of adjacent papillae results in an irregular vascular network reminiscent of the pattern seen in angiosarcoma. However, key histologic features in identifying IPEH are the thrombotic matrix, the intraluminal location, and the relative absence of both cytologic atypia and mitotic activity. Necrosis and solid cellular areas are absent. GHs differ from IPEH by showing conglomerates of blood-filled capillaries lined by endothelial cells that may display clear vacuoles and eosinophilic globules.

Bacillary Angiomatosis Synonym: Epithelioid angiomatosis This characteristic disorder typically occurs in patients with AIDS 104,105 and is more thoroughly reviewed in Chapter 19. Briefly, bacillary angiomatosis (BA), a zoonotic infection linked to domestic

cats, is associated with a gram-negative bacillus identified as Bartonella (formerly Rochalimaea) henselae (or, rarely, Bartonella quintana),105 and on low power, the lobular vascular configuration may mimic PG. Older lesions show progressive fibrosis, and the resemblance to KS may be striking. The clinical and pathologic features allow distinction from other vascular lesions such as PG, EH, KS, and angiosarcoma. The most helpful histologic features for the recognition of BA are the presence of neutrophils and the interstitial, finely granular aggregates. Silver stains and, if needed, electron microscopy may be used to detect the bacilli and confirm the diagnosis. Although there may be vague lobular aggregates of blood vessels, BA lacks the well-organized lobular architecture that typifies PG. In contrast to KS, BA lacks spindled cells, hyaline globules, and thin-walled vessels that dissect dermal collagen. Moreover, the inflammatory cell infiltrate of KS is predominantly lymphoplasmacytic. Finally, HHV-8 has been not demonstrated in BA.

Angioendotheliomatosis In 1959, Pfleger and Tappeiner described a rare vascular disorder that they subsequently named angioendotheliomatosis proliferans systemisata.106,107 Subsequently, two different variants of angioendotheliomatosis have been reported: reactive and malignant. Malignant angioendotheliomatosis, also known as neoplastic angioendotheliosis, cerebral angioendotheliomatosis, and angiotropic large cell

Synonyms: Angioendotheliomatosis proliferans systemisata, Tappeiner-Pfleger disease RAE is extremely rare, with fewer than 50 cases reported.110 The etiology has not been clearly established; however, inflammatory or immunologic reactions with elaboration of a circulating angiogenic factor has been suggested. Endothelial proliferative reactions in RAE have been triggered by exposure to bacterial antigens, cryoproteins, and hypoxia.111 Thus, RAE has been reported in association with chronic infections, cryoproteins, cold agglutinins,112 monoclonal gammopathy,113 antiphospholipid syndrome,114 rheumatoid arthritis,115 iatrogenic hemodialysis-related arteriovenous fistulas,116 dermal amyloid angiopathy,117 cholesterol emboli, sarcoidosis,118 underlying hepatopathy and hypertensive portal gastropathy,119 and postrenal transplantation. CLINICAL FEATURES RAE shows no gender predilection and is usually seen in adults, although patients range in age from infancy to the eighth decade of life. Lesions of RAE are multiple and may occur as red-brown patches or plaques and purple-red nodules. 120,121 Sites of involvement include the face, earlobes, trunk, and limbs. Diffuse dermal angiomatosis, a presumed variant of RAE, may involve the lower extremities of individuals with severe atherosclerosis122,123; the distal upper extremities in patients with iatrogenic, hemodialysisrelated arteriovenous fistula116; and the breast.124 Necrosis and ulceration may occur. Many patients have constitutional symptoms such as fever, malaise, and weight loss. Lesions of RAE generally resolve slowly over time, and no deaths from RAE have been reported. Diffuse dermal

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Reactive Angioendotheliomatosis

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angiomatosis may regress with revascularization of an atherosclerotic limb.

818

HISTOPATHOLOGIC FEATURES RAE shows dilated dermal and subcutaneous vessels disposed in diffuse, lobular, or mixed patterns. The latter vascular channels contain proliferations of small to enlarged endothelial cells that variably fill and often occlude vascular lumina (Fig. 31-21). Focal glomeruloid features, foci of histiocytes or epithelioid endothelial cells, and fasciitis-like dermal alterations may occur.110-112 In contrast, diffuse dermal angiomatosis manifests an extravascular interstitial proliferation of endothelial cells, often with inconspicuous lumen formation. Nonetheless, primitive vascular differentiation is evidenced by cytoplasmic vacuolization. The endothelial nuclei in RAE often appear vesicular. Fibrin thrombi may be present. The constituent cells in RAE usually express the endothelial markers CD31, CD34, von Willebrand factor, and (to a lesser degree) Ulex europaeus lectin 1. DIFFERENTIAL DIAGNOSIS The reactive form of angioendotheliomatosis must be distinguished from intravascular malignant lymphoma (angiotropic lymphoma). The intravascular lymphoma displays cytologically malignant cells that mark as lymphoid cells by immunohistochemistry. GH), associated with POEMS syndrome, in contrast to RAE, shows more distinctively glomeruloid features and eosinophilic globules. GH nonetheless

may be a clinicopathologic variant of RAE. Diffuse dermal angiomatosis bears striking resemblance to acroangiodermatitis but typically exhibits more extensive dermal involvement and lacks the abundant hemosiderin, the extravasated red blood cells, and the vaguely lobular configuration of acroangiodermatitis.

Acroangiodermatitis Synonyms: Stasis dermatitis, angiodermatitis, and pseudo-Kaposi sarcoma Acroangiodermatitis (AAD) is an infrequent reactive vasoproliferative condition most commonly associated with venous stasis,87,125,126 First described by Mali in 1965, the importance of AAD relates to its striking resemblance to KS, hence the synonym pseudo-KS. CLINICAL FEATURES Most of the original patients with AAD were middle-aged to elderly men.127 However, subsequent reports have emphasized the occurrence of acroangiodermatitis in younger patients with relatively chronic venous insufficiency associated with AVMs, either of congenital or acquired origin, and arteriovenous shunts surgically established for hemodialysis.126,128 AAD has also been seen in individuals with venous stasis associated with paralytic feet, in the hypertrophied leg of a patient with the Klippel-Trenaunay syndrome, in the setting of an above-the-knee amputation stump, and attributed to chronic circulatory disturbance from a poorly fitting suction-type prosthesis.129-131

 FIGURE 31-21 Reactive angioendotheliomatosis. Tufted proliferation of cells in intraluminal location. Small to enlarged endothelial cells variably fill and often occlude vascular lumina.

The clinical lesions of acroangiodermatitis are scaly, violaceous plaques, papules, and nodules. In chronic venous insufficiency of the lower extremities, the lesions are most numerous over the extensor surfaces of the toes and foot. They tend to spare areas of the foot where direct pressure, either extrinsic or intrinsic, is applied. Areas of sparing include points where adjacent digits contact each other or a shoe.127 Lesions may also occur on the lateral aspect of the ankle and anterior lower leg.129 Surrounding tissues are edematous and show changes of stasis dermatitis. AAD arising in the setting of AVM presents a similar clinical picture and is usually limited to the extremity involved by the AVM. HISTOPATHOLOGIC FEATURES Reactive epidermal hyperplasia and compact hyperkeratosis are frequent features of AAD (see Table 31-10). The most striking histologic changes involve the papillary and superficial to mid-reticular dermis. A proliferation of small blood vessels with dilated, round lumina are distributed throughout the dermis in a loose, vaguely lobular arrangement (Fig. 31-22).87,125,129 The vessels tend to be relatively uniform in size and regular in contour. The endothelial

Table 31-10 Acroangiodermatitis

Clinical Features Chronic venous insufficiency Venous stasis Extremity with arteriovenous malformation or hemodialysis shunt Middle age or older Younger distribution with congenital or acquired arteriovenous causes Scaly, violaceous papules, plaques, and nodules Distal lower extremities, particularly extensor foot and toes Accompanying stasis dermatitis Histopathologic Features Epidermal acanthosis and compact hyperkeratosis Proliferation of small blood vessels with dilated, round lumina Upper half of the dermis Dermal edema and variable fibrosis Extravasated erythocytes and hemosiderin, especially perivascular Inconspicuous mononuclear inflammatory infiltrate Differential Diagnosis Kaposi sarcoma Pyogenic granuloma, dermal type

VASCULAR LESIONS WITH INDETERMINATE OR BORDERLINE STATUS

Kaposi Sarcoma

cells are plump and one cell layer in thickness. The cytologic features are bland. The neovascular proliferation is superimposed on a background of dermal edema, fibrosis, erythrocyte extravasation, and hemosiderin deposition. The contribution of each component varies from lesion to lesion and varies in individual lesions over time. The dermal edema may be quite pronounced, particularly in the papillary dermis. Fibrosis is more variable and ranges from inconspicuous, represented by a relatively sparse number of fibroblasts, to quite pronounced, with dense dermal fibrosis. Similar vascular proliferation is seen around sweat gland coils. Extravasated erythrocytes and sometimes exuberant hemosiderin deposits are most commonly distributed in superficial perivascular patterns. An inconspicuous, mononuclear inflammatory infiltrate is an inconstant feature, and plasma cells are usually absent. DIFFERENTIAL DIAGNOSIS The clinical lesions of AAD may closely resemble those of classic KS. However, the clinical contexts of chronic venous insufficiency with stasis changes or an AVM or fistula should prompt consideration of AAD. Moreover, an underlying AVM must always be considered when either AAD or KS is suspected in a young individual.

The microscopic features of AAD are distinctly different from those of KS. The vessels of AAD are arranged in a lobular pattern; have round, regular contours; are centered in the papillary dermis; and show no tendency to localize about preexisting dermal structures. KS, in contrast, shows a haphazard arrangement of slitlike vascular spaces disposed about dermal structures. The inflammatory infiltrate in KS is more pronounced than that of AAD and contains greater numbers plasma cells. The confusion of AAD with KS occurs primarily when biopsies of either entity are interpreted without due consideration of clinical information. Attention to clinical history, physical findings, and correlation of histologic findings should lead to the correct diagnosis. Chronic lesions of atrophie blanche (hyalinizing segmental vasculitis) may demonstrate similar vasoproliferative changes as in AAD but can usually be distinguished from AAD by vascular fibrin deposits. Also, the lobular pattern of vascular proliferation may be quite pronounced and may vaguely mimic the vascular proliferation of dermal PG, a point emphasized by Barnhill and Ryan in a chapter maintaining that lobular proliferation of microvessels is the fundamental process in many or most benign vascular tumors and reactive conditions.87

CLINICAL FEATURES The classic, chronic or “European,” form of KS is uncommon, generally affects individuals older than

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-22 Acroangiodermatitis. Subepidermal lobular vascular proliferation with deposition of hemosiderin.

This vascular neoplasm was first described by Kaposi in 1872 as “idiopathic multiple pigmented sarcoma of the skin.”132-136 Four variants of KS have been characterized. The classic form is a rare indolent disease affecting predominantly elderly men of Mediterranean, Eastern European, and Jewish origins. The endemic form affects both children and adults from Central Africa and is often aggressive with disseminated disease. The iatrogenic form is described in transplant recipients treated with immunosuppressive drugs. The final epidemic form is associated with HIV-1 infection, affects predominantly homosexual men, and often progresses rapidly with disseminated or visceral involvement (or both). With the increased frequency of KS over the past three decades as well as the occurrence of the disorder in a younger population that is prone to have other generally benign vascular lesions, intimate knowledge of the disease spectrum of KS has become essential to the correct diagnosis. This is particularly true for the recognition of early lesions of KS. It is now established, by in situ hybridization and immunohistochemistry, that HHV-8 (or KS-associated herpesvirus, a gamma variant of herpesvirus partially homologous to Epstein-Barr virus [EBV] and herpesvirus saimiri) is present in the spindle cells and a subset of endothelial cells, at all stages and in all forms of the disease. This observation strongly suggests a role for this agent in the pathogenesis of KS.137-140 KS is apparently characterized by a long period of latent infection with HHV-8. The onset of clinically evident KS is possibly accelerated or triggered by the additional effects of EBV, HIV, other infections, immunosuppressive drugs, or age. There has been a long-standing controversy as to whether KS is a true neoplasm, a reactive hyperplasia, or both. However, lesions of KS have recently been shown to be more often oligoclonal rather than clonal. Multifocal lesions thus appear to develop from different clones, suggesting that disseminated lesions represent distinct primary expansions of spindle cells infected with HHV-8. The latter information thus suggests that KS is a reactive process.141

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50 years of age, and shows a strong predilection for men (Table 31-11).132,133 There is an increased incidence of KS in Ashkenazi Jews and individuals of Mediterranean descent. KS typically begins on the distal lower extremities, either unilaterally or bilaterally. Over time, the lesions may increase in number and arise more proximally. The upper extremities may become affected, and occasionally this may be the initial site of presentation. Characteristically, KS lesions evolve through stages as erythematous patches and reddish brown violaceous to blue plaques and nodules; however, any or all the latter clinical lesions may be observed in the same patient (Fig. 31-23A). Lesions may gradually coalesce, and nodules may eventually ulcerate. The clinical course of the classic form of KS is relatively indolent. Occasional lesions may regress while others progress. However, one should be aware that up to one-third of patients with the classic form of KS subsequently develop a second primary neoplasm, often of hematopoietic origin. In equatorial Africa, KS is a common neoplasm. Men again predominate, but this endemic African form of KS affects a younger population than the classic European variant, with the age difference averaging about 10 years in most reports; children are also affected. The disease can be subclassified into four clinical groups: nodular, florid, infiltrative, and lymphadenopathic. Patients with the nodular variant present with a limited number of circumscribed cutaneous nodules and manifest an indolent clinical course. Patients with the florid and infiltrative subtypes exhibit more aggressive disease as evidenced by extensive cutaneous lesions on one or more extremities and often involvement of the bones. The lymphadenopathic type occurs mainly in children, in whom lymph node involvement is usually the sole manifestation, and in young adults who may have concomitant skin involvement. AIDS-associated or epidemic KS occurs in a population of individuals with unique demographics. About 95% of all cases are homosexual men followed by intravenous drug users and other populations at risk for AIDS. All but very rare cases have serologic antibody titers to HIV-1. Indirect evidence for cofactors being involved in the pathogenesis of KS is the decrease in the incidence of KS in the AIDS-affected homosexual population since the early 1980s. Upon initial medical presentation, lesions of KS are often small and few in number. They may be light purple or

Table 31-11 Kaposi Sarcoma

Clinical Features Clinical forms of Kaposi sarcoma Classic (European) Predominantly men, older than age 50 years Ashkenazi Jews; Mediterranean descent Distal lower extremities Relatively indolent clinical course African (endemic) Males, younger age distribution Nodular, florid, infiltrative, lymphadenopathic subgroups AIDS-associated (epidemic) Homosexual men more than other risk groups Upper half of the body Early lesions, small, pink to light purple Disseminated disease Immunosuppression Organ transplant recipients Disseminated disease Rare variants Stewart-Treves–like syndrome developing years after ipsilateral radical mastectomy Lymphangioma-like variant with bulla-like clinical appearance Histopathologic Features Patch stages Inconspicuous, irregular, angulated blood vessels Upper to entire reticular dermis Promontory sign Lymphocytic perivascular infiltrate, plasma cells Plaque stage Vessels fill the dermis and involve the supeficial subcutis Obvious spindle cells Slitlike spaces containing erythrocytes Extravasated erythrocytes, hemosiderin, apoptotic endothelial cells, hyaline globules Nodular (or tumor) stage Extensive spindle cell infiltrate in fascicles and sheets Numerous slitlike spaces in sievelike pattern, containing erythrocytes Mitotic figures, variable numbers All stages Expression of lymphatic endothelial markers, HHV-8 (LANA-1): Differential Diagnosis Acroangiodermatitis (pseudoKaposi sarcoma) Benign lymphangioendothelioma Targetoid hemosiderotic hemangioma Immature scar Bacillary angiomatosis Spindle cell hemangioma Kaposiform hemangioma Angiosarcoma

pink rather than deeply violaceous as with more established lesions of KS. The upper half of the body is frequently affected without the tendency of classic KS to first involve the distal lower extremities. Another population of patients more recently established as having risk for the development of KS are those receiving immunosuppressive agents, particularly organ transplant recipients. The incidence is low; for example, estimates of KS after renal transplantation are approximately 0.5%. As with classic KS, there is a propensity toward individuals of Jewish or Mediterranean descent. However, women are more frequently affected in this group than in the other clinical forms of KS. Cutaneous and visceral involvement may occur, but no particular pattern of distribution has been emphasized. The clinical course is more aggressive than classic KS, with a significant percentage of patients dying from disseminated disease. Lesions may regress with the reduction or withdrawal of immunosuppressive therapy. Rarely, KS (rather than angiosarcoma) presents with a Stewart-Treves–like syndrome that develops in a chronically lymphedematous upper extremity years after an ipsilateral radical mastectomy.142,143 Also rare is the lymphangioma-like variant of KS, the clinical hallmark of which is a bulla-like appearance that occurs in many, but not all, cases.144,145

HISTOPATHOLOGIC FEATURES The histologies of cutaneous lesions associated with the various clinical forms of KS are essentially identical and are described together in accordance with their stage at presentation (Table 31-11). Although some authors believe there are subtle differences between classic and AIDS-associated KS, others have not confirmed this impression. The alleged differences and diagnostic difficulties ascribed to AIDSassociated KS seem more related to the subtle changes inherent in early lesions rather than to distinct findings unique to this form of KS. In patch-stage KS, the earliest features are inconspicuous, and on initial review, they may often be considered nondiagnostic or inflammatory. The earliest histologic manifestations essential for the recognition of KS include subtle microvascular alterations largely confined to the superficial half of or the entire reticular dermis. These critical findings are a proliferation of small, irregular or jagged microvessels about normal or ectatic dermal vascular channels and adnexal structures

A

B

(Figs. 31-23 and 31-24). These newly formed vessels may protrude into a vascular lumen or surround and partially isolate normal dermal structures, a feature referred to as the promontory sign. In some lesions, these microvessels aggregate into clusters that resemble small hemangiomas. The endothelium may be inconspicuous or plump, a single layer in thickness, and shows little or no atypia or mitotic activity. Irregular, branching, thinwalled bland vascular channels may be seen dissecting between collagen bundles. These neovascular structures tend to be contiguous with preexisting dermal blood

vessels. In well-developed patch-stage lesions, KS involves the entire dermis. A highly suggestive but subtle finding that may be seen only with careful examination of multiple levels of sections is the presence of small numbers of bland spindle cells in close proximity to the newly formed vessels. Usually, predominantly lymphocytic perivascular infiltrates with variable numbers of plasma cells are present as well. Other features that are relatively inconspicuous in patch-stage KS are apoptotic endothelial cells, extravasated erythrocytes, hemosiderin, and hyaline globules.

 FIGURE 31-24 Kaposi sarcoma, patch stage. Newly formed vessels may protrude into a vascular lumen or surround and partially isolate normal dermal structures; a feature referred to as the promontory sign. The angulated thin-walled lumina are the clue for the diagnosis.

Hyaline globules are distinctive small, faintly eosinophilic, PAS-positive, and diastase-resistant spheres that may be deposited extracellularly or may be seen intracellularly within endothelium or macrophages. They often exhibit a characteristic densely clustered microscopic pattern. The globules most likely represent phagocytized red blood cells and their degenerative forms. They are a useful diagnostic criterion but are neither necessary nor sufficient for the diagnosis of KS. They may be seen in other neoplastic and inflammatory processes with abundant erythrocyte extravasation such as angiosarcomas, PGs, and inflammatory granulation tissue. In contrast to patch-stage KS, the latter features are much more conspicuous in well-developed plaques and nodules of KS. Plaque-stage lesions of KS show further progression of the neoplastic process with diffuse and more densely cellular involvement of the entire dermis and superficial subcutaneous tissue. The most characteristic feature of this stage is a significant spindle cell component. These relatively bland spindle cells are dispersed between dermal collagen bundles and around preexisting dermal vessels. Between these spindle cells, irregular clefts or slit-like spaces are formed, creating new, angulated vascular channels that contain small numbers of erythrocytes. The disposition of erythrocytes with a square box-like morphology in a linear single-file pattern between these spindle cells is highly characteristic of KS and has been termed “vascular slits.” Hemosiderin deposits and hyaline globules are more prominent than in patch-stage KS. The vasoproliferative changes of the patch stage persist at the

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-23 Kaposi sarcoma. (A) Faint erythematous patches and reddish-brown papules and plaques are present on the foot. (B) Kaposi sarcoma, patch stage. This lesion exhibits irregular vascular channels and hemosiderin deposits.

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 FIGURE 31-25 Kaposi sarcoma, tumor stage. The compact spindle cell proliferation mimics other soft tissue sarcomas.

periphery of plaques. The predominantly lymphocytic, perivascular inflammatory infiltrate persists along with its component of plasma cells. Nodular lesions of KS show an even more pronounced proliferation of spindle cells into intersecting fascicles and sheets (Fig. 31-25). Amid the spindle cell proliferation, slit-like vascular spaces containing erythrocytes are conspicuous. The spindle cells show a degree of cytologic atypia that generally ranges from mild to moderate. Frank anaplasia of the spindle cell component is distinctly uncommon and is more frequently described in the endemic African form of KS. Apoptotic cells, hyaline globules, and hemosiderin deposition are all readily visible. Mitotic figures vary in number but may be frequent. The dermal lymphoplasmacytic inflammatory infiltrate persists, and at the periphery of the nodules, ectatic blood vessels and lymphatics are generally noted. Lymphangiomatous or lymphangiomalike lesions of KS have been reported as both a focal and predominant clinicopathologic pattern in otherwise typical KS (Fig. 31-26).136 The process usually involves the entire dermis and often extends into the superficial subcutaneous tissue.146 Angulated, irregular, narrow to ectatic, thin-walled vascular channels lined by a single layer of flattened, bland endothelium interconnect and dissect collagen bundles. The majority of the vascular spaces lack red blood cells. Features typical of KS, such as a significant inflammatory infiltrate,

extravasated erythrocytes, hemosiderin, and hyaline globules, have not been reported. Occasional cases show sparse numbers of spindle cells in close association with the vascular elements, but these cells are never a prominent feature.

HISTOGENESIS The histogenesis of KS has been the subject of considerable debate for many years. KS may be a lesion that arises from pluripotential stem cells variably differentiating toward blood vessel endothelium. However, an alternative theory has suggested a multicentric hyperplasia that combines lymphatic venular anastomoses with elements derived from both lymphatic and blood vessel endothelium. Despite their erythematous clinical appearance, early lesions of KS typically have thin-walled vessels with a lymphatic-like histologic appearance. Enzyme histochemistry shows these vessels to have a staining profile of lymphatic endothelium. Variable immunohistochemical results have been obtained, but endothelial cells of KS are usually negative or weakly positive for von Willebrand factor and weakly positive for Ulex europaeus lectin 1, with variable levels of expression of CD31, CD34, and VE-cadherin. These cells also variably express monocyte or macrophage markers such as CD68 as well as smooth muscle cell markers and do not react with PalE and anti-eNos antibodies, which are specific markers for blood vessels. More recently, antibodies to VEGFR-3, LYVE-1, podoplanin (including D2-40 antibody), and CD206 labeled nearly all

 FIGURE 31-26 Kaposi sarcoma, lymphangiomatous variant. Highly irregular dilated vascular spaces dissect collagen and surround other blood vessels.

DIFFERENTIAL DIAGNOSIS The difficulty in diagnosis usually occurs with early lesions of KS rather than the well-developed lesions of tumor-stage KS. Among the entities to be considered in the differential diagnosis of KS are acroangiodermatitis, benign lymphangioendothelioma, THH (Table 31-12), early scar, BA, and angiosarcoma. More cellular lesions of KS must be differentiated from aneurysmal hemosidertotic fibrous histiocytoma and from SCH. Readers are referred to sections on

Kaposiform Hemangioendothelioma Synonyms: Kaposi-like infantile hemangioendothelioma, hemangioma with Kaposi sarcoma–like features KHE is a rare, locally aggressive, vascular tumor that occurs almost exclusively

in childhood and involves the deep soft tissues and skin.30 CLINICAL FEATURES Most patients reported thus far have been younger than 10 years of age, with girls and boys equally affected.30 Rarely, KHE presents in utero,152,153 at birth,154 and in adults.31,32,155-158 The tumor most commonly presents as a deep soft tissue mass of the trunk, extremities, or retroperitoneum; however, KHE may develop in diverse anatomic sites. The skin may be the initial site of involvement, and cutaneous lesions appear as an ill-defined, infiltrated, violaceous mass that is often warm and tender. Some tumors have developed in the context of a LM (so-called lymphangiomatosis) and in one case with congenital lymphedema. Rare multifocal lesions have been reported.159 A majority of KHEs have been associated with life-threatening profound thrombocytopenia and consumption coagulopathy, KMS or phenomenon. This life-threatening coagulation disorder demonstrates a very low platelet count (generally < 10,000/mm3), low fibrinogen and high D-dimers, and often anemia in an infant or child with a vascular tumor.9 It has recently been shown that the tumors associated with KMS are almost

Table 31-12 Comparison of Histologic Features In MVH, KS, THH, and PG

Microvenular hemangioma

Kaposi sarcoma (patch stage) l

Targetoid hemosiderotic hemangioma

Pyogenic granuloma

MAJOR CLINICAL FEATURES Single, small, purple to red lesions favoring the extremities of young to middleaged adults Usually multiple, pink to purple, broad, flat lesions favoring the lower extremities of elderly men in the classic form; more disseminated in the AIDS-associated form Single, small, annular, often target-like lesions on the the trunk and extremities of young to middle-age adults Single or multiple, rapidly growing lesions of the skin or mucosal surfaces of individuals of all ages

IRREGULAR ANASTOMOSING VASCULAR SPACES 1+

CYTOLOGIC AND IMMUNOHISTOCHEMICAL FEATURES OF ENDOTHELIAL CELLS Normal to plump HHV-8 – (+ in one case)

CELLULARITY 1–2 +

INFLAMMATION 0 to sparse lymphocytic

HEMOSIDERIN 0–1+

4+

Cells lining vessels normal; others spindle-shaped, hyperchromatic with variable atypia HHV-8 +

0–1 +

Sparse perivascular lymphocytes and plasma cells

0–3 +

2–3 + with epithelioid fronds in early lesions

Normal to epithelioid HHV-8 –

1–2 +

3–4 +

0–1 +

Normal HHV-8 –

3–4 +

0 to sparse lymphocytes (and variable but often intense red cell extravasation) 0–4 + Intense acute and chronic inflammation associated with ulcerated lesion

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

these topics for discussions of the differential features. In particular, histologic findings that are often important for the recognition of early KS include the predilection for the initial process, that is, the newly formed, irregular, thin-walled vascular channels and spindle cells to involve preexisting neurovascular and adnexal structures and to dissect collagen of the reticular dermis; the promontory sign; lymphoplasma cellular infiltrates; and extravasation of erythrocytes and hemosiderin deposition. Important criteria for more evolved lesions include spindle cells, slitlike spaces containing erythrocytes (“vascular slits”), hyaline globules, apoptotic cells, and hemosiderin deposition. It should be recognized, however, that there is a continuum of these features from patch to tumor stage. Finally, the detection of latent nuclear antigen of HHV-8 (LANA-1) is of considerable aid in discriminating KS from its mimics.151

cases of KS, strongly suggesting a lymphatic immunophenotype for the spindle cells of KS.140,147-149 Moreover, the gene expression microarray profile of KS cells more closely approximates that of lymphatic endothelial cells rather than the profile of blood vascular endothelial cells. Finally, latent nuclear antigen of HHV-8 (LANA-1) is strongly expressed in the spindle cells and in a proportion of endothelial cells of KS. HHV-8 has been shown to be capable of reprogramming cultured blood vascular endothelial cells toward the expression of lymphatic lineage-specific genes. Thus the latter investigations suggest that blood vascular endothelial cells may transform to a lymphatic phenotype in KS lesions.140,150

0–1+

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 824

always KHE or TA rather than IH as had previously been suggested.10,11 The coagulation disorder is often of sudden onset and is accompanied by increase in the volume of the vascular tumor, which becomes tense, edematous, and echymotic or purpuric. With therapeutic intervention to restore the platelet levels, these vascular lesions often diminish rapidly in size but fail to show complete tumor regression. It has been suggested that KHE lesions not associated with thrombocytopenia tend to be smaller than those manifesting KMS.158 However, the latter hypothesis has not been confirmed in all studies.156 KHE lesions may exhibit locally aggressive behavior and lymph node involvement by contiguous or somewhat more distant spread. However, no patients have developed distant metastases. Because of the potential for local and regionally aggressive disease, these tumors have been considered to be borderline malignancies. However, the basis for the latter assertion has been questioned owing to the lack of distant metastasis, the generally benign behavior of cutaneous KHE, and usual cure by complete excision. Moreover, the adverse prognosis of noncutaneous KHE, particularly KHE involving retroperitoneal or visceral sites, seems directly related to the anatomic site, extent of tumor development and local spread, possible delay in diagnosis, and the development of Kasabach-Merritt phenomenon. HISTOPATHOLOGIC FEATURES KHE involving the skin and subcutis usually presents as a multinodular tumor composed of nodules or sheets of spindle cells that are connected and surrounded by dense hyalinized fibrous tissue. Such nodules exhibit elongated or crescent-shaped vascular spaces and spindle cells with minimal cytologic atypia (Fig. 31-27).30 On occasion, rounded vascular lumina lined by attenuated endothelial cells may be observed. Platelet aggregates and fibrin thrombi may be present within vascular lumina, even in cases with normal platelet counts. Among the spindle cell areas, one may encounter fairly discrete aggregates of cytologically bland epithelioid endothelial cells (glomeruloid clusters). The latter cells often contain hemosiderin and hyaline globules. Some tumor lobules are thus partitioned into spindle cell areas and round glomeruloid clusters, realizing a “nodules in the nodule” pattern. Well-formed vascular channels are often nested at the periphery of tumor nodules and may also be surrounded by crescentic slitlike vessels. In general, the mitotic rate is low and often less than 3 mitoses per hpf. Inflammatory cell

 FIGURE 31-27 Kaposiform hemangioendothelioma. Note the spindle cells and associated vascular channels that are elongated or have a crescent-shaped morphology, suggesting Kaposi sarcoma.

infiltrates containing lymphocytes and plasma cells are usually absent. In large specimens of KHE, some areas may show smaller disseminated lobules that may suggest TA on a small biopsy, again providing some evidence that TA may have some relationship to KHE.32-35,160 The spindle cells comprising the tumor are positive for CD34, D2-40, and VEGFR-335,147,157 and are generally negative for von Willebrand factor and Ulex europaeus lectin. Actin-positive cells are mainly located in the center of the lobules and glomeruloid areas.35,156 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes KS, capillary hemangioma, spindle cell hemangioma, and TA. In contrast to KS, KHE generally affects younger individuals; presents as a deep solitary mass; shows no association with HHV-8, HIV, or immunodeficiency; and is frequently associated with KMS. KHE does not show the diffusely infiltrative and multicentric pattern or the lymphoplasmacytic infiltrates noted in KS. In addition, KHE exhibits epithelioid cell aggregates, a feature not typically observed in KS. KHE differs from capillary hemangioma by demonstrating nodules of spindle cells with slitlike vascular channels resembling KS and frequent hemosiderin deposition and by expressing VEGFR-3 and D2-40 but not GLUT-1. KHE does not contain the cavernous vascular spaces that typify spindle cell hemangioma. TA is distinguished from KHE by discrete cellular nodules containing typical vascular channels and

lacking prominent fascicles of spindle cells suggesting KS. In addition, there is intervening normal dermis between the tumor islands in TA. The clinical differential diagnosis of congenital or neonatal lesions of KHE includes congenital hemangioma and neonatal hemangiomatosis; the latter are differentiated from KHE by being IHs.154

HEMANGIOPERICYTOMA The hemangiopericytoma is a relatively rare soft-tissue neoplasm that is thought to derived from the pericyte.161-165 The diagnosis is often difficult because other soft tissue tumors may be highly vascular and show hemangiopericytoma-like patterns. Its occurrence in the skin proper is controversial, and some authors deny its existence. An example of this is the unique case report of a polypoid dermal hemangiopericytoma, which has been alternatively viewed by another author as an epithelioid cell histiocytoma with prominent hemangiopericytomalike vascularity.166,167 CLINICAL FEATURES Hemangiopericytomas generally occur as deep-seated softtissue tumors in adults with a median age of 45 years in one large series. The most common sites are the lower extremities and the pelvic retroperitoneum, but the tumor has a wide distribution. Typically, the tumor arises as a painless mass that is often several centimeters in size by the time of clinical

presentation. Hypoglycemia may be associated with large retroperitoneal lesions. Hemangiopericytomas are wellvascularized tumors, and excision is often complicated by hemorrhage. Benign and malignant forms of hemangiopericytomas have been recognized. However, some intermediate or borderline cases of hemangiopericytoma defy classification and make prognostication difficult. A median survival of 19 months was reported for patients with malignant hemangiopericytomas. Malignant tumors frequently recur and metastasize.

DIFFERENTIAL DIAGNOSIS Other soft tissue tumors with a hemangiopericytoma-like pattern must be considered before rendering a diagnosis of hemangiopericytoma. Among these tumors are solitary

fibrous tumor of the skin (SFTS), solitary myofibromatosis, the recently described myopericytoma, glomangiopericytoma, synovial sarcoma, extraskeletal mesenchymal chondrosarcoma, malignant schwannoma, and malignant fibrous histiocytoma. Immunohistochemical staining and ultrastructural examination are important adjuncts to diagnosis. Because SFTS has both histologic and immunohistochemical similarities to hemangiopericytoma, distinguishing the two can be difficult. However, the hemangiopericytoma-like features of typical SFTS are less diffuse and less prominent than those in hemangiopericytoma, and SFTS has interlacing fascicles of uniform spindle cells and displays alternating areas of hypercellularity and hypocellularity with thick hyalinized, often keloidlike, collagen.171,172 Monophasic forms of synovial sarcoma can cause particular confusion with hemangiopericytoma by light microscopy, but fortunately, most synovial sarcomas show a biphasic pattern of glandlike areas and sarcomatous stroma. Immunohistochemical marking for cytokeratin is typical of synovial sarcomas but is absent in hemangiopericytomas. In particular, the diagnosis of synovial sarcoma should always be considered when a tumor is near a knee or other large joint, particularly in young adults. Extraskeletal mesenchymal chondrosarcoma has foci of well-differentiated cartilage and, rarely, bone. Areas of hypocellular, myxoid change are commonly seen in malignant schwannoma in contrast to hemangiopericytoma. Malignant fibrous histiocytoma is more apt to show a storiform pattern than is hemangiopericytoma and may display pleomorphic or fascicular patterns. Moreover, the fascicular pattern of fibrosarcoma, synovial sarcoma, and malignant schwannoma is not a feature of hemangiopericytoma. Finally, tumors with features common to hemangiopericytoma and myofibromatosis and hemangiopericytoma and glomus tumor, respectively— myopericytoma and glomangiopericytoma—have been described.155,172

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

HISTOPATHOLOGIC FEATURES Tumor cells are rounded or spindle shaped and are present outside the numerous, admixed blood vessels.161-165 A reticulin stain will demonstrate that the endothelial cells of the vessels lie inside a delicate reticulin sheath and are thus separated from the peripheral population of tumor cells. The rich network of blood vessels has a varied morphology ranging from capillaries to large sinusoidal-like spaces. The latter spaces often appear to divide in antler-like or “staghorn” configurations (Fig. 31-28). Lipomatous hemangiopericytoma of deep soft tissue has been reported and is characterized by mature adipose tissue in benign hemangiopericytoma.168 It has been suggested that lipomatous hemangiopericytoma represents a fat-containing variant of solitary fibrous tumor.169 Malignant hemangiopericytomas are characterized by hemorrhage, necrosis,

and increases in both cellularity and mitotic activity. Whereas the presence of 4 or more mitotic figures per 10 hpf is associated with recurrence and metastasis, benign hemangiopericytomas generally show fewer than 2 or 3 mitoses per 10 hpf. In one study, recurrent or metastatic hemangiopericytoma was associated with trabecular patterns, necrosis, mitoses, vascular invasion, and cellular pleomorphism.170 Being derived from the pericyte, the hemangiopericytoma is generally negative for endothelial markers. Reactivity for Ulex europaeus lectin 1 is absent, and factor VIII-related antigen is negative or only weakly positive. Conversely, the endothelial cells of the accompanying vasculature are richly stained by both markers. Hemangiopericytomas stain for vimentin and laminin; often stain for CD34; and rarely show focal staining for smooth muscle actin but are generally negative for CD31, desmin, cytokeratin, and S-100. Ultrastructurally, basal lamina– like material is present and either partially or completely surrounds tumor cells. This feature, along with the presence of myogenic filaments and pinocytotic vesicles, serves to support a diagnosis of hemangiopericytoma in a histologically compatible tumor.

Papillary Intralymphatic Angioendothelioma

 FIGURE 31-28 Hemangiopericytoma. Note the characteristic antlerlike or staghorn pattern of vessels that is nonetheless shared by a number of other tumors.

Synonyms: Malignant endovascular papillary angioendothelioma, Dabska tumor This exceedingly rare vascular lesion was first reported by Dabska in 1969 as malignant endovascular papillary angioendothelioma of the skin in childhood.173 However, the cumulative experience

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

in the literature with about 30 reported cases indicates that papillary intralymphatic angioendothelioma (PILA) has a wider age distribution and a generally good prognosis despite local invasion and regional lymph node metastasis in a few cases. It is now regarded as a vascular tumor of “borderline” or low-grade malignancy.

826

CLINICAL FEATURES Dabska reported six children, 4 months to 15 years of age, who presented with enlarging cutaneous lesions, 4 to 9 cm in diameter, occurring as either a diffuse swelling or an intradermal tumor on the head, neck, and extremities with penetration through the cranial vault in one case. Lymph node metastasis was seen in two children, one of whom showed involvement of eight axillary lymph nodes. Local recurrence was observed only once but resolved with a second surgical procedure. All of the children were well without evidence of disease on follow-up examinations 4 to 16 years. In 1998, a report of 12 cases indicated a wider age distribution (range, 8 to 59 years; mean age, 30 years) and no recurrences after excision for the eight patients with a mean follow-up of 9 years.174 PILA affects mainly the skin and subcutis, but individual cases have been reported to involve the spleen, skeletal muscle, and bone. PILA may be associated with or develop in lymphatic or VMs or lymphedema. HISTOPATHOLOGIC FEATURES The most characteristic feature of PILA is dilated lymphatic-like vessels containing intraluminal papillary structures. The latter structures are lined by endothelial cells showing minimal to moderate cytologic atypia and little or no mitotic activity (Fig. 31-29).173,174 The endothelial cells are cuboidal to columnar with apically situated nuclei manifesting a hobnail or matchstick-like appearance. Clear intracytoplasmic vacuoles may be present in tumor cells reminiscent of EH and hemangioendothelioma, but the cytoplasm is not eosinophilic or amphophilic. The associated matrix of the papillations may appear eosinophilic and hyalinized or suggest a hyaline globule on transverse sections. The basal part of the cytoplasm of the matchstick-like cells seems to merge imperceptibly with the hyalin core of the papillae. Papillary formations resembling renal glomeruli may also be seen. Tumor cells appear to float free in the lumina around hyaline globules, in clumps, or as single cells. The globules have the staining

 FIGURE 31-29 Papillary intralymphatic angioendothelioma (endovascular papillary angioendothelioma; Dabska tumor). Intraluminal papillary structures are lined by multilayered endothelial cells that show atypia. The clumps of cells appear to float free in the lumina. (Courtesy of Dr. C.D.M. Fletcher.)

characteristics and ultrastructural appearance of basement membrane contain collagen type IV.174 Hemorrhage, cholesterol clefts, and necrosis may be present. Lymphocytes may infiltrate the endothelial cells. The latter association suggests that the endothelial cells of PILA show differentiation toward “high” endothelial cells of postcapillary venules with attraction of lymphocytes mediated by intercellular adhesion molecule 1 (ICAM-1).175 However, immunohistochemical staining for lymphatic markers (D2-40 and VEGFR-3) and the presence of lymphatics or a LM adjacent to PILA suggest a lymphatic phenotype for PILA.174,176 DIFFERENTIAL DIAGNOSIS9 The differential diagnosis includes LM, IPEH, angiosarcoma, GH, and RH. An LM may suggest PILA because of cystic spaces on gross sectioning and scanning microscopic examination and lymphocytic infiltrates but fails to show the proliferative endothelial features of PILA. In contrast to PILA, IPEH has a generally flattened endothelial lining and an underlying thrombotic matrix and lacks the lymphocytic infiltrate of PILA. Angiosarcoma is extremely rare in childhood; it also differs from PILA by showing conspicuous cytologic atypia with piling up of the endothelial cells, frequent mitotic figures, and dissection of collagen bundles. Compared with the flattened endothelium of GH, PILA demonstrates intraluminal papillations

lined by endothelium with a hobnail or matchstick appearance. The vascularity in PILA is more primitive, and the endothelial cells within lumina may appear to float free as single cells or in clumps. The hemorrhage, cholesterol clefts, and necrosis of more cellular lesions of PILA are not usually observed in GH. Finally, RH may share many features with PILA, including hobnail and matchstick-like endothelial cells and papillations. However, whereas these papillations are only focal in RH, PILA presents with conspicuous papillary tufts and more dilated vascular lumina and typically lacks the arborizing rete testis-like appearance of RH.174 Nonetheless, the striking morphologic similarities between PILA and RH have suggested that these two lesions may be categorized under the term hobnail hemangioendothelioma. It seems, however, that besides differences in patient age and tumor location, some phenotypic differences also exist between these two lesions because PILA constantly express D2-40, which is found only in a minority of RH cases.174,176,178 Further studies are needed, however, to clarify this point because the number of cases studied is small.

Retiform Hemangioendothelioma RH is a recently described vascular tumor that is considered a well-differentiated and low-grade form of angiosarcoma

usually presenting on the extremities of young adults.179,180 Although this tumor is prone to recurrences, metastatic spread appears to be very uncommon. Only one case with lymph node metastasis has been reported, and no deaths have occurred. Human HHV-8 has been detected by polymerase chain reaction (PCR) in one case of RH181; however, additional study is needed to confirm any etiologic role.

DIFFERENTIAL DIAGNOSIS As already discussed, RH and PILA share clinical and histopathologic features; indeed, it has recently been proposed that these tumors represent the adult (RH) and pediatric (endovascular papillary angioendothelioma) counterparts of the same tumor. THH may be confused with RH. In contrast to RH (and PILA), THH is a more circumscribed superficial lesion. Also, it lacks the retiform

Composite Hemangioendothelioma Composite hemangioendothelioma (CH) is a recently described vascular tumor that is considered to be a low-grade malignancy mimicking but less aggressive than conventional angiosarcoma.182 CH has been reported on the hands and feet of adults (median age, 42 years; range, 21 to 75 years)183,184 as poorly circumscribed uni- or multinodular lesions. Nodules have ranged in size from 0.7 to 30 cm. In five patients, the lesions were congenital or developed in childhood, and one patient manifested Maffucci syndrome. Fifty percent of the patients described thus far have experienced local recurrences or persistence of disease. Three patents have exhibited local lymph node metastases and one an EHE-like solid metastasis to the thigh. HISTOPATHOLOGIC FEATURES These tumors usually develop in the dermis and subcutis and show a complex histology that varies within the individual lesion and among different patients. Typical components imperceptibly merging with each other include EHE, RH, and welldifferentiated angiosarcoma-like areas; less often, spindle cell hemangioma and endovascular papillary angioendothelioma may be present. High-grade angiosarcoma has been observed in one case. Underlying vascular anomalies,

 FIGURE 31-30 Retiform hemangioendothelioma. Branching and arborizing blood vessels are reminiscent of rete testis. (Courtesy of Dr. C.D.M. Fletcher.)

most commonly LMs and less commonly arteriovenous and VMs, and a lesion resembling angiomatosis of soft tissue (AST) have been described among eight cases.183 DIFFERENTIAL DIAGNOSIS The differential diagnosis of each individual component of CH is described elsewhere in this chapter. The recognition of CH depends on extensive sampling of the tumor. Small biopsies may result in sampling error and the failure to detect all the histologic components of CH. For example, sampling an angiosarcoma-like area could foster inappropriately aggressive therapy.

Epithelioid Hemangioendothelioma Synonyms: histiocytoid hemangioma, intravascular bronchioloalveolar tumor, sclerosing endothelial tumor, sclerosing angiogenic tumor, sclerosing interstitial vascular sarcoma, sclerosing epithelioid angiosarcoma EHE is a rare entity that has been reported in systemic organs and in the skin as a biologically “borderline” neoplasm because of an occasional association with local recurrence or metastasis.188-191 Visceral presentations of EHE tend to be considered overtly malignant owing to a metastatic rate of 20% to 30% and a mortality rate of 10% to 20%, even if cutaneous lesions seem less aggressive.192 CLINICAL FEATURES EHE is an angiocentric and often multifocal neoplasm that has been described in soft tissue and in various organs such as the lung, liver, and bone (Table 31-13).188-191 EHE presenting in the skin is rare and often involves the upper and lower extremities of adults of both genders, favoring the third and fourth decades of life. Cutaneous EHE usually involves underlying bone, although cases of EHE limited to the skin, including the palm, scalp, oral cavity, upper lip, nose, neck, thorax, knee, leg, anus, and penis, have been described.193-197 Cutaneous lesions of EHE may be solitary or multiple. Manifestations of cutaneous EHE have varied from asymptomatic dermal nodules to lesions with severe burning pain, hyperesthesia, swelling, and hyperhidrosis of reflex sympathetic dystrophy. EHE of soft tissue usually presents as a solitary, slightly painful mass. Ossifying EHE has been described intramuscularly in the cheek as a 1-cm encapsulated nodule with a shell of mature lamella.198

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

HISTOPATHOLOGIC FEATURES The tumor has a predominantly subcutaneous location and is composed of ill-defined, arborizing, thin-walled vessels lined by a monotonous population of small protuberant hobnail endothelial cells (Fig. 31-30).179 The vascular architecture is reminiscent of rete testis. Frequently, the tumor is surrounded by lymphocytic infiltrate, and in some instances, lymphocytes are present within the lumina of the neoplastic vessels. Solid areas exhibiting epithelioid or spindled endothelial cells may be present.

architecture of RH and the papillary fronds of PILA.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 31-13 Epithelioid Hemangioendothelioma

828

Clinical Features Favors the third and fourth decades of life Upper and lower extremities Solitary or multiple skin lesions Usually involves underlying bone but can be limited to skin Occurs in other sites: soft tissue, lung, liver Histopathologic Features Cutaneous tumors Relatively inconspicuous vascularity Small vascular channels lined by cuboidal endothelial cells Acanthosis, acrosyringeal proliferation Soft tissue tumors: often angiocentric arising from medium to large veins Hyaline to myxoid or myxochondroid stroma Cords or solid nests of rounded or slightly spindled, epithelioid cells Intracytoplasmic vacuoles Histology—poor correlation with prognosis “Benign”: cytologically bland, mitotic figures inapparent (bland-appearing lesions have metastasized and caused death) “Malignant”: cytologic atypia, >1 mitosis per 10 hpf, necrosis, focal spindling of cells (more than 6 mitoses per 10 hpf better correlates with poor prognosis) Differential Diagnosis Metastatic carcinoma Malignant melanoma Epithelioid sarcoma Epithelioid angiosarcoma Angiolymphoid hyperplasia with eosinophilia Cutaneous mixed tumor

The prognosis of EHE is variable. Patients with EHE of the lung and liver have a higher mortality than do those with EHE of soft tissue. Mortality rates of 65%, 35%, and 13%, respectively, have been reported. Local recurrence and metastatic disease to regional lymph nodes or to lung may occur, yet fewer than 50% of patients with metastases succumb to their disease. Histologically benign-appearing forms of EHE generally have a better prognosis than do those that appear malignant, but histologically bland-appearing lesions have occasionally been associated with metastasis and death. Whether the relatively indolent tumors previously described as cutaneous epithelioid angiosarcoma belong to the spectrum of EHE is unclear. Some of these patients experienced slow, protracted disease

associated with numerous local recurrences and regional lymph node metastases.191 Although the prognosis for primary cutaneous EHE without underlying bone involvement and treated by local excision appears good, the length of follow-up for reported cases is quite limited. HISTOPATHOLOGIC FEATURES EHE displays epithelioid-appearing or “histiocytoid” endothelial cells that may be angiocentric and, in at least half of soft tissue cases, arise from and expand the wall of a medium- to large-size vein.188-191 (see Table 31-13 and Fig. 31-31). A hyaline, myxoid or myxochondroid-appearing stroma is common. The endothelial cells appear as cords or solid nests of rounded or slightly spindled epithelioid cells. Small intracytoplasmic lumina appear as vacuoles; occasionally, these vacuoles are large and may distort the cell, mimicking the mucin-containing (“signet ring”) cells of an adenocarcinoma. Red blood cells may be present within the intracytoplasmic lumina. In contrast to the angiocentric pattern that may be seen with EHE in soft tissue, the vascularity in cutaneous EHE is relatively inconspicuous and, when present, generally consists of small vascular channels that may be lined by cuboidal endothelial cells. Cutaneous EHE is often associated with an acanthotic epidermis that may be accompanied by marked acrosyringeal proliferation reminiscent of eccrine syringofibroadenoma.195

“Benign”-appearing EHE is cytologically bland without appreciable mitotic activity. In contrast, the features of “malignant”-appearing, clinically more aggressive cases of EHE in the past have included significant cytologic atypia, more than 1 mitotic figure per 10 hpf, necrosis, and focal spindling of cells. However, a recent review has emphasized the difficulty of correlating histologic features with prognosis. Only a mitotic rate of more than 6 per 10 hpf clearly correlated with an adverse prognosis.194 Such aggressive forms of EHE may merit designation as “malignant” EHE.199 A reticulin stain will reveal a network of reticulin fibers outlining individual cells and groups of cells. Immunohistochemically, EHE usually marks with CD31, CD34, and von Willebrand factor and less consistently with Ulex europaeus lectin. The staining for von Willebrand factor is accentuated about intracytoplasmic lumina, and varies in distribution and with the degree of tissue preservation. EHE endothelial cells may express simple epithelial keratins, especially K18 and also K7; epithelial membrane antigen is focally present in a minority of cases.194,200 By electron microscopy, EHE shows features of endothelial cells such as Weibel-Palade bodies, pinocytotic vacuoles, and welldeveloped basal lamina. Abundant cytoplasmic intermediate filaments are present. By cytogenetic study, an identical chromosomal translocation t(1;3)(p36.3;q25)

 FIGURE 31-31 Epithelioid hemangioendothelioma. Cords of epithelioid cells in a fibrous stroma. Note the similarities to an infiltrative carcinoma.

was recently detected in two cases of EHE.201

MALIGNANT VASCULAR LESIONS

Angiosarcoma Synonyms: malignant hemangioendothelioma, lymphangiosarcoma Angiosarcoma is a rare, malignant endothelial tumor that arises in skin, soft tissue, breast, bones, liver, and other viscera.142,202-205 Cutaneous angiosarcoma is the most common form of angiosarcoma.

CLINICAL FEATURES In the skin, angiosarcoma most commonly arises in the scalp and face of elderly individuals, with men affected more frequently than women (Table 31-14). Angiosarcoma may also occur in the setting of chronic lymphedema, often developing in a lymphedematous upper extremity as a late sequela of radical mastectomy as described by Stewart and Treves.142 Other causes of lymphedema (idiopathic, filarial, traumatic), congenital hereditary lymphedema (Milroy disease),202 and morbid obesity have also been implicated. Ionizing radiation has been linked to the development of angiosarcoma, with cases developing in the breast after radiation for breast cancer, in the abdominal region after irradiation of pelvic tumors, and on the face after irradiation of a congenital hemangioma.206 Rarely, angiosarcoma arises in association with foreign material (bullets, shrapnel, retained surgical sponges, gouty tophus) and with arteriovenous fistulae and vascular grafts.207,208 Angiosarcoma metastatic to the skin is exceedingly rare but can herald the presence of an occult tumor of an internal site such as the heart and the aorta.209,210 Angiosarcoma generally appears as ill-defined, asymptomatic, red to violaceous patches, plaques, or nodules.203,204 Satellite lesions are frequent. Angiosarcoma frequently presents with multifocal disease, and there is a tendency toward both local recurrence and distant metastasis. The clinical appearance of angiosarcoma varies somewhat according to the degree of histologic differentiation. Histologically more undifferentiated angiosarcoma lesions may grow rapidly, with fungating and ulcerative appearances. Undifferentiated angiosarcoma lesions may appear epithelioid and are high-grade neoplasms that generally affect deep, usually intramuscular, soft tissue and rapidly develop metastases. Cutaneous occurrence has been reported, although a few of the described cases had a distinctly better prognosis than other undifferentiated angiosarcoma. Such cutaneous tumors perhaps may fall into the spectrum of EHE. HISTOPATHOLOGIC FEATURES Cutaneous angiosarcoma extensively infiltrates the dermis, with microscopic involvement extending well beyond

Table 31-14 Angiosarcoma

Clinical Features Clinical settings for cutaneous angiosarcoma Scalp and face of the elderly—men more affected than women Postmastectomy (Stewart-Treves syndrome) and other causes of chronic lymphedema Postradiation therapy Foreign bodies Arteriovenous fistulas and vascular grafts Metastatic from an occult tumor of heart or aorta Ill-defined, red to violaceous patches, plaques, and nodules Extension well into adjacent, normalappearing skin Satellite lesions Local recurrence and distant metastases Histopathologic Features Angiomatous Individual or widely anastamosing vessels in dissection of collagen bundles Variably atypical endothelial cell lining, one or more layers Mixed inflammation, often with plasma cells Hemosiderin, variable extent Lymphangiomatous-appearing areas, minimal cytologic atypia Spindled Bundles of spindled cells Cleftlike spaces containing erythrocytes Syncytium of cells with insignificant blood vessel formation Undifferentiated or epithelioid Circumscribed nodules Sheets of epithelioid-appearing cells Intracytoplasmic lumen formation Cytologic atypia Prominent mitotic activity Starry-sky pattern in a subgroup of epithelioid angiosarcoma Differential Diagnosis Kaposi sarcoma Lymphangioma-like Kaposi sarcoma Hemangiopericytoma Epithelioid angiosarcoma Poorly differentiated carcinoma Malignant melanoma Epithelioid hemangioendothelioma Composite hemangioendothelioma

the clinically apparent boundaries (see Table 31-14).142,202-204 The epidermis may be normal, atrophic, or ulcerated. Direct epidermal invasion or involvement of the papillary dermis does not usually occur. Three distinct patterns of proliferation have been described: angiomatous, spindled, and undifferentiated (Figs. 31-32 to 31-34). Individual tumors

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

DIFFERENTIAL DIAGNOSIS EHE is similar to a variety of tumors that exhibit epithelioid histologic patterns. Among these are metastatic carcinoma, malignant melanoma, epithelioid sarcoma, EH, and epithelioid angiosarcoma. Carcinomas, malignant melanoma, and epithelioid angiosarcoma generally show significant cytologic atypia and mitotic activity that distinguish them from most cases of EHE. Mucin stains mark the vacuoles and signet ring cells of adenocarcinoma but are negative in EHE. Melanomas lack the intracytoplasmic vacuoles of EHE and often show evidence of melanin pigment. EH may show intracytoplasmic vacuoles; however, EH characteristically shows welldeveloped vascularity lined by tombstone-like epithelioid endothelial cells and has a prominent inflammatory infiltrate of lymphoid follicles and eosinophils. Epithelioid sarcoma perhaps has the closest similarity to EHE, but epithelioid sarcoma generally displays a nodular arrangement of cells with central cores of necrotic debris and collagen. EHE exhibiting a well-developed chondromyxoid matrix must be distinguished from chondrosarcoma and chordoma. Cutaneous mixed tumor may also enter the differential diagnosis but can be distinguished by its broader epithelial differentiation, including follicular and sweat gland differentiation, squamous metaplasia, and ducts. Immunohistochemistry is often important in the diagnosis of EHE. A panel of antibodies should be used, and the pattern of reactivity will help in differentiating EHE from its various mimickers. In particular, EHE reacts with endothelial markers, contrary to carcinomas and epithelioid sarcoma, but may express simple epithelia keratins. It is negative for the S-100 protein staining of cutaneous mixed tumor and malignant melanoma and for the other conventional markers of melanoma.

The prognosis for angiosarcoma is poor. In one series of 72 patients with angiosarcoma of the face and scalp, 36 died within 15 months of presentation.

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 FIGURE 31-33 Angiosarcoma. Epithelioid endothelial cells in multilayered patterns fill vascular spaces and infiltrate the dermis.

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are composed of varying proportions of each pattern. In angiomatous areas, vascular spaces that are distinctly individual or widely anastomosing are dispersed between dermal collagen bundles in a dissecting fashion (see Fig. 31-32). The endothelium may be one to several cell layers in thickness and shows variable degrees of cytologic atypia. A mixed inflammatory response often containing plasma cells is usual. Hemosiderin deposition is variable. Some

 FIGURE 31-32 Angiosarcoma, well-differentiated type. Irregular, thin-walled anastomosing vascular spaces dissect collagen throughout the dermis.

lymphedema-associated tumors have a lymphangiomatous appearance with irregular vascular channels devoid of erythrocytes dissecting dermal collagen bundles. The endothelium in these areas may be attenuated and show only subtle cytologic atypia. These foci are usually interspersed with more classic angiosarcomatous areas. In spindle cell areas, spindled tumor cells are arranged in bundles that traverse the dermis in multiple directions, often enveloping adnexal str-uctures.

Cleftlike spaces and cracks containing erythrocytes are formed. The tumor may appear as a syncytium of cells without significant blood vessel formation. Undifferentiated areas are usually encountered as circumscribed nodules within more characteristic areas of angiosarcoma. Solid sheets of “epithelioid” tumor cells with abundant acidophilic cytoplasm and large, atypical nuclei expand the dermis (see Figs. 31-33 and 31-34). Lumen formation is usually only evident at the intracytoplasmic level. Intralesional hemorrhage may be prominent; this may not only obscure the diagnosis of angiosarcoma, but with the addition of endothelial papillary hyperplasia, may appear as an organizing hematoma. A starry-sky histologic pattern has been noted in a subgroup of epithelioid angiosarcomas.211 Recently, risk stratification of cutaneous angiosarcoma has been proposed based on the presence of necrosis, epithelioid features, and patient age older than 70 years. Tumor depth also has been correlated with the risk of local recurrence.212 Angiosarcoma may show considerable heterogeneity, as evidenced by variants suggesting EHE; spindle cell hemangioma; cavernous and capillary hemangioma; granular cell neoplasms; and lymphoproliferative, inflammatory, and infective disorders.213-215 Studies of angiosarcoma have indicated variable blood vascular or lymphatic differentiation; consequently, the histogenesis of angiosarcoma has remained controversial. Ultrastructurally, angiosarcoma generally shows features of endothelial cells, and cases often suggest blood vessel differentiation. Angiosarcoma may react with Ulex europaeus lectin 1, vimentin, and laminin (a constituent of basal lamina). von Willebrand factor, the most sensitive marker in one study,213 is variable, often stains only focally, and is absent in some tumors. CD31 and CD34 may react weakly and favor areas with greater vascular differentiation. Markers of lymphatic endothelial cells (VEGFR-3, Podoplanin/D2-40, LYVE-1) are expressed in a subset of angiosarcoma, representing approximately half of the cases.147-149,164,216 LYVE-1 seems to be more frequently expressed than other lymphatic markers.149 Furthermore, the immunohistochemical pattern of angiosarcoma may vary within tumors, suggesting mixed differentiation of both blood vascular and lymphatic endothelium. Further clarification of the histogenesis must await the development of additional endothelial markers or progress in molecular biology.

DIFFERENTIAL DIAGNOSIS KS displays dissection of dermal collagen by newly formed vascular channels similar to that of angiomatous- and lymphangiomatous-appearing areas of angiosarcoma. An important feature distinguishing angiosarcoma from KS are endothelial “layering” and cytologic atypia. In contrast, the endothelial lining of KS is usually inconspicuous and almost always one cell layer in thickness. Particular confusion, however, may still arise between the lymphangiomatous pattern of angiosarcoma and the lymphangiomatous variant of KS. The clinical setting associated with each entity is very helpful as are areas of more typical angiosarcoma identified in lymphedemaassociated angiosarcoma. In general, angiosarcoma displays more intralesional variation than KS. In contrast to KS and despite some contradictory data, HHV-8 is not closely linked to angiosarcoma,217 except perhaps in patients with AIDS.219 Angiosarcoma with a predominant spindle cell pattern may mimic plaques and nodules of KS. Features of distinction include the identification of angiomatous areas in angiosarcoma and cytologic atypia exceeding that observed in even florid nodules of KS. The clinical presentation is also helpful because angiosarcoma is usually confined to the head and neck of elderly individuals or unilaterally to a lymphedematous upper extremity versus the clinical localization of KS.

In contrast to angiosarcoma, hemangiopericytomas contain dilated sinusoidal spaces with a characteristic antlerlike or staghorn configuration lined by a single layer of flattened endothelial cells. A reticulin stain will further highlight differences between these two entities. Whereas in angiosarcoma, the delicate reticulin sheath is present peripheral to the inner lining of atypical endothelial cells, the tumor cells lie outside this reticulin sheath in hemangiopericytoma. Epithelioid angiosarcoma may be mistaken for poorly differentiated carcinoma or melanoma. Compounding the difficulty in distinction from carcinoma is the coexpression of cytokeratin and endothelial markers by epithelioid angiosarcoma.204 Thus, a broad panel of antibodies is required when such epithelioid tumors are being evaluated. Finally, some squamous cell carcinomas have an intense acantholytic pattern closely resembling the histology of well-differentiated AS. The demonstration of keratins and the absence of endothelial markers by immunohistochemistry are diagnostic.

VASCULAR MALFORMATIONS Vascular malformations are rare lesions representing inborn localized errors in vascular morphogenesis. Their diagnosis and classification have been historically hampered by a confusing nomenclature. For many years, they have been grouped with other vascular tumors as

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-34 Angiosarcoma. Large atypical epithelioid endothelial cells protrude into vascular spaces.

hemangiomas. Their pathogenesis (when known), natural history, and treatment are completely different from those of vascular tumors, from which they merit distinction.3,6,8,220 In 1996, the ISSVA recommended an updated classification scheme based on the distinction between proliferative lesions (vascular tumors and reactive proliferative lesions) and vascular malformations (Table 31-1). Vascular malformations may be further classified as to the type or caliber of main vascular channels present25,220,221 and as their truncal or tissular nature (Table 31-15).8 Truncal vascular malformations are anomalies of caliber, length, course, or number of individual vessels and are generally of large size. Apart from rare lesions, such as caliber persistent labial artery, truncal vascular malformations are not cutaneous lesions and are not dealt with in this chapter. In rare instances, vascular malformations may be associated with nonvascular anomalies; in various, often eponymous, syndromes; and with vascular tumors, especially IH in PHACE (the association of posterior fossa brain malformations, infantile hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities) syndrome,222 PELVIS (perineal IH, external genitalia malformations, lipomyelomenin-gocele, vesicorenal abnormalities, imperforate anus, and skin tag) syndrome, and SACRAL (spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with angioma of lumbosacral localization) syndrome.223,224 VMs, spindle cell hemangiomas, and enchondromas are associated in Maffucci syndrome. LMs may be associated with kaposiform hemangioendothelioma and endovascular papillary angioendothelioma.225 Most vascular malformations are sporadic, affecting 0.3% to 0.5% of the population.226 However, several types of familial cutaneous vascular malformations have been recently described, and several causative mutations have been identified, providing new insight into the pathogenesis of these lesions.227,228

Capillary Malformations Capillary malformations (CMs) are the more common vascular malformation. They are due to congenital dilatation of the capillary network of the skin and mucosa. They may also affect deeper structures, especially in the face. They are composed mainly of common CMs, also known as a PWSs or nevus flammeus, and other telangiectasias.

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of thin-walled vascular channels with lumina that vary in size or sometimes exhibit thicker walls, histologically simulating acral AVM (Fig. 31-37). In hypertrophic PWS, nodular aggregates of venous-like channels may be found in the deep dermis and subcutis.

Table 31-15 Classification of Vascular Malformations A. Truncal Vascular Malformations Affect arteries, veins, or lymphatics Anomalies of length, diameter, course, number Atresia, aneurysms Persistence of embryonal vessels Direct arteriovenous fistulaa

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

B. Tissular (Nontruncal) Malformations

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Capillary malformations Port wine stain Other telangiectasia Angiokeratomas Venous malformations Common Nodular With glomus cells (glomangioma) Angiomatosis of soft tissue Lymphatic malformations Capillary type (“acquired progressive lymphangioma”) Micro or macrocystic Arteriovenous malformationsa

DIFFERENTIAL DIAGNOSIS Other vascular ectasias, such as generalized essential telangiectasia, hereditary benign telangiectasia, hereditary hemorrhagic telangiectasia (HHT), unilateral nevoid telangiectasia, and spider angioma, enter into the differential diagnosis. PWS differs from the other conditions based on congenital onset, rather distinctive macular to papular clinical lesions, and fairly discrete dilated capillaries or venules in the upper reticular dermis. Clinically, PWS must be differentiated from the pink macule that may precede the development of an IH, and more importantly, from a quiescent AVM.

C. Combined Vascular Malformations Vascular malformations associating items of A, B, or both Veno-lymphatic malformations Capillary or arteriovenous malformation (RASA1) Arteriovenolymphatic malformations D. Vascular Malformations Associated with Other Anomalies Items of A, B, or C may be associated with nonvascular anomalies of bones, soft tissues or viscera, in complex eponymous syndromes, including Sturge-Weber, Klippel-Trenaunay, Parkes Weber, and Proteus syndromes a

High-flow or “hemodynamically active” malformations Adapted with permission from Wassef, 2006#8.

Common Capillary Malformations (Port Wine Stain) Synonym: Nevus flammeus PWS mainly involves the head and neck with often a unilateral distribution, but they may occur anywhere.2-4,7,229 They are present at birth and generally persist throughout life. However, some variants that affect the midline of the head, such as the forehead, eyelids, and glabella (the so-called salmon patch), or nape (stork bite), may lighten and disappear in the postnatal period or generally before 5 years of age (Table 31-16). There may be an association with other vascular malformations and with syndromes involving other organs. CLINICAL FEATURES The initial lesions present at birth are pink to reddish macules that are often irregular in configuration. The lesions grow proportionately with the child, and their color tends to

darken in adulthood. PG may develop on PWS, usually more frequently than on normal skin. Some PWSs become papular, keratotic, and thickened with time, and nodules may develop. Such papulonodular lesions are most common on the head and neck, especially in the area of the second and third branches of the trigeminal nerve.230 In the head region and especially the mandibular area, PWS may be associated with underlying soft tissue and bone hypertrophy (hypertropic PWS). HISTOPATHOLOGIC FEATURES The essential findings are widely dilated, thin-walled capillaries or venules scattered throughout the upper dermis (Fig. 31-35) or the entire reticular dermis (Fig. 31-36).2,3,8,25,229 A decrease in the number of capillaryassociated small nerves has been suggested to explain the vascular dilation.231 Papular or nodular lesions developing in PWS are composed of a proliferation

SYNDROMIC CAPILLARY MALFORMATIONS CMs may be associated with numerous syndromes that in general have been termed congenital dysplastic angiopathies by Bean. Their clinical presentation are highly variable.229,232 The main syndromes commonly associated with port wine stains are: Sturge-Weber syndrome (encephalotrigeminal angiomatosis): This syndrome is characterized by a unilateral CM in the distribution of the ophthalmic branch of the fifth (trigeminal) cranial nerve; seizures and hemiplegia or hemiparesis related to a vascular malformation involving the leptomeninges; possible choroidal vascular malformations; mental retardation; and glaucoma.229,232 Klippel-Trenaunay-Weber syndrome (hemihemangiectatic hypertrophy, congenital dysplastic angiopathies, angioosteohypertrophy): In addition to a CM in the affected limb, the primary defining feature is the unilateral hypertrophy of a limb, most commonly the lower extremity, often with associated varicosities.229,232 In most instances, there is overgrowth of both bone and soft tissue. Commonly, there is an underlying VM, but LM and angiokeratomas circumscriptum (capillary–LM) are also seen. Klippel-Trenaunay syndrome must be differentiated from Servelle-Martorelle syndrome, in which the CM and varicosities are associated with limb undergrowth. Parkes Weber syndrome: This syndrome is characterized by CM associated with

Capillary Malformation–Arteriovenous Malformation

Table 31-16 Capillary Malformations

limb overgrowth and multiple arteriovenous fistulas or AVM and sometimes LM. At least some cases of Parkes Weber syndrome are due to a RASA1 gene mutation.233

Cobb syndrome: Individuals with this syndrome have an AVM involving the spinal cord and a port wine stain–like lesion in the distribution of the corresponding dermatome of the skin.234

This recently described hereditary disease, reported in six families,233 is caused by an inactivating mutation of the RASA1 gene situated on chromosome 5. It is characterized by multiple, small, round to oval, pale pink to red CMs in patients with AVMs or fistulas in the soft tissues, bone, or brain. HISTOPATHOLOGIC FEATURES AND DIFFERENTIAL DIAGNOSIS The lesions of CM–AVM have not been described histologically. The diagnosis is based on the peculiar clinical features of CM lesions and, when present, the association with AVM or arteriovenous fistula.

Hereditary Benign Telangiectasia Affected individuals exhibit widespread telangiectasias without evidence of visceral organ involvement or systemic disease.235 Several familial cases showing autosomal dominant inheritance have been reported, with one family demonstrating linkage to the CMC1 locus, which is also the site of the RASA1 gene for CM–AVM.236 CLINICAL FEATURES Clinical lesions may involve the face, trunk, and extremities and are often polymorphic, presenting as discrete reddish papules resembling cherry angiomas, plaques, and lesions with erythematous or arborizing appearances.235,237 An underlying AVM (or more probably an arteriovenous fistula) identified by image analysis was recently reported for a group of patients with hereditary benign telangiectasia.238 It was, however, suggested that these cases may be actually cases of CM–AVM.239

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Clinical Features Onset at birth Often involves head and neck but may occur anywhere Pink macular lesions but may become papular and keratotic Some lesions regress “Stork bite” on nape of neck “Salmon patch” on eyelids Some persistent lesions, such as the port wine stain, are associated with particular syndromes Cobb syndrome: arteriovenous malformation in spinal cord and port wine stain in corresponding dermatome Sturge-Weber syndrome: unilateral port wine stain involving the ophthalmic branch of trigeminal cranial nerve; seizures, hemiparesis, hemiplegia from vascular malformation of contralateral leptomeninges; occasional vascular malformations in other sites such as the choroid; mental retardation; glaucoma Klippel-Trenaunay-Weber syndrome: unilateral hypertrophy of a limb (bone and soft tissue overgrowth); varicosities; venous malformation, lymphatic malformation on occasion; arteriovenous malformation often present; other vascular malformations on occasion Parkes-Weber syndrome: unilateral limb hypertrophy; multiple arteriovenous fistula or arteriovenous malformation; lymphatic malformation on occasion Capillary malformation arteriovenous malformation syndrome: small patchy port wine stains associated with arteriovenous fistulas or arteriovenous malformations, hereditary, caused by mutations in the RASA1 gene Histopathologic Features Widely dilated thin-walled venules in upper dermis or throughout reticular dermis Differential Diagnosis Ateriovenous malformation, when in quiescent stage Telangiectases Spider angioma

HISTOPATHOLOGIC FEATURES The principal findings are widely dilated capillaries or venules in the superficial dermis.235,237 DIFFERENTIAL DIAGNOSIS This condition must be distinguished from other telangiectasias.

Hereditary Hemorrhagic Telangiectasia

 FIGURE 31-35 Nevus flammeus. Dilated, thin-walled microvessels are seen in the superficial dermis.

Synonyms: Osler disease, Osler-WeberRendu disease HHT is a rare autosomal dominant disorder. Several genes are implicated in the pathogenesis of HHT. These gene loci include endoglin (HHT1), which is involved in the TGFβ signaling pathway;

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 31-17 Hereditary Hemorrhagic Telangiectasia

 FIGURE 31-36 Nevus flammeus. Note the dilated, thin-walled microvessels throughout the entire dermis.

symptomatic, may be associated with high-output heart failure, portal hypertension, ascites, variceal bleeding, and biliary disease.242 Recurrent nosebleeds beginning in childhood may herald the presence of the disorder, but the characteristic mucocutaneous telangiectasias are usually not seen before puberty. GI hemorrhages may produce recurrent episodes of melena. The clinical severity of HHT depends on the location and frequency of hemorrhage.  FIGURE 31-37 Arteriovenous hemangioma. Note thick-walled vessels in the dermis.

ALK1 (HHT2), which encodes a type 1 serine-threonine kinase receptor in endothelial cells; and a third locus (HHT3), which maps to 5q31.5-32. HHT typically presents with recurrent epistaxis in childhood and mucocutaneous telangiectasias by the third and fourth decades of life. Visceral involvement by telangiectasias and arteriovenous fistulas (so-called AVMs) may result in variable hemorrhage, cerebral abscesses, and even death.

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Clinical Features Autosomal dominant Telangiectases involving mucocutaneous sites, developing at puberty Face, lips, ears, fingers, nail beds, palms, soles, nasopharynx, oral mucosa involved Nonpulsatile, punctate or linear vascular lesions Recurrent epistasis Vascular anomalies and arteriovenous malformations sometimes involving viscera, especially the brain and lungs Melena from gastrointestinal hemorrhage Anemia Histopathologic Features Dilated, thin-walled irregular capillaries and venules beneath epithelial layers Differential Diagnosis Telangiectases in many other conditions Hereditary benign telangiectasia Ataxia-telangiectasia Generalized essential telangiectasia Unilateral nevoid telangiectasia

CLINICAL FEATURES Telangiectasias occur as nonpulsatile, punctate, or linear

lesions that may involve any cutaneous site. However, there is a predilection for the face, ears, lips, fingers, nail beds, palms, and soles (Table 31-17). Capillary microscopy of the nail, which may assist in diagnosis, often reveals one or more giant loops of tortuous capillaries situated between normal capillaries.240 Any mucous membrane site may be affected from the nasopharynx and oral mucosa to the GI tract.241 Vascular aneurysms and arteriovenous fistulas may develop in organs such as the brain, lungs, and liver and potentially manifest clinically as brain abscesses. Liver disease, when

HISTOPATHOLOGIC FEATURES Dilated, thinwalled, irregular capillaries and venules occur directly beneath the surface of mucocutaneous epithelia (Fig. 31-38). Anomalies of endothelial cells, endothelial cell junctions, and perivascular connective tissue have been described.241 DIFFERENTIAL DIAGNOSIS Telangiectasias may be seen as primary cutaneous lesions in patients with other disorders such as ataxia telangiectasia, generalized essential telangiectasia, hereditary benign telangiectasia, and unilateral nevoid telangiectasia syndrome, as well as secondary to many other conditions or insults. The extensive mucocutaneous telangiectasias with recurrent mucosal hemorrhages and systemic visceral involvement serve to distinguish HHT from other telangiectasias.

including capillaries and venous channels. There may be atrophy and ulceration of the overlying skin. Men and women are equally affected by CMTC, and unilateral involvement of an extremity is the most common presentation.250 The vascular abnormalities tend to improve with age. The disorder may be inherited as autosomal dominant. Other abnormalities reported include enlargement or hypoplasia of an affected limb, skeletal anomalies, glaucoma, and mental retardation. Recently, concurrent hypospadia was identified in four of 111 cases of CMTC.251

Ataxia-Telangiectasia (Louis-Bar Syndrome) CLINICAL FEATURES Patients present with telangiectasias, cutaneous atrophy, and mottled hyper- and hypopigmentation involving the head and neck and commencing in childhood.243 Patchy, segmental pigmentary anomalies, reminiscent of Blaschko lines, were found on one child.244 Patients may also have ectasia of bulbar conjunctival vessels and premature graying of the hair. Other important components of this autosomal recessive syndrome, which is due to mutations in the ATM gene on chromosome 11q22-23, include progressive cerebellar ataxia from cerebellar cortical atrophy; a combined immunodeficiency involving cellular and humoral immunity; recurrent infections; chromosomal instability from a striking sensitivity to ionizing radiation; and a markedly increased incidence of neoplasia, particularly lymphoma and leukemia. HISTOPATHOLOGIC FEATURES There is ectasia of venules in the superficial vascular plexus.243 DIFFERENTIAL DIAGNOSIS Ataxia-telangiectasia must be distinguished from other genodermatoses associated with chromosomal instability and telangiectasia such as Bloom syndrome, RothmundThomson syndrome, and xeroderma pigmentosum.

Unilateral Nevoid Telangiectasia CLINICAL FEATURES In this condition, delicate telangiectasias with a unilateral and often dermatomal distribution are noted at birth or later in life.245 This condition most frequently involves the face followed by the neck, chest, and arms. Its presentation may relate to relatively increased levels of circulating estrogen such as occurs with pregnancy, puberty, and the altered liver metabolism associated with both alcoholic cirrhosis and hepatitis C.246 However, the occurrence of unilateral nevoid telangiectasia in a healthy 33-year-old man suggests that the pathogenesis of this disorder may not necessarily have a hormonal basis.247 HISTOPATHOLOGIC FEATURES Dilated capillaries are observed in the superficial and middle dermis.245

Cutis Marmorata Telangiectatica Congenita Synonym: Congenital generalized phlebectasia CLINICAL FEATURES Neonates with cutis marmorata telangiectatica congenita (CMTC) present with a localized or generalized reticular or netlike vascular mottling of the skin that suggests livedo reticularis but is persistent rather than transient.248,249 The mottling is explained by ectasia of a range of vessel types,

DIFFERENTIAL DIAGNOSIS The clinical findings are usually distinctive. Livedo reticularis is a transient mottling that is related to sluggish blood flow from many causes rather than a vascular structural abnormality.

Angioma Serpiginosum Angioma serpiginosum is an unusual benign vascular lesion that was first described by Hutchinson in 1889 as a peculiar form of serpiginous and infective nevoid disease. It was more specifically characterized by Crocker in 1894, and additional reports over time have clarified its clinicopathologic features. CLINICAL FEATURES Angioma serpiginosum typically occurs during the first two decades of life, is more common in women, and occurs at any site.253,254 The lower extremities are most commonly involved, and the palms and soles are typically spared. Extensive involvement of the trunk and extremities occurs infrequently.253 Minute violaceous-red puncta, at times requiring magnification for adequate visualization, occur in gyrate or serpiginous configurations. Groups of puncta may coalesce into patches. Peripheral extension occurs through the formation of satellite puncta. Angioma serpiginosum usually occurs sporadically in individuals, but familial transmission has been reported. Autosomal dominant inheritance with variable penetrance favoring women has been suggested, but recessive inheritance cannot be excluded.254 Angioma serpiginosum may spontaneously regress but is usually slowly progressive. However, there

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-38 Hereditary hemorrhagic telangiectasia. Dilated venules are present in the papillary dermis.

HISTOPATHOLOGIC FEATURES One observes dilated capillaries, venules, and venous vessels throughout the dermis and possibly the subcutis. In rare cases, there may be a proliferation of vascular channels in the reticular dermis.247,252

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may be periods of relative quiescence or prolonged stability.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

HISTOPATHOLOGIC FEATURES Angioma serpiginosum is characterized by increased numbers of dilated capillaries in the superficial dermis. The overlying epidermis is normal, and there is no significant inflammation. Red cell extravasation and hemosiderin are absent. The dilated capillaries are relatively thick walled.

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DIFFERENTIAL DIAGNOSIS The absence of red cell extravasation and hemosiderin differentiate angioma serpiginosum from pigmented purpuric dermatoses and Henoch-Schönlein purpura. Clinical similarities to angiokeratoma circumscriptum exist, but the latter condition differs from angioma serpiginosum because of a verrucous, hyperkeratotic surface.

Angiokeratoma Angiokeratomas traditionally occur as five clinical variants.61,255,256 (Table 31-18): 1. Mibelli type, characterized by hyperkeratotic lesions on the dorsal fingers and toes 2. Fordyce type, characterized by involvement of the scrotum and vulva 3. Angiokeratoma corporis diffusum (ACD), a lysosomal storage disease inherited as an X-linked recessive disorder in Fabry disease (α-galactosidase A deficiency) but also seen with the autosomal recessive disorder, fucosidosis (α-L-fucosidase deficiency), and rarely with β-galactosidase deficiency, alone or in combination with neuraminidase deficiency. 4. The solitary or multiple type, which may involve any site but favors the lower extremities 5. Angiokeratoma circumscriptum, characterized by lesions in groups or bands usually on an extremity In contrast to the fundamental telangiectatic nature of the other variants of angiokeratoma, the fifth type of angiokeratoma—angiokeratoma circumscriptum—may demonstrate a deep component composed of a variable admixture of dilated capillaries, lymphatics, and veins. These lesions are best classified as hyperkeratotic capillary, lymphatic, venous, or combined vascular malformations.6,62,246,257 The existence of a sixth type of angiokeratoma, angiokeratoma serpiginosum, clinically simulating angioma serpiginosum, has been suggested.

Table 31-18 Angiokeratoma

Clinical Features Onset in first two decades of life common, but also in older individuals Solitary or multiple Sites vary (see below) Hyperkeratotic lesions that may be pink-red, purple, brown, blue, or black Melanoma often a clinical concern Five clinical types: Mibelli type: lesions on dorsal fingers and toes Fordyce type: lesions on scrotum and vulva Angiokeratoma corporis diffusum: Fabry disease (α-galactosidase A deficiency) Fucosidosis (α-L-fucosidase deficiency) β-Galactosidase deficiency Solitary or multiple type–common on lower extremities but may occur anywhere Angiokeratoma circumscriptum (hyperkeratotic capillary–lymphatic or venolymphatic malformation), usually on the extremities Histopathologic Features Ectatic thin-walled vascular channels in the papillary dermis Vascular spaces intimately associated with or encased by epidermis Intraluminal thrombosis and organization common Differential Diagnosis Telangiectases Targetoid hemosiderotic hemangioma Verrucous hemangioma Vascular malformation with angiokeratoma-like features

CLINICAL FEATURES Most forms of angiokeratoma present during the first two decades of life (see Table 31-18). Angiokeratoma circumscriptum, in contrast, may be visible at birth. Angiokeratomas of the ACD type usually present in late childhood, and angiokeratoma scroti and the solitary or multiple types of angiokeratoma generally arise during the second to fourth decades of life. Vulvar angiokeratomas usually occur in the third and fourth decades and are identical to angiokeratoma scroti because of their anatomic location and pathogenesis related to conditions of increased venous pressure. Angiokeratomas occur as variably hyperkeratotic lesions that may be pink, red, purple, brown, blue, or black. Clinically, the differential diagnosis includes hemangioma, verruca, nevus, and (when thrombosed and deeply

pigmented) malignant melanoma. The latter occurrence has been emphasized in individual case reports. Angiokeratomas usually manifest no symptoms; however, with local trauma, they may become irritated and can bleed, given their highly vascular nature. HISTOPATHOLOGIC FEATURES Angiokeratomas are telangiectasias, and all angiokeratomas are histologically similar except for the addition of certain features in ACD and angiokeratoma circumscriptum (see Table 31-18).61,255 Ectatic, thin-walled vascular spaces occur in the papillary dermis and are intimately associated with and variably encased by a hyperplastic epidermis. The epidermis shows elongated rete ridges and hyperkeratosis that is often slight but usually accentuated on acral sites (Fig. 31-39). Fibrin thrombi in various degrees of organization may be present. Dilated veins often drain the vascular lacunae of angiokeratoma scroti and vulvar angiokeratoma. Angiokeratomas of ACD may show subtle vacuolization of the endothelium, arrector pili muscle, and vascular smooth muscle cells. The latter vacuoles may be highlighted by lipid stains such as Sudan black B or PAS staining of the glycolipid. The lipid is doubly refractile and can be visualized in frozen tissue sections examined by polarized light. Ultrastructural examination reveals characteristic electron-dense lamellar inclusion bodies. DIFFERENTIAL DIAGNOSIS The diagnosis of angiokeratoma is seldom difficult, and the clinical setting allows for appropriate subclassification. It is important to recognize angiokeratomas with enzyme deficiencies because of the obvious systemic implications. Because of their superficial component, VHs may mimic angiokeratomas, and when small, they may enter into the differential diagnosis. However, because angiokeratomas are telangiectasias, they lack the “proliferative” vascular component of VH and the even more extensive deep involvement, possibly including muscle or bone of hyperkeratotic capillary–LMs.

Verrucous Hemangioma Synonyms: Keratotic hemangioma, unilateral verrucous hemangioma, angiokeratoma circumscriptum naeviforme, nevus keratoangiomatosus, nevus vascularis unius lateralis VH is an uncommon vascular lesion that tends to arise at or near birth or in childhood.258 In 1967, Imperial and

reported. The linearity of VH has been theorized to reflect genetic mosaicism.260 VH enlarge proportionately with body growth and tend to recur after surgical excision. Accordingly, they are best removed early in life when they are still small. In contrast to angiokeratomas, which respond to various superficial means of therapy, removal of VH requires a deep and relatively wide surgical excision. Otherwise, the lesions are apt to recur.

Helwig, at the Armed Forces Institute of Pathology, defined the clinicopathologic features of 21 VHs in a retrospective review of 1175 cases that had been previously classified as angiokeratoma or various types of hemangioma.258 CLINICAL FEATURES In Imperial and Helwig’s series, approximately half of VHs developed in the perinatal period, and six others presented by the age of 17 years (Table 31-19).258The most

common site is the lower extremity, particularly distally. VH typically occurs as unilateral, grouped, sometimes linear or serpiginous, discrete to confluent, hyperkeratotic angiomatous papules.259 Early lesions are bluish-red, well demarcated, soft, and compressible. Over time, VHs gradually enlarge, satellite nodules may arise, and ultimately a verrucous hyperkeratotic appearance develops. An unusual case of a young girl with multiple eruptive VH papules developing and progressing since birth, and suggesting infantile hemangiomatosis, has been

Table 31-19 Verrucous Hemangioma

Clinical Features Origin in infancy and childhood Distal lower extremity Hyperkeratotic angiomatous papules Grouped, discrete to confluent, sometimes linear or serpiginous Verrucous appearance developing over time Histopathologic Features Capillary to venous vascular proliferation Pandermal involvement with extension into the subcutis Lateral extension into clinically normalappearing skin Reactive acanthosis, papillomatosis, and hyperkeratosis Occasional inflammatory crusting or ulceration Differential Diagnosis Angiokeratomas Angiokeratoma circumscriptum Angioma serpiginosa Cutaneous keratotic hemangioma

 FIGURE 31-40 Verrucous hemangioma. The epidermis shows papillomatous hyperplasia and is intimately associated with ectatic vascular channels containing erythrocytes. The features are indistinguishable from angiokeratoma. However, a deep vascular component is present.

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-39 Angiokeratoma. A thin-walled ectatic vascular channel is surrounded by epidermis.

HISTOPATHOLOGIC FEATURES VH is mostly composed of small vessels 10 to 50 μmin diameter with multilaminated basement membranes in the dermis and subcutis that are compartmentalized by fibrous or adipose tissue. These vessels are sometimes grouped in vague lobules. Larger, dilated, thin-walled vessels are observed in the papillary dermis and occasionally in the subcutis.62 The vascular component is associated with secondary reactive epidermal changes such as acanthosis, papillomatosis, and hyperkeratosis (Table 31-19 and Fig. 31-40).6,62,246 Although the superficial portion of VH may bear resemblance to angiokeratoma, the VH is distinct since a vascular component extends deeply into the reticular dermis and underlying subcutaneous tissue. Often the vascularity extends laterally into adjacent clinically normalappearing skin. The upper dermis may show fibrosis, hemosiderin, and inflammation. The surface may manifest inflammatory and hemorrhagic crusts and occasional ulceration.

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DIFFERENTIAL DIAGNOSIS Clinically, the differential diagnosis includes angiokeratoma, Cobb syndrome, angioma serpiginosum, LM (angiokeratoma circumscriptum), verrucae, and occasionally pigmented lesions. ACD, scrotal angiokeratomas, and angiokeratoma of Mibelli occurring on the fingers and toes are clinically distinct. Except for angiokeratoma circumscriptum, angiokeratomas are telangiectasias and can be differentiated from VH by the absence of a deep angiomatous component. Angiokeratoma circumscriptum may actually represent localized hyperkeratotic capillary-lymphatic or capillary–lymphatic– venous combined malformations composed of dilated, thin-walled vessels.6,257 Angioma serpiginosum, which often involves the legs, does not have a verrucous, hyperkeratotic surface and typically presents as minute violaceous-red puncta in gyrate or serpiginous configurations. Cobb syndrome is a rare congenital vascular nevus with dermatomal distribution on the trunk, the appearance of angiokeratoma circumscriptum or nevus flammeus, and an associated meningospinal vascular malformation. Finally, cutaneous keratotic hemangioma is histologically similar to VH but is clinically distinct because it is an acquired vascular tumor occurring on the volar aspect of the fingers.

Venous Malformation Synonyms: Cavernous hemangioma, cavernous malformation This rather characteristic type of vascular proliferation usually presents at birth or in childhood but may also appear in older individuals and may be associated with a number of syndromes, such as blue rubber bleb nevus syndrome (BRBNS) and Maffucci syndrome.2,3,229,261-263 The term cavernous refers to widely dilated vascular channels that resemble those in corpus cavernosum. This term is misleading because it has been used for number of different lesions with dilated vessels, including fully developed IH, and thus should not be used as a diagnostic term. CLINICAL FEATURES VM usually presents as soft, blue to purple nodules or plaques that have a compressible quality and increase in size with venous pressure or when dependent (Table 31-20). The most common sites include the head and neck; however, lesions may occur anywhere. The onset may be at birth, in the first few weeks of life, or later. VMs may rarely be familial.264 Familial mucocutaneous VMs

Table 31-20 Venous Malformation

Clinical Features Onset commonly at birth or in childhood Involve head and neck most commonly, but may occur anywhere Soft, blue to purple nodules, masses, or plaques Compressible and rubbery, inflate when dependent Sometimes associated with lymphatic malformation (venolymphatic malformation) Rarely familial (mucocutaneous venous malformation) Associated with particular syndromes: Blue rubber bleb nevus syndrome: autosomal dominant; venous malformations involving the skin, gastrointestinal tract, liver, spleen, and central nervous system; pain and hyperhidrosis; melena and anemia Maffucci syndrome: venous malformations, rarely lymphatic malformations, and phlebectasias; spindle cell hemangioma; multiple enchondromas and bony deformities from nonossifying cartilage; high risk of chondrosarcoma and increased risk of angiosarcoma Klippel-Trenaunay syndrome (see Table 31-16) Histopathologic Features Location usually in deep dermis or subcutis Generally diffuse; rarely circumscribed Vascular channels are dilated and often encased in fibrous tissue Vessels contain single layer of endothelium surrounded by fibrous tissue in vessel wall Smooth muscle may be observed in the vessel wall but is often inconspicuous Differential Diagnosis Lymphatic malformation Glomuvenous malformation (glomangioma) Port wine stain Arteriovenous and other malformations Involuting juvenile capillary hemangioma

are related to a mutation of Tie2 gene, which is located on chromosome 9.265 Individuals with BRBNS present at birth with numerous VMs involving the skin, GI tract, central nervous system, liver, and spleen.229,261,262 Patients may exhibit pain and hyperhidrosis from the cutaneous lesions and melena and anemia from those situated in the GI tract. An autosomal dominant inheritance pattern has been suggested for some BRBNS, but these cases seem to correspond to familial mucocutaneous VMs. Two cases of unilateral dermatomal cavernous

hemangiomatosis have been reported; the VMs are similar to those of BRBNS, but they occur only in the skin without the systemic involvement of BRBNS and without the enchondromas and malignant tumors of Maffucci syndrome.266 The principal findings typifying Maffucci syndrome include four varieties of vascular lesions: VMs, LMs, phlebectasias, and spindle cell hemangioma. Nonvascular lesions include multiple enchondromas and bony deformities resulting from nonossifying cartilage in the metaphyses of growing bones, frequent fractures of bone from the latter defects, and the frequent development of chondrosarcoma and angiosarcoma in up to 50% of affected individuals.229,263 HISTOPATHOLOGIC FEATURES VMs are usually situated in the dermis and subcutis and are generally diffuse (Table 31-20 and Fig. 31-41).8,267 The vascular channels form a complex network of slitlike, stellate, or open vessels dissecting the tissues and encasing normal structures such as hair follicles, nerves, arterioles, and cutaneous smooth muscle bundles (Fig. 31-42). In some cases, some fibrosis may be found. The vessels exhibit a single layer of endothelium surrounded by a thin or relatively thickened layer of fibrous tissue. Various amounts of smooth muscle elements may be observed in the fibrous lining of the vessels; this smooth muscle component may be focal or extensive. VMs frequently contain organized thrombi, which manifest either as concentrically hyalinized structures and calcified round phleboliths or as intravascular papillary hyperplasia of Masson. A subset of VM, nodular venous malformations,267 are composed of well-defined nodules containing dilated vascular lumina engorged with erythrocytes. The vascular structures are separated by regular fibrous septa in a honeycomb pattern without intervening normal elements. Generally, the vascular nature of these lesions is not recognized clinically, and they are considered to be “cysts” or nonvascular tumors. Another type of VM, sinusoidal hemangioma,268 demonstrates dilated, interconnecting, thin-walled vascular channels with pseudopapillary features; a generally lobular architecture; and an ill-defined infiltrative pattern in areas. It must be emphasized that VMs may occur as a component of many complex or combined VMs or as part of many of the syndromes described above. Thus, for example, one may observe capillary–venous, lymphatico– VMs, or even more complex combinations of channels.

similar to nodular VM. However, in contrast to nodular VM, spindle cell hemangiomas are distinguished by a solid cellular spindle cell component.

Glomus Tumor and Glomuvenous Malformation

DIFFERENTIAL DIAGNOSIS VM must be distinguished from LMs, glomuvenous malformations (glomangioma), AVMs, CMs, and spindle cell hemangioma. An LM may have a very similar and sometimes identical architecture as a VM, and histologic distinction of the two may not be possible without additional information. LMs may contain blood due to intralesional hemorrhage before or during surgery. Distinction is possible only if the lumina contain numerous lymphocytes or if lymphocytic aggregates are present in the vicinity of the malformed vessels. Encasing of normal elements within the vascular lumina is a feature more commonly noted in VM than

A

in LM. Glomuvenous malformations (GVMs; glomangioma) are also structurally similar to VM but harbor cuboidal glomus cells at least focally in their vessel walls. AVMs differ from VMs by exhibiting arterial-type channels, some with a well-developed internal elastic lamina, and fewer thin-walled vessels. CMs are generally situated in the superficial dermis and are composed of regular round dilated capillaries or venules. They do not display the slitlike vascular channels, the uneven thicknesses of vascular walls, or the anastomosing patterns of VM. Spindle cell hemangiomas may show a honeycomb pattern and organizing thrombi and phleboliths

CLINICAL FEATURES The typical solitary glomus tumor occurs in an adult as a small, blue-red nodule, less than 1 cm in diameter in the deep dermis or subcutis of the extremities. The most common site is the subungual region of the finger, where glomus tumors typically produce a triad of symptoms, including pain that may be paroxysmal, tenderness, and temperature sensitivity. Unusual sites of glomus tumors have included the stomach, rectum, cervix, vagina, mesentery, chest wall, bone, eyelid, and nose. Intravascular or intravenous glomus tumors have been reported.274

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-41 Venous malformation (cavernous hemangioma). A circumscribed aggregate of large vascular channels with walls thickened by smooth muscle and fibrous tissue.

In 1924, Masson described the glomus tumor as a distinct neoplasm with morphologic similarities to the normal neuromyoarterial glomus, an arteriovenous shunt concerned with temperature regulation located in the reticular dermis of the skin of the nail beds, pads of the fingers and toes, volar side of the hands and feet, ears, and center of the face.269-271 Glomus tumors may be classified into solitary and multiple types (Table 31-21). 269-271 The multiple type, which is generally composed of dilated venous-like channels, tends to be considered a vascular malformation termed GVM.220,272,273 In 64% of cases, GVM is an autosomal dominant condition with incomplete penetrance and variable expressivity.227 The mutated gene encodes for glomulin, a protein of unknown function.

B

 FIGURE 31-42 Venous malformation. (A) The vascular channels form a complex network of open vessels dissecting the tissues and encasing normal structures such as hair follicles, nerves, arterioles, and cutaneous smooth muscle bundles. (B) Microvessels encased by malformation (inset).

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Table 31-21 Glomus Tumor and Glomuvenous Malformation

840

Clinical Features Glomus tumor Adults Nail beds, pads of fingers and toes, volar surfaces of hands and feet, ears, center of face Blue-red nodule <1 cm Pain, often paroxysmal Tenderness Temperature sensitivity Glomuvenous malformation Childhood common Proximal >>distal sites Regional or disseminated Familial in 64% of cases Bluish nodules Often >1 cm Often asymptomatic Histopathologic Features Solitary type Dermal or subcutaneous Well circumscribed Encapsulated usually Nests and sheets of monotonous round or cuboidal cells Glomus cells cuff small vascular channels Round nucleus with amphophilic or eosinophilic cytoplasm Smooth muscle may be present (glomangiomyoma) Nerve fibers present Occasional myxoid stroma Multiple type Large, irregularly shaped vascular channels (glomangioma) Usually fewer layers of glomus cells cuffing vessels Glomus cells may blend with smooth muscle (glomangiomyoma) Immunohistochemistry Positive for vimentin, smooth- or pan-muscle actin, myosin, desmin (variable) Negative for von Willebrand factor–related S-100 protein Differential Diagnosis Adnexal tumor Eccrine acrospiroma Chondroid syringoma (mixed tumor) Mastocytoma Melanocytic nevi (pseudoangiomatous) Cavernous malformation Hemangiopericytoma Angioleiomyoma

In contrast to solitary glomus tumors, GVM are uncommon, often present in childhood, only rarely occur subungually, and may be subdivided anatomically into regional or disseminated variants. In general, GVM tend to be larger than solitary glomus tumors, may reach several centimeters in size, or more rarely present as large plaquelike lesions that may be congenital.270,273,275,276 Widespread GVMs presenting in infancy may mimic BRBNS, and large GVM with their blue hue may mimic venous malformations.277 GVMs differ clinically from VMs because they are pink to purple or dark blue rather than blue with a cobblestone appearance and often hyperkeratosis, especially on the extremities. They are commonly tender, less compressible, less prone to increase in volume when dependent, rarely affect the mucosa, and spare the muscles and viscera.273 Glomangiosarcoma, or malignant glomus tumor, is rare.278,279 These tumors typically exhibit a malignant component superimposed on a preexisting glomus tumor. The initial cases reported as glomangiosarcoma lacked metastases, and thus the prognosis was considered good. Perhaps the latter conclusion was based on the excision of small tumors at an early stage of development. However, cases with widespread metastases have been reported,280,281 a potential de novo malignant variant has been suggested. At present, evidence suggests that superficially situated glomus tumors with malignant-appearing histologic features

show less aggressive behavior than similar-appearing tumors in deep locations. HISTOPATHOLOGIC FEATURES The histology of the glomus tumor is very distinctive (Table 31-21).269-271,283,284 The typical glomus cell is round or cuboidal with a round nucleus in amphophilic to eosinophilic cytoplasm and occurs in monotonous nests and sheets that are interrupted by blood vessels, around which the glomus cells may form collars (Figs. 31-43). Solitary glomus tumors are usually encapsulated, contain numerous small blood vessels, and are associated with ample nerve fibers. Glomangiomyomas are an uncommon variant of glomus tumor and show glomus cells blending with a population of smooth muscle cells. These features are best seen at the periphery of large blood vessels. Solid forms are also seen with a remarkable epithelioid appearance of solid lobules of glomus cells with scant lumen formation. GVM are composed of large, irregularly shaped vascular spaces that may resemble those of a venous malformation (Fig. 31-44). These spaces may be filled with blood or contain organized thrombi. Typically, only a few layers of glomus cells surround these large spaces, and some vessels may lack glomus cells. In contrast to the solitary tumors, nerve fibers about multiple glomus tumors are few. Extensive GVM have been named glomangiomatosis.

 FIGURE 31-43 Glomus tumor, solid variant. Note the similarities to an epithelial tumor. The tumor is composed of uniform cuboidal cells.

of glomus tumors will readily distinguish the two. Glomangiopericytoma, a tumor characterized by branching vessels surrounded by glomoid-appearing cells and thereby having composite features of hemangiopericytoma and glomus tumor, has been described.294 Glomangiosarcomas with a primitive round cell appearance must be differentiated from melanoma and various small round cell tumors such as lymphoma, Merkel cell carcinoma, primitive neuroectodermal tumor, neuroblastoma, Ewing sarcoma, and some sarcomas. Immunohistochemistry and electron microscopy aid in the distinction.

 FIGURE 31-44 Glomus tumor (glomuvenous malformation, glomangioma). Cavernous vascular channels that resemble a venous malformation are present and are lined by several layers of glomus cells, sometimes scant in number.

Glomangiosarcomas are characterized by short spindle cells, disordered arrangements of cells, moderate pleomorphism, single large nucleoli, and numerous mitoses. Recently, criteria for malignant glomus tumor (reserved for lesions with marked risk of metastasis) have been proposed: (1) greater than 2 cm size and a deep location or (2) atypical mitotic figures or (3) moderate to high nuclear grade and greater than or equal to 5 mitotic figures per 50 hpf. Unusual or atypical glomus tumors failing to meet these criteria did not metastasize and were classified as glomus tumor of uncertain malignant potential (high mitotic activity and superficial location, large size, or deep location) and as the two benign groupings symplastic glomus tumor (high nuclear grade) and glomangiomatosis (diffuse or disseminated venous-like lesion and excess glomus cells).281 Immunohistochemically, glomus tumors express vimentin, muscle actins, myosin, pericellular collagen type IV, and variably desmin but are negative for von Willebrand factor, cytokeratin, and S-100 protein. Ultrastructurally, the cells of glomus tumors show characteristics of modified smooth muscle cells such as intracytoplasmic myofilaments with characteristic focal densities, numerous pinocytotic vesicles, and dense attachment plaques on cell membranes. These features suggest that glomus tumors are not derived from capillary pericytes, as was once thought, but instead derive

from smooth muscle cells of the vascular part of the neuromyoarterial glomus. DIFFERENTIAL DIAGNOSIS The histology of benign glomus tumors is so characteristic that it is not readily confused with that of other tumors. An exception is the occasional GVM that exhibits only a subtle, multifocal population of glomus cells. However, careful scrutiny of such GVM for glomus cells will avoid confusion with venous malformations, including those that occur multiply in the setting of BRBNS. Mastocytomas have their own monotonous proliferation of cells, but these unencapsulated tumors lack significant vascularity, and mast cells can be identified by metachromatic stains and immunohistochemistry, if they are not readily recognized by light microscopy and experience. Mast cells express c-kit (CD117) and tryptase. Glomus tumors appearing as cellular sheets of cells may evoke the epithelioid appearance of an adnexal tumor (eccrine acrospiroma or chondroid syringoma); however, the vascularity of glomus tumors combined with their lack of both ductal differentiation and epithelial mucin serve to differentiate these tumors. It should be noted that occasional glomus tumors may exhibit a strikingly myxoid stroma. Pseudoangiomatous melanocytic nevi are usually not confused with glomus tumors, but if there is doubt, the S-100 and melan-A reactivity of nevi and not

Synonyms: Lymphangioma simplex, lymphangioma circumscriptum, cavernous lymphangioma, cystic hygroma LM is composed of variably dilated lymphatic vessels usually present either at birth or within the first few years of life.1-3,6,229 Various clinical types of LM have been reported over the years under a variety of terms, including lymphangioma simplex, lymphangioma circumscriptum, cavernous lymphangioma, and cystic hygroma, the last entity perhaps being a macrocystic (widely dilated lymphatic spaces) variant of LM occurring on typical clinical sites. LM typically have a deep component. Generalized LM (lymphangiomatosis) is exceedingly rare. In general, the features of the above types of LM form a continuum and show considerable overlap, thus making the exact classification of individual cases difficult at times. Moreover, the principal characteristics that determine the prognosis and choice of treatment for an individual lesion are the size of LM cavities (microcystic versus macrocystic LM) and extent of the disease.25,220 CLINICAL FEATURES Microcystic LM have been reported as: Lymphangioma simplex, which appears in infancy as a solitary, rather welldefined, skin-colored dermal, mucosal, or subcutaneous lesion often smaller than a few centimeters in size, usually with a smooth and slightly elevated contour. Lymphangioma circumscriptum, which is clinically characterized by cutaneous vesicles. The localized form is single and of small size. It is present at birth but may be inapparent and may appear in childhood or adulthood. In contrast, the classic form of lymphangioma circumscriptum usually appears at birth or in early childhood, is generally of larger size, and is composed of solitary or multiple

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Lymphatic Malformations

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patches. Common sites are the proximal extremities, limb girdle, neck, tongue, and buccal mucosa. The degree of involvement may sometimes be quite extensive. Microcystic LM may include vesicles with a variably sanguinous or violaceous appearance due to the presence of admixed red blood cells. Acquired LM-like lesions with features similar to microcystic LM have developed in the setting of lymphedema subsequent to radical mastectomy and radiotherapy. Among such lesions are acquired vulvar microcystic LM, which can be idiopathic but commonly arises secondary to impaired lymphatic drainage from various causes such as congenital lymphedema, infections, Crohn disease, and surgery or radiotherapy of cervical carcinoma. These genital LM-like lesions may present as verrucous papules mimicking condyloma acuminatum.287 Macrocystic LM has been reported as cavernous lymphangioma or cavernous LM and usually presents at birth or in infancy. This large, ill-defined lesion may occur at many sites but favors the head, neck, mouth, and extremities. A particular subtype of macrocystic LM, the cystic hygroma, has extensive, often deforming, cystic dilatations that generally occur on the neck but may also involve the axilla, groin, popliteal fossa, mediastinum, and retroperitoneum. An axillary lesion with a concurrent Becker nevus has been reported.288 HISTOPATHOLOGIC FEATURES Various LMs generally differ based on the size of the lymphatic vessels,1-3,6,229 even if vessels of various sizes occur in some lesions. Lymphangioma simplex is composed of small capillary-sized lymphatic vessels and is similar to the so-called APL or benign lymphangioendothelioma. Microcystic LM is characterized by dilated lymphatic channels occupying the superficial dermis. The overlying epidermis is often elevated and is variably thinned to acanthotic. Papillomatosis and hyperkeratosis may be present, particularly in the classic type of lymphangioma circumscriptum (Fig. 31-45). Also, in contrast to the localized type of lymphangioma circumscriptum, this classic type has deep extension of the lymphatic vessels into the lower dermis and subcutis. Other lesions have widely dilated lymphatic channels occupying and expanding the dermis and subcutis (Fig. 31-46). The wall of the LM vessels may be limited to endothelial cells and a thin fibrous layer but may contain smooth muscle cells in various amounts, sometimes grouped in discontinuous bundles. The intervening stroma may be

 FIGURE 31-45 Lymphatic malformation (lymphangioma circumscriptum). Large lymphatic lumen impinging upon the epidermis. Note the absence of red blood cells.

inapparent or variably fibrotic. The architecture of the lesion is similar to that of venous malformation. “Cystic hygromas” show large unilocular or multilocular cysts with thin or fibrous walls, generally associated with a more conventional macrocystic or microcystic LM component. LMs show homogenous, lightly stained lymph fluid within their lymphatic spaces and may have a variable number of intravascular or stromal lymphocytes. Red blood cells are frequently present, at least

focally, within lymphatic lumina, and macrophages may also be seen. DIFFERENTIAL DIAGNOSIS The diagnosis of LM may have to suffice when clinical correlation is lacking and when vessels of mixed size are present. Moreover, the presence of admixed erythrocytes within a particular LM may generate consideration of a combined lesion (hemolymphatic or venolymphatic malformation). The papillary dermal component of superficial

 FIGURE 31-46 Lymphatic malformation (cavernous lymphatic malformation). Widely dilated lymphatic channels are surrounded by fibrous tissue and lymphocytic infiltrates. The lumina contain proteinaceous material.

LM (lymphangioma circumscriptum) bears similarity to that of an angiokeratoma, and as stated earlier, angiokeratoma circumscriptum is generally a lymphatic or combined hyperkeratotic vascular malformation. The diagnosis of cavernous and cystic lymphangiomas is seldom difficult, and the clinicopathologic features for the cystic hygroma, in particular, are quite unique. Immunohistochemistry using lymphatic endothelial markers as VEGFR-3 and D2-40 may be useful to detect a lymphatic component in lesions that lack intravascular or interstitial lymphocyte aggregates.

Synonyms: Benign lymphangioendothelioma, angioendothelioma (lymphatic type) APL is an entity that has undergone a nosologic evolution over three decades. We prefer the term APL because of the antinomy between benign and lymphangioendothelioma. As with hemangioendothelioma, lymphangioendothelioma should designate lesions with borderline or lowgrade malignant status. APL is a rare entity that may offer diagnostic difficulty with low-grade angiosarcoma and the lymphangioma-like form of KS. CLINICAL FEATURES The incidence of APL is relatively similar in males and females (Table 31-22). Patients range in age from 5 to 90 years. At the point of recognition,

HISTOPATHOLOGIC FEATURES The epidermis is unremarkable. The lesions are

dermal with a tendency to involve the papillary and superficial to mid-reticular dermis (see Table 31-22). Occasional lesions show full-thickness dermal involvement and may involve superficial subcutaneous tissue.292,293 The unifying histologic features identified in all cases are jagged, irregularly shaped vascular channels distributed between dermal collagen bundles (Fig. 31-47). The lumina of these thin-walled vascular spaces may be dilated or collapsed and inconspicuous. The vessels are intimately associated with the dermal collagen, appearing to dissect between the collagen bundles. The thin-walled vessels tend to be arranged in horizontal array, although they may be quite haphazard in distribution. The endothelial lining is one cell layer in thickness. The cytologic features tend to be bland, although occasional plump or hyperchromatic endothelial cells are observed. Pronounced cytologic atypia is not a feature of APL. Exceptionally, a single case report described occasional multinucleated endothelial cells. More recent is a case with aggregated endothelial cells, resembling multinucleate giant cells.289 Occasionally, intraluminal papillary projections may be seen. Rarely, endothelial cells may detach from the vascular wall and appear to float freely within the vessel lumen. Mitotic activity is absent. The vascular spaces are typically empty but may contain a faintly eosinophilic, proteinaceous material. A scant, mononuclear,

Table 31-22 Acquired Progressive Lymphangioma

Clinical Features Men and women equally affected Childhood to elderly Diverse sites Well-demarcated dermal plaques, dull pink to violaceous Variable size (3-30 cm) Slow enlargement over time Histopathologic Features Variable degree of dermal involvement, favoring the upper half Thin-walled, irregular vascular channels “dissecting” collagen Bland endothelial cells Scant or absent mononuclear inflammatory infiltrate Lack of plasma cells, extravasated erythrocytes, and hemosiderin Differential Diagnosis Low-grade angiosarcoma Lymphangioma-like Kaposi sarcoma Lymphatic malformation

 FIGURE 31-47 Acquired progressive lymphangioma (benign lymphangioendothelioma). Thinwalled, infiltrative, staghorn-shaped vessels devoid of red blood cells.

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Acquired Progressive Lymphangioma

clinical lesions have been present for periods ranging from 2 months to 20 years.289 Sites of involvement are diverse and include the head, neck, oral mucosa, trunk, breast, buttock, shoulder, forearm, thigh, and foot. Multiple sites of involvement, both synchronous and asynchronous, are documented. APL may occur after trauma to the affected area, including a report of APL arising in a traumatized birthmark,290 as well as at the site of a tick bite.291 Clinical lesions are well-demarcated dermal plaques that range in color from dull pink to dusky to violaceous. The lesion borders are usually clearly delineated from the surrounding uninvolved skin.292,293 In general, the lesions have ranged in size from 3 to 30 cm. Presentation as a subcutaneous nodule has been reported. Characteristically, the dermal plaques are painless and nontender. Most lesions tend to pursue a relatively static clinical course, slowly increasing in size over a period of years. There are no reports of malignant transformation. Regression of two asynchronous lesions after oral prednisolone therapy and spontaneous regression of a case of APL have been documented. The significance of lesional regression after steroid therapy is uncertain and requires further investigation. Clinical recurrence after excision has not been reported.

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inflammatory infiltrate is a variable feature. Plasma cells, extravasated erythrocytes, spindle cell proliferation, and hemosiderin are not reported features of APL. There are striking similarities between APL and capillary-type LM, and the nosologic relationship between these lesions has not been resolved. Immunohistochemical studies have been inconsistent, but the endothelial cells of APL most commonly express CD31, CD34, and Ulex europaeus lectin 1. Staining with antibodies to von Willebrand factor is variably reported,289 and smooth muscle cells are found in variable amount and distribution. In any event, the pattern of immunoreactivity is not useful in distinguishing APL from other benign and malignant vascular proliferations. The HHV-8 genome has not been found in the single case of APL studied with PCR.294 In a single case, electron microscopy failed to demonstrate Weibel-Palade bodies. DIFFERENTIAL DIAGNOSIS APL is a histologic mimic of both low-grade or welldifferentiated angiosarcoma and patchstage KS. The clinical setting for each of these entities is distinctive, and an important caveat is that a diagnosis of APL should not be made on a small biopsy in the absence of a clinical history. Considering the relative histologic similarities of APL and angiosarcoma, it seems likely that several early series of cutaneous angiosarcoma may have contained examples of APL, the latter cases constituting the rare cases of angiosarcoma with an indolent course, good prognosis, and odd clinical presentation. Cutaneous angiosarcomas, excluding Stewart-Treves syndrome and postradiation angiosarcomas, are malignant tumors essentially confined to the head and neck of elderly individuals. If an adequate biopsy of angiosarcoma is obtained, the degree of cytologic atypia far exceeds that observed in the spectrum of APL. In addition, APL almost always fails to show extravasated erythrocytes, hemosiderin deposition, and inflammatory infiltration. Patch-stage lesions of KS, in both the classic and epidemic forms, may be clinically subtle. In contrast to APL, however, they tend to be small and multiple and show clinical progression over a relatively short period. Histologic features of KS that are distinct from APL include the tendency for the neovascular channels of KS to aggregate about preexisting dermal structures, erythrocyte extravasation, hemosiderin deposition, and a dermal inflammatory infiltrate that nearly always includes plasma cells.

Immunohistologic detection of HHV-8 in KS will probably be of help, but the HHV-8–negative status of APL has been demonstrated by PCR in only one case and needs confirmation. Lymphangioma circumscriptum demonstrates one or more clusters of vesicles favoring the limb girdles; contains large, dilated lymphatic vessels elevating the epidermis; and lacks the dissection of collagen pattern seen in APL. Hobnail cytomorphology, when present in APL, is only focal and not as prominent a feature as that observed in the typically smaller THH. Giant cell fibroblastoma may, in some rare settings, be confused with APL. The presence of the giant cells and the endothelial marker–negative pseudolumina should facilitate distinction from APL.

Angiomatosis of Soft Tissue This lesion was first definitively described and illustrated in 1992 by Rao and Weiss, who reported a series of 51 cases.295 Unfortunately, the definition they used: “a histologically benign vascular lesion that extensively involves a region of the body or several different tissue types in a contiguous fashion” is rather nonspecific because it may be applied to any type of large vascular malformation. This imprecision in definition may explain why this lesion remains underreported. However, the lesion they described is unique and clearly different from other types of vascular malformations. Because angiomatosis may refer to many types of large or multifocal vascular anomalies with diverse histologies, we suggest that this lesion be described as angiomatosis of soft tissue as a diagnosis or as angiomatosis, Rao and Weiss type. CLINICAL FEATURES AST is a relatively rare and probably underrecognized condition that usually presents in children or young adults with persistent swelling or pain in the soft tissue, muscle, and dermis.295 Nearly two-thirds of the cases involve the extremities, but all body areas may be affected. Occasional lesions extend into bone (Table 31-23). Angiomatosis is associated with a very high rate of recurrence, with up to 90% in one series. Recurrence of AST is probably due to underestimation of the extent of the lesions and incomplete resection. AST often affects several adjacent tissue types but may be confined to one tissue. HISTOPATHOLOGIC FEATURES AST is characterized by infiltration of the dermis and soft tissue by multiple discrete

nodules composed of an admixture of veins, cavernous vascular spaces, and thickwalled vessels with onion-skin concentric appearance (Figs. 31-48 and 31-49).295 The veins demonstrate media of uneven thickness with fissures and muscular pads. Slitlike, tortuous, thin-walled vessels directly branch from their walls of these veins. In addition to such veins, aggregates of open vessels separated by thin fibrous septa in a honeycomb pattern are frequently seen. We have observed as well in many cases a lymphatic component composed of vessels containing lymphocytes and lymphocyte aggregates in the interstitium. As in many vascular lesions affecting skeletal muscles, large amounts of adipose tissue surround intramuscular AST. This feature may cause confusion with adipose tumors. The subtype of angiomatosis characterized by capillary-sized vessels with occasional larger “feeder” vessels described by Rao and Weiss may be a different variety of vascular lesion. DIFFERENTIAL DIAGNOSIS Distinction between AST and other subcutaneous or intramuscular vascular malformations (mainly venous malformation) essentially depends on the presence of the rather characteristic constellation of findings that defines AST. However, due to heterogeneous nature of the lesion, diagnosis may be difficult on small specimens. The small size and discrete nature of angiolipoma preclude confusion with AST.

Arteriovenous Malformations Synonyms: Arteriovenous hemangioma, superficial arteriovenous hemangioma,

Table 31-23 Angiomatosis of Soft Tissue

Clinical Features Usually presents in children and young adults Soft tissue mass, generally tender or painful High recurrence rate Histopathologic Features Ill-defined infiltrating contours Made of veins with uneven walls, honeycomb cavernous spaces, thick onion-bulb vessels, lymphatics and lymphocytes aggregates Rarely capillary-sized vessels Differential Diagnosis Intramuscular hemangioma Venous malformations Lymphatic malformations Soft tissue tumor Angiolipoma

Table 31-24 Acral Arteriovenous Malformation

 FIGURE 31-49 Angiomatosis of soft tissue. Note the thick-walled vascular channels with “onionskin” configuration.

acral arteriovenous tumor, arteriovenous shunt, cirsoid aneurysm Two different types of AVM with different presentations, evolution, and prognosis are described: acral AVM (aAVM) and AVM not otherwise specified.

Acral Arteriovenous Malformation Synonyms: Arteriovenous hemangioma, acral arteriovenous tumor In 1974, Girard and coworkers296 characterized the salient clinical and histologic features of arteriovenous hemangioma.

Subsequent reports have confirmed the benign nature of these vascular lesions and have emphasized their acral distribution as acral arteriovenous tumor.297,298 Their developmental origin has not been clearly established. They have been considered “cirsoid” aneurysmal dilatations of cutaneous arterial structures or vascular channels comparable to the fibromuscular vessels of the Sucquet-Hoyer canal. CLINICAL FEATURES aAVM is a relatively common acquired lesion primarily affecting middle-aged to elderly adults

with a male predominance and a peak incidence in the fourth and fifth decades of life (Table 31-24).296-298 Rare cases have been reported in children, with patients as young as 6 weeks. The lesions present as single red or violaceous papules ranging in size from 1 mm to 3 cm with an average of 4 to 6 mm in the head or neck region and less commonly involve the fingertips and mucosa.299 Most lesions are asymptomatic; however, enlargement, pain, or pruritus may occur. Rarely, aAVM are associated with angiolymphoid hyperplasia with eosinophilia, verruciform xanthoma, and basal cell carcinoma.300-302 HISTOPATHOLOGIC FEATURES aAVM lesions are well circumscribed and unencapsulated (Table 31-24 and Fig. 31-50).295-298 They are composed of an intimate admixture of thick-walled and thinwalled blood vessels distributed within the superficial and middle dermis. The proportion of thick-walled to thinwalled vessels is variable, although the former typically predominates. The vessels may be closely approximated to and dispersed between the cutaneous and mucosal adnexa. The lining endothelium is typically bland. Occasionally, the endothelial cells protrude into the vessel lumen in a “hobnail” fashion. Thrombi,

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-48 Angiomatosis of soft tissue. The dermis and subcutis contain multiple discrete nodules composed of an admixture of veins and cavernous vascular spaces.

Clinical Features Most common in individuals 30 to 50 years of age Affects men more after than women Head and neck, acral sites Red or purple papules Usually solitary, 4-6 mm (≤3 cm) Cutaneous or mucosal Histopathologic Features Well circumscribed, not encapsulated Aggregates of thick-walled and thin-walled vessels Variation in vessel caliber Single layer of bland endothelium in vessels but occasional hobnail features present Vessel walls contain fibrous tissue with occasional small smooth muscle component A true arterial component usually present Differential Diagnosis Cherry angioma Lobular capillary hemangioma Venous lake Angioleiomyoma

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A

846

B

 FIGURE 31-50 Acral arteriovenous malformation (arteriovenous hemangioma). (A) These lesions are well circumscribed and unencapsulated. They are composed of an intimate admixture of thick-walled and thin-walled blood vessels distributed within the superficial and middle dermis. (B) Some of the vessels resemble arteries.

often showing organization and recanalization, are an occasional finding. Girard and colleagues described direct communication between arteries and veins in a subset of their cases. Inflammation is an infrequent feature; when present, it is described as a mixed, chronic inflammatory cell infiltrate associated with accentuation of fibrous changes within vessel walls. Elastin stains typically show vessels with finely fibrillar elastinophilic fibers scattered throughout their walls, alternating with a true arterial component with an internal elastic lamina.

AVM may affect the skin, soft tissue, viscera, bone, and brain.

Arteriovenous Malformation (Not Otherwise Specified)

CLINICAL FEATURES Superficial AVM involves mainly the head and neck; however, it can occur in any location. The lesion is warm and pulsating except in a quiescent stage in children, and a murmur or a thrill may be present. The underlying skin presents variable red discoloration. AVMs may remain stable for years or may show clinical progression with increased erythema, warmth, and a more evident thrill. These changes may be triggered by trauma or hormonal stimuli such as puberty or pregnancy (Table 31-25).305 Capillary steal syndrome may develop with skin atrophy, ulceration, pain, and sudden life-threatening hemorrhage. AVM are staged according to the scheme of Schobinger. Stage I represents the quiescent stage when AVM mimics a CM or an IH; stage II connotes clinical progression to lesions that are warmer, larger, and throbbing with thrills or bruits; stage III indicates progression to a destructive phase as evidenced by the onset of ulceration, hemorrhage, and bony lytic lesions; and stage IV is rare and is composed of all of above plus congestive heart failure owing to increased cardiac output and left ventricle hypertrophy.303,304 In clinical stages II and III, AVM may extend into previously clinically normal contiguous tissues.220

AVM is the rarest and most aggressive type of vascular malformation. It is a high-flow lesion and contains direct arteriovenous communications or fistulas. AVM is present at birth but is often undetected or masquerades as a CM. AVM becomes clinically apparent in childhood or adolescence, and only 20% are detected during adulthood.25,220,303,304

HISTOPATHOLOGIC FEATURES AVM are illdefined lesions comprised of vessels of different calibers and thicknesses evenly distributed throughout the affected tissues and accompanied by variable amounts of fibrosis (Fig. 31-51 and 31-52).8,18,25,267 The thickness of the vessel walls is generally proportionate

DIFFERENTIAL DIAGNOSIS The morphology of aAVM is characteristic, and a limited number of entities enter into the differential diagnosis. Clinically, venous lakes and cherry angiomas are a consideration because of their occurrence in a distribution and age group similar to those of aAVM. The histology of each is characteristic and easily distinguished from AH. The limitation of the lesion and restriction to the dermis separate aAVM from more aggressive AVM. Histologically, vascular leiomyomas are a consideration. The abundance of smooth muscle associated with these lesions is distinct from aAVM, as is the clinical setting.

to the diameter of the lumen but may vary from one segment to another of the same vessel section. Some dilated vessels with thin walls, resembling those of VM, may also occur. The type and structure of the vessels wall is best visualized with elastin stains, which show arteries, veins with thickened walls, and a majority of abnormal unclassified or intermediate vessels with defective elastic architecture. Direct communications between arteries and veins or unclassified vessels

Table 31-25 Arteriovenous Malformation (Not Otherwise Specified)

Clinical Features Present at birth; generally undetected Equally affects both genders Becomes apparent during childhood or adulthood Pulsation, murmur, or both generally present May progress after trauma or hormonal change May be stages according to Schobinger: Stage I: quiescent, asymptomatic Stage II: progression and expansion Stage III: destruction with necrosis and hemorrhage Stage IV: high output cardiac failure Histopathologic Features Ill-defined infiltrative lesion Composed of arteries, veins, arterialized veins, and unclassified vessels Variable capillary component Abnormal vessels evenly distributed, with round or oval contours and relatively thick wall Arteriovenous communications on elastic stains Differential Diagnosis Capillary malformation in AVM quiescent stage Venous malformation

Mitoses, without abnormal figures, may be numerous in the capillary component. Hypervascularization of the subcutaneous fat lobules occurring adjacent to AVM is frequent and may mimic angiolipoma.

ACQUIRED TELANGIECTASIAS

Generalized Essential Telangiectasia  FIGURE 31-51 Arteriovenous malformation. Vessels of different calibers and thicknesses are evenly distributed throughout the affected tissues and are accompanied by variable amounts of fibrosis.

CLINICAL FEATURES This condition most commonly affects adult women and is typified by onset on the lower extremities with subsequent involvement of the trunk, upper extremities, head, and neck.306 Characteristically, there is no evidence of systemic disease or visceral organ involvement. More recently, however, a unique case of generalized essential telangiectasia associated with GI bleeding has been reported.307 HISTOPATHOLOGIC FEATURES The major finding is a dilated capillary vessel in the papillary dermis without inflammation (Fig. 31-53).

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

DIFFERENTIAL DIAGNOSIS Knowledge of the clinical presentation is important in the diagnosis and differential diagnosis of AVM. AVM can be distinguished from more benign acral AVM by the small size and limitation of the latter. Thickness of vessels walls, random distribution in the tissue and, when present, the capillary component allows distinction from VM. Predominance in the superficial dermis and thin walls differentiate CM (PWS) from AVM; however, the nodules that may appear in CM may exhibit thickwalled vessels similar to those in AVM. The differential diagnosis requires the presence of more conventional CM at the periphery of the specimen or knowledge of the clinical presentation.

Secondary Telangiectasias

 FIGURE 31-52 Arteriovenous malformation. The thickness of the vessel walls is generally proportionate to the diameter of the lumen but may vary from one segment to another of the same vessel section.

may be seen, especially on elastin stains. A capillary component is present in some cases, either as ill-defined capillary lobules, especially in the skeletal or

cutaneous muscles, or as sheets of individual or anastomozing capillaries in the dermis. These capillaries may be found even without a history of ulceration.

Secondary causes of telangiectasia are manifold and include conditions such as acne rosacea, varicose veins, trauma, lupus erythematosus, dermatomyositis, scleroderma, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, radiation dermatitis, poikiloderma, xeroderma pigmentosum, chronic sun exposure, and mastocytosis.

Venous Lake A venous lake is an acquired venular ectasia that develops on exposed skin of the head and neck in elderly patients probably from lack of support from the surrounding tissue.308

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HISTOPATHOLOGIC FEATURES The principal finding is a single ectatic vascular structure (usually a venous channel) often containing a thrombus.311 The vascular channel exhibits an unremarkable endothelial lining that is surrounded by a concentric layering of fibrous tissue without smooth muscle or elastic lumina.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other ectatic vascular channels with or without thrombosis such as a venous lake, enlarged and torturous arterial and lymphatic channels, and angiokeratoma.

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Arterial Spider

 FIGURE 31-53 Essential telangiectasia. Telangiectases are present in the superficial dermis.

CLINICAL FEATURES The lesions are often solitary, dark-blue papules 3 to 10 mm in diameter and commonly involve the ears, lips, face, and neck.308 (Table 31-26). PG arising after cryosurgery to a venous lake has been reported.309 HISTOPATHOLOGIC FEATURES The lesion is an ectatic vascular space localized to the superficial to middle dermis and is usually lined by a single layer of endothelium (Fig. 31-54); however, smooth muscle elements may occasionally be associated with the wall of the vessel.308,310 The surrounding dermis usually shows solar elastosis and diminished collagen.

DIFFERENTIAL DIAGNOSIS The lesion is distinctive; however, other vascular ectasias might be considered in the differential diagnosis.

Capillary Aneurysm (or Thrombosed Capillary Aneurysm) CLINICAL FEATURES The lesion usually presents as a solitary bluish papule on the face or trunk, occasionally with itching or tenderness.311 Such lesions may develop slowly or abruptly. Lesions with rapid onset are attributed to occlusion of the vessels by a thrombus. The primary clinical concern in many instances is to rule out melanoma.

Synonyms: Nevus araneus, spider angioma, spider nevus, spider telangiectasis The arterial spider is a common cutaneous lesion often seen as an incidental finding in healthy children.229 Some of these lesions persist into adulthood and may occur as acquired manifestations of pregnancy, hepatic cirrhosis, and thyrotoxicosis.312,313 CLINICAL FEATURES The principal finding is an erythematous central punctum often slightly elevated, pulsatile on diascopy, and the source of an array of peripherally radiating fine vessels. The spider angioma typically blanches with pressure and upon release refills rapidly with blood flow originating from its center. Solitary or multiple arterial spiders occur, and they may be numerous, particularly in chronic liver disease. The most common sites are the face, particularly the upper infraorbital cheeks, neck, trunk, and hands (Table 31-27).

Table 31-26 Venous Lake

Clinical Features Predilection for exposed (“weathered”) skin of elderly individuals—face, ears, lips Dark-blue papule, 3-10 mm, can appear suspicious for melanoma Histopathologic Features Dilated thin-walled vascular channel in dermis Uncommon smooth muscle in wall Occasional intraluminal thrombosis Solar elastosis and lack of supporting dermal collagen Differential Diagnosis Telangiectases Venous malformation

 FIGURE 31-54 Venous lake. A widely dilated, thin-walled vascular channel filled with red blood cells is present in the dermis.

Table 31-27 Arterial Spider

Clinical Features Common in children, young adults, women more than men, individuals with liver disease and thyrotoxicosis Involves face, neck, trunk, and hands Pulsatile red punctum with arborizing channels Blanches with pressure Histopathologic Features Vertically oriented arterial vascular channel in dermis Branching into smaller vessels Differential Diagnosis Telangiectases

DIFFERENTIAL DIAGNOSIS The clinical appearance of the arterial spider, with its pulsatile nature, is distinctive compared with simple telangiectasias. In contrast to the arterial spider, the lesions of HHT, an inherited mucocutaneous disorder that is described above, are numerous and consist of nonpulsatile, punctate, or linear telangiectasias.

Cherry Angioma Synonyms: Senile angioma, Campbell de Morgan spot. The cherry angioma is the most common vascular lesion encountered in the skin in adults. The lesions develop in adults and increase in number with age.229 CLINICAL FEATURES Cherry angiomas often develop in adults beginning in adolescence and are especially common in older adults (Table 31-28).229 They occur at all sites but especially involve the trunk. They present as uniform bright to dull red papules ranging in size from 2 or 3 to 10 mm. Eruptive cherry angiomas have been reported in association with solid organ transplantation; chronic graft-versus-host disease; primary biliary cirrhosis; and exposure to various chemical compounds, including cyclosporine, 2-butoxyethanol (glycol ether solvent), bromides, sulfur mustard gas, and nitrogen mustard.314 HISTOPATHOLOGIC FEATURES Cherry angiomas are usually raised, dome-shaped lesions that exhibit an epidermal collarette.

 FIGURE 31-55 Spider angioma. An arterial vessel is present in the superficial to mid-dermis.

They manifest fairly well-defined lobules composed of thin-walled dilated vascular channels that are largely confined to the papillary dermis (Fig. 31-56). The vascular channels in general are capillary to venular. The vascular lobules

Table 31-28 Cherry Angioma

Clinical Features Prevalent lesion that increases in frequency with age Often multiple involving trunk and extremities Well-defined 2-mm papules Bright red to dusky purple Histopathologic Features Dome shaped Epidermal collarettes Lobular vascular proliferation Lobules containing thin-walled vascular channels, variable cellularity Lobules often separated by fibrous septa Differential Diagnosis Pyogenic granuloma Acral arteriovenous malformation Venous malformation

are separated by fibrous septa that vary in thickness depending on the age of the lesion. DIFFERENTIAL DIAGNOSIS The entities to be considered include PG and BA because of the lobular architecture and epidermal collarettes. Cherry angioma does not show the endothelial proliferation noted in PG or the inflammatory infiltrates of neutrophils, granular debris, and epithelioid endothelium observed in BA.

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

HISTOPATHOLOGIC FEATURES A central arteriole in the superficial dermis (Fig. 31-55) demonstrates branching into smaller anastomosing venules and capillaries.229 Rarely, the wall of the central arterial vessel may contain glomus cells.229

Benign Acquired Vascular Lesions in Irradiated Skin Synonyms: Acquired lymphangiectasies, atypical vascular lesion (proliferation) of the skin, benign lymphangiomatous papules after radiotherapy, lymphangioma circumscriptum, benign lymphangioendothelioma or APL The development of vascular lesions in the irradiated skin of women undergoing radiation therapy for breast or ovarian cancer raises suspicion for high-grade angiosarcoma.315-317 Clinically these lesions appear as solitary or multiple small

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 FIGURE 31-56 Cherry angioma. A dome-shaped lesion contains dilated vascular channels in a vaguely lobular configuration.

papules or reddish to bluish plaques with or without vesicles. Postradiation intervals for the development of such lesions have ranged from 1 to 20 years. A growing body of evidence supports the benign nature of most of these relatively small lesions. However, there is also recent evidence that some of these vascular lesions may be precursors to angiosarcoma. Much more definitive data are needed, however, to clarify the relationship between such atypical vascular lesions and angiosarcoma. HISTOPATHOLOGIC FEATURES These vascular lesions are reasonably circumscribed and confined to the dermis, usually without involvement of the subcutis. However, there are exceptions to the latter characteristics. Two main patterns have been delineated: (1) a pattern composed of dilated lymphatic vessels in the upper dermis, comparable to lymphangioma circumscriptum and designated benign lympangiomatous papule and 2) a pattern characterized by slitlike lymphatic vessels that dissect dermal collagen, reminiscent of APL or THH, and sometimes referred to as atypical vascular proliferation. The abnormal vessels are lined by flat, bland endothelial cells. However, rare lesions exhibit plump endothelial cells with “piling up” of these cells. In addition, thin papillary projections lined by bland endothelial cells or focal micropapillary tufts, reminiscent of Dabska tumor, may often be seen in these peculiar vessels. Inflammatory cells, including rare plasma cells and hemosiderin deposits, may be observed.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes well-differentiated angiosarcoma and patch-stage or lymphangioma-like KS. Angiosarcoma presents generally as large, often multiple, ill-defined lesions with frequent involvement of the subcutis. In addition, angiosarcoma shows well-developed cytologic atypia and multilayering of endothelium. However, the differential diagnosis may be difficult in some cases, and clinicopathologic correlation and long-term surveillance of patients are essential. The clinical presentation of KS is also different. Moreover, KS histologically usually demonstrates areas with spindle cell cytomorphology, and the immunohistochemical expression of HHV-8 is distinctive.

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tures and clinical outcome in 51 cases. Am J Surg Pathol. 1992;16:764-771. Girard C, Graham JH, Johnson WC: Arteriovenous hemangioma (arteriovenous shunt). A clinicopathological and histochemical study. J Cutan Pathol. 1974;1:73-87. Carapeto FJ, Garcia-Perez A, Winkelmann RK: Acral arteriovenous tumor. Acta Derm Venereol. 1977;57:155-158. Connelly MG, Winkelmann RK: Acral arteriovenous tumor. A clinicopathologic review. Am J Surg Pathol. 1985;9:15-21. Kadono T, Kishi A, Onishi Y, et al: Acquired digital arteriovenous malformation: a report of six cases. Br J Dermatol. 2000;142:362-365. Onishi Y, Ohara, K: Angiolymphoid hyperplasia with eosinophilia associated with arteriovenous malformation: a clinicopathological correlation with angiography and serial estimation of serum levels of renin, eosinophil cationic protein and interleukin 5. Br J Dermatol. 1999;140:1153-1156. Kishimoto S, Takenaka H, Shibagaki R, et al: Verruciform xanthoma arising in an arteriovenous haemangioma. Br J Dermatol. 1998;139:546-548. Feinmesser M, Taube E, Badani E, et al: Basal cell carcinomas arising over arteriovenous malformations: some speculations on the theme. Am J Dermatopathol. 1997;19:575-579. Enjolras O, Logeart I, Gelbert F, et al: [Arteriovenous malformations: a study of 200 cases]. Ann Dermatol Venereol. 2000;127:17-22. Kohout MP, Hansen M, Pribaz JJ, et al: Arteriovenous malformations of the head and neck: natural history and management. Plast Reconstr Surg. 1998;102: 643-654. Enjolras O, Mulliken JB: The current management of vascular birthmarks. Pediatr Dermatol. 1993;10:311-333. McGrae, JD, Jr., Winkelmann, RK: Generalized essential telangiectasia:

307.

308. 309. 310. 311. 312.

313.

314.

315.

316.

317.

report of a clinical and histochemical study of 13 patients with acquired cutaneous lesions. JAMA. 1963;185:909-913. Checketts SR, Burton PS, Bjorkman DJ, et al: Generalized essential telangiectasia in the presence of gastrointestinal bleeding. J Am Acad Dermatol. 1997; 37:321-325. Bean WB, Walsh JR: Venous lakes. AMA Arch Derm. 1956;74:459-463. Cecchi R, Giomi A: Pyogenic granuloma as a complication of cryosurgery for venous lake. Br J Dermatol. 1999;140:373-374. Alcalay J, Sandbank, M: The ultrastructure of cutaneous venous lakes. Int J Dermatol. 1987;26:645-646. Epstein E, Novy FG Jr, Allington HV: Capillary aneurysms of the skin. Arch Dermatol. 1965;91:335-341. Li CP, Lee FY, Hwang SJ, et al: Spider angiomas in patients with liver cirrhosis: role of vascular endothelial growth factor and basic fibroblast growth factor. World J Gastroenterol. 2003;9:2832-2835. Henry F, Quatresooz P, Valverde-Lopez, JC, et al: Blood vessel changes during pregnancy: a review. Am J Clin Dermatol. 20067:65-69. Ma HJ, Zhao G, Shi F et al: Eruptive cherry angiomas associated with vitiligo: provoked by topical nitrogen mustard? J Dermatol. 2006;33:877-879. Diaz-Cascajo C, Borghi S, Weyers W, et al: Benign lymphangiomatous papules of the skin following radiotherapy: a report of five new cases and review of the literature. Histopathology. 1999;35:319-327. Requena L, Kutzner H, Mentzel T, et al: Benign vascular proliferations in irradiated skin. Am J Surg Pathol. 2002;26:328337. Gengler C, Coindre JM, Leroux A, et al: Vascular proliferations of the skin after radiation therapy for breast cancer: clinicopathologic analysis of a series in favor of a benign process: a study from the French Sarcoma Group. Cancer. 2007;109:1584-1598.

CHAPTER 32 Tumors of Adipose Tissue, Muscle, Cartilage, and Bone Shady El-Zayaty Thomas Krausz

superficialis. This is also characterized by mature adipose tissue in the dermis but occurs in adults and is not associated with other defects, and the surrounding collagen is normal.

Nevus Lipomatous Superficialis CLINICAL FEATURES Nevus lipomatous superficialis is a rare lesion of young adults most commonly presenting as unilateral lesions on the lower trunk or gluteal region.4 These are skin-colored papules that may coalesce into plaques with a cerebriform surface up to 10 cm

in diameter. Single and multiple lesions occur; multiple lesions occur in younger patients and often are grouped in a zonal distribution on the buttock. Solitary lesions overlap clinically and histologically with fibroepithelial polyps (skin tags). Only rare recurrences are reported. HISTOPATHOLOGIC FEATURES Histologically, variable amounts of mature adipose tissue are present within the papillary dermis (Fig. 32-1). This often is clustered around blood vessels of the superficial dermal vascular plexus, which may be increased in number. The overlying

Tumors of adipose tissue are common in the skin and subcutaneous tissue (Table 32-1). Although most are lipomas, a number of other lesions have been described with distinct clinical and pathologic features. Several of these have worrisome histologic findings that may lead to confusion with liposarcoma. Although liposarcomas are more common in deep soft tissues, liposarcomas of all types may occur superficially, albeit rarely. The prognosis for these tumors depends not only on grade but also on site and age. Recently, characteristic cytogenetic features have been identified in some of these tumors.

Table 32-1 Generalized Approach to Tumors of Adipose Tissue Mature Adipose Tissue No other features Thrombosed capillaries Spindled cells, collagen, myxoid change Floret cells and spindle cells Chondroblast-like cells and lipoblasts Smooth muscle Brown fat Immature Adipose Tissue Young patient Older patient, presence of lipoblasts

Lipoma Angiolipoma Spindle cell lipoma Pleomorphic lipoma Chondroid lipoma Myolipoma Hibernoma Lipoblastoma Liposarcoma

Hamartomas A hamartoma is a focal malformation that is composed of tissue elements normally found at that site, arranged in a disorganized manner. Hamartomas occur in many different parts of the body, including the skin, and are most often asymptomatic. Although generally benign, they can be a cosmetic issue for patients.

Focal Dermal Hypoplasia CLINICAL AND HISTOPATHOLOGIC FEATURES Focal dermal hypoplasia is an X-linked dominant multisystem birth defect affecting tissues of ectodermal and mesodermal origin, due to a defect in the PORCN signaling in the WNT pathway.1 Clinically, it may be associated with anomalies of the skin, skeleton, eyes, and ears.2 It is more common in women. The lesions may appear anywhere as yellow to red nodules in a reticular pattern. Histologically, the dermis is underdeveloped and replaced by mature adipose tissue.3 The surrounding dermal collagen fibers may be smaller than normal. Focal, total absence of skin may be present. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes nevus lipomatous

 FIGURE 32-1 Nevus lipomatous superficialis. A polypoid lesion containing mature adipose tissue that extends into the papillary dermis.

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857

epidermis may be normal, acanthotic, or hyperkeratotic. A variable degree of myxoid change is often seen, and the histologic features of nevus lipomatous superficialis overlap significantly with dermal spindle cell lipomas.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

DIFFERENTIAL DIAGNOSIS When single, differentiation from a skin tag with herniation of adipose tissue may be impossible but is of little clinical significance. Mature dermal melanocytic nevi occasionally can consist largely of “metaplastic” adipose tissue, obscuring the melanocytes. Distinction from focal dermal hypoplasia is discussed in the preceding text.

Benign Neoplasms Benign adipocytic tumors are the largest group of soft tissue tumors, due largely to the prevalence of lipomas. The World Health Organization’s (WHO’s) classification of benign adipocytic tumors will form the framework of this section (Table 32-2). As with their malignant counterpart, our concept of these tumors has been enhanced by recent advances in molecular studies. Diagnosis of these tumors, however, is still largely based on their morphologic and clinical features, rather than genetic aberrations.

Lipoma CLINICAL FEATURES Lipomas are common, with an annual clinical incidence of at least approximately 0.1% of the population.5 They comprise up to 5% of all benign tumors and 25% to 50% of all soft tissue tumors. They are most common in the fifth and sixth decades of life. They occur anywhere but most are subcutaneous. The head and neck, arm, and upper thorax often are affected; lesions of the lower leg and hand are distinctly uncommon. Up to 7% are multiple; the latter are often more common in younger

Table 32-3 Lipoma

Clinical Features Adults Upper body, but wide distribution Histopathologic Features Mature adipose tissue Encapsulated Differential Diagnosis Angiolipoma Lipomatosis ALT/WDL

men.6 Solitary lesions affect men and women equally. Most are smaller than 5 cm in diameter. Fewer than 1% recur; recurrence suggests incomplete excision or possibly a more aggressive lipomatous lesion that has been misdiagnosed.7, 8 HISTOPATHOLOGIC FEATURES Lipomas are composed of lobules of mature adipose tissue enclosed in a thin fibrous capsule (Table 32-3). The adipocytes are uniform in size and appearance (Fig. 32-2). Fibrous tissue and scattered capillaries may also be present. Several histologic variants are recognized depending on the secondary features, such as myxoid change (myxolipoma) (Fig. 32-3) or fibrosis (fibrolipoma). Occasional cases have metaplastic bone or cartilage. Degenerative changes, including foamy macrophages, lymphocytes, myxoid change, and calcification, may be seen. Multiple karyotypic abnormalities have been described, including rearrangement

of chromosome bands 12q13-15, resulting in deregulation of the HMGA2 gene, loss of material from or rearrangement of chromosome 13, and aberrations of chromosome band 6p21.8 DIFFERENTIAL DIAGNOSIS Adipose tissue hypertrophy is similar but lacks the circumscription of a lipoma or a capsule. However, some cases cannot be distinguished histologically. Nodular–cystic fat necrosis is a rare lesion of uncertain origin that may be confused with lipoma. It occurs in adolescent boys and middleaged women, may be related to trauma, and consists of infarcted adipose tissue with well-preserved cell outlines and no nuclei contained within a thin fibrovascular capsule. It may occasionally show degenerative changes, including hyalinized pseudomembranes, which may resemble amyloid, and dystrophic calcifications.9 The lack of nuclei distinguishes it from lipoma. Distinction from other benign adipose tissue tumors is discussed in the following pages. Well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) is the most important lesion to exclude. Liposarcomas are discussed in the following text but in general are defined by the presence of enlarged hyperchromatic cells within irregular fibrous septa or lipoblasts, are often greater than 5 cm in size, and commonly are located in the thigh and retroperitoneum.10

Angiolipoma CLINICAL FEATURES Compared with lipomas, angiolipomas are one-fifth as

Table 32-2 WHO Classification of Benign Adipocytic Tumors

858

Lipoma Lipomatosis Lipomatosis of nerve Lipoblastoma or lipoblastomatosis Angiolipoma Myolipoma Chondroid lipoma Extrarenal angiomyolipoma Spindle cell lipoma or pleomorphic lipoma Hibernoma

 FIGURE 32-2 Lipoma. Uniformly sized adipocytes without atypia.

Spindle Cell Lipoma  FIGURE 32-3 Myxolipoma. Abundant myxoid matrix may obscure the lipogenic nature of the tumor.

common, occur at a younger age (17 to 24 years), are more commonly multiple, and often are painful (Table 32-4).5 They occur most commonly in the forearm or on the trunk but also in similar locations as lipomas. Grossly, they may be firmer than lipomas, usually measure less than 2 cm, and are always subcutaneous. Angiolipomas are benign and cured by simple excision.

pericytes. Fibrin microthrombi are present in almost all cases. Examples in which the vascular component comprises the bulk of the lesion are known as cellular angiolipomas.14 DIFFERENTIAL DIAGNOSIS The normal karyotype of subcutaneous angiolipoma as well as its distinct clinical and morphologic features suggests a different

CLINICAL FEATURES Spindle cell lipoma occurs predominantly as a solitary subcutaneous mass in the shoulder and posterior neck of men between the ages of 45 and 70 years (Table 32-5).13 A significant minority of cases arise on the face. They comprise approximately 1.5% of adipo-cyte lesions and are 1/60th as common as lipoma but 10 times as common as pleomorphic lipoma. 14 Local recurrence is rare. Multiple spindle cell lipomas are rare and may mimic Madelung disease (symmetrical lipomatosis). Familial and nonfamilial cases have been reported, with no risk of

HISTOPATHOLOGIC FEATURES The lesion is encapsulated and composed of mature adipose tissue and a variably prominent capillary network that is often denser at the periphery (Fig. 32-4; see also Table 32-3). The vessels may have a complex branching pattern and prominent

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

pathogenesis from pure lipomas.11 In cases with few capillaries, distinction from lipoma may be difficult. The presence of fibrin thrombi may be helpful. Highly vascular lesions may be confused with hemangioma or even Kaposi sarcoma.12 In contrast to angiolipoma, Kaposi sarcoma has more poorly formed vascular spaces, solid aggregates of spindle cells, and hyaline globules and is poorly circumscribed. In hemangiomas, the capillaries radiate out from a central larger vessel, but in angiolipoma, the capillaries are located peripherally and radiate inward. Spindle cell lipomas with prominent vascularity may be similar but present in older individuals, are solitary, and have organized arrays of spindle cells often associated with hyaline collagen bundles.5,10

Table 32-4 Angiolipoma

Clinical Features Young adults Painful, often multiple Upper body Histopathologic Features Mature adipose tissue Capillaries (mainly peripheral) Fibrin thrombi Differential Diagnosis Lipoma Hemangioma Angiomyolipoma

 FIGURE 32-4 Angiolipoma. Numerous vascular channels are present mostly at the periphery of the tumor, some with microthrombi, admixed with adipocytes.

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Table 32-5 Spindle Cell Lipoma

Clinical Features Men Subcutaneous Shoulders, upper back, face Histopathologic Features Mature adipose tissue Bland spindle cells Ropey collagen Mucinous background Mast cells Differential Diagnosis Pleomorphic lipoma Neurofibroma ALT/WDL Solitary fibrous tumor

progression to liposarcoma.15 Both spindle cell and pleomorphic lipomas show karyotypic aberrations of 16q and 13q.14 HISTOPATHOLOGIC FEATURES Grossly, the lesions are circumscribed and average 4 cm in size (range, 1-14 cm). Histologically, they are usually well demarcated and composed of variable amounts of mature adipose tissue, uniform spindle cells in a myxoid matrix, and thick (ropey) bundles of refractile collagen (Fig. 32-5). 16 Cases with little to no

adipose tissue occur and are often mistaken for benign nerve sheath tumors.17 The spindle cells are small, with a single elongated nucleus and slender bipolar cytoplasmic processes. These cells stain positively for CD34 and are often oriented along bundles of collagen or form very short fascicles that are interspersed with the adipocytes. Mitoses are rare. It must be emphasized that otherwise typical spindle cell lipomas may contain lipoblasts. Cases with increased vascular areas and marked pseudoangiomatous degeneration have been described.18 Exceptional cases may contain bone or cartilage. When multiple spindle cell lipomas occur, the tumors become more cellular as the disease progresses, often with features of pleomorphic lipoma.15 Although pleomorphic cells are not present in classic spindle cell lipomas, it is well recognized that spindle cell and pleomorphic lipomas comprise a histologic spectrum of a single biologic entity. As such, hybrid lesions are not uncommonly encountered. DIFFERENTIAL DIAGNOSIS The characteristic age, gender, and site are very helpful in making the diagnosis. Heavily vascular cases may be mistaken for angiolipoma. Classic pleomorphic lipoma is distinguished by the presence of large bizarre cells, cells with multiple nuclei in a floretlike pattern, and occasional lipoblasts.

As mentioned previously, cases with a prominent spindle cell component may be confused with neurofibroma. However, in spindle cell lipoma, the nuclei are not as wavy, and the spindle cells are S-100 protein–negative (the adipocytes can be positive). Cases with a prominent myxoid background may be mistaken for myxoid liposarcoma. However, spindle cell lipoma has very monotonous spindle-shaped cells and abundant thick collagen, lacks the characteristic “chicken wire” vascular pattern, and usually lacks lipoblasts. Cellular cases may be mistaken for well-differentiated or sclerosing liposarcoma. WDL may contain thick bundles of collagen but has a less uniform appearance, with large atypical cells clustered around fibrous septa. Finally, very cellular lesions may resemble solitary fibrous tumor. Solitary fibrous tumors may contain mature adipose tissue and exhibit a similar immunohistochemical profile (so-called lipomatous hemangiopericytoma).19,20 However, spindle cell lipoma lacks the characteristic staghornlike vessels of solitary fibrous tumor. In addition, the spindle cells of solitary fibrous tumor are more often curved rather than straight, do not form discrete fascicles, and are often less associated with either ropey collagen or a myxoid background.

Pleomorphic Lipoma CLINICAL FEATURES Pleomorphic lipoma, similar to spindle cell lipoma, occurs principally in the neck, upper back, and shoulders of men in the fifth to seventh decades of life (Table 32-6).21,22 It is located in the subcutis almost exclusively. Twenty-five percent of cases have areas resembling spindle cell lipoma, and essentially, these lesions form a morphologic

Table 32-6 Pleomorphic Lipoma

860

 FIGURE 32-5 Spindle cell lipoma. Bland spindled cells arranged in short bundles admixed with adipocytes and characteristic ropey collagen.

Clinical Features Men Subcutaneous Shoulders, upper back, face Histopathologic Features Mature adipose tissue Bland spindle cells Floret cells Rare lipoblasts Differential Diagnosis Spindle cell lipoma ALT/WDL Solitary fibrous tumor

continuum. Both spindle cell and pleomorphic lipomas show similar karyotypic aberrations of 16q or 13q.23 Despite the worrisome cytologic features, pleomorphic lipomas are benign.

Chondroid Lipoma CLINICAL FEATURES Chondroid lipoma is a rare and distinctive tumor..24 It occurs more commonly in women over a wide age range and a variety of sites. The tumors are well circumscribed (1-11 cm)

A

and located subcutaneously, within fascia, or intramuscularly. Whether these tumors show true chondroid differentiation is controversial but unlikely. To date, no recurrences or metastases have been reported. HISTOPATHOLOGIC FEATURES A mixture of mature adipose tissue interspersed with nests of round, uni- and multivacuolated cells within a basophilic myxoid background are found (Fig. 32-7). The vacuolated cells often have a prominent cytoplasmic border resembling chondroblasts.5 In some areas, the vacuolated cells form cords superficially resembling myxoid chondrosarcoma. In addition, admixed with these cells are typical multivacuolated lipoblasts. Mitoses are rare. Chondroid lipoma is highly vascular and may exhibit degenerative changes, including hemorrhage, fibrosis, and inflammation. Wellformed cartilage is not seen. Periodic acidSchiff (PAS) stains reveal intracellular glycogen; the tumors are reactive for S-100 protein, CD68, and vimentin. DIFFERENTIAL DIAGNOSIS The pathologic features of chondroid lipoma are unique. Chondromas of soft tissue lack adipose tissue and have mature hyaline cartilage as well as multinucleated giant cells. Mixed tumors may contain fat, but they also contain keratin-positive myoepithelial cells that often form glands and epithelial cords. Myxoid liposarcoma is distinguished by its characteristic vasculature, uniform myxoid background, and lack of vacuolated chondroblast-like cells. Limited cytogenetic data suggest that whereas chondroid lipoma is characterized by t(11;16)(q13;p12-13), myxoid liposarcoma have a typical t(12;16) (q13;p11) translocation.25 Lesions without mature fat may be confused with extraskeletal myxoid chondrosarcoma, but the tumor cells of extraskeletal myxoid chondrosarcoma are smaller, more uniform and round, and lack the extensive cytoplasmic vacuolization. Extraskeletal myxoid chondrosarcomas are also typically large lesions that display prominent hemorrhage. In addition, they display the chromosomal aberration t(9;22), which is not seen in chondroid lipoma.

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

HISTOPATHOLOGIC FEATURES Grossly, the lesions are well circumscribed, range from 1 to 12 cm in diameter (average, 4 cm), and resemble lipomas. Histologically, they are circumscribed and characteristically have a mixture of variably sized fat cells with a varying number of pleomorphic enlarged cells (Fig. 32-6; see also Table 32-5). These cells contain moderate amounts of eosinophilic cytoplasm, are often multinucleated, and often have nuclei arranged in a circumferential pattern that has resulted in the term floret cell. The chromatin can be fine or smudgy and hyperchromatic. Rare lipoblasts, with cytoplasmic vacuoles indenting the nucleus, can also be found. Scarce mitoses may be present, but necrosis is not observed.

DIFFERENTIAL DIAGNOSIS They may be distinguished in general from liposarcoma by their typical location, numerous floret cells greatly outnumbering any lipoblasts, and the absence of necrosis. In addition, in well-differentiated or sclerosing liposarcoma, the atypical cells and lipoblasts are concentrated along fibrous septa and are seen in association with hyperchromatic bizarre stromal cells. Pleomorphic liposarcoma has numerous lipoblasts and lacks floret cells. The atypical cells in pleomorphic liposarcoma are so numerous that they form sheetlike masses rather than being scattered between adipocytes.

Myolipoma B  FIGURE 32-6 Pleomorphic lipoma. Mature adipocytes and multinucleated floret-like giant cells. The background may exhibit abundant ropey collagen and rare mature adipocytes (A), or may be variably myxoid (B).

CLINICAL AND HISTOPATHOLOGIC FEATURES Myolipoma is an uncommon neoplasm occurring in adults but only infrequently arising in subcutaneous tissue.26 Although deep lesions have reached 25 cm in diameter, subcutaneous lesions were

861

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 862

 FIGURE 32-7 Chondroid lipoma. Vacuolated cells simulating lipoblasts arranged in nests admixed with adipocytes within a myxochondroid matrix.

solitary fibrous tumor with mature adipose tissue. The spindle cells of spindle cell lipoma have scant cytoplasm and a myxoid background and are not immunoreactive for actin or desmin. WDLs (atypical lipomatous neoplasms) may have a smooth muscle component (lipoleiomyosarcoma) but these would also exhibit nuclear atypia or lipoblasts.27 Smooth muscle hamartoma may closely resemble this lesion but is usually dermal and congenital. Leiomyomas with fatty infiltration have long, regular fascicles but are unusual outside of the uterus and rarely have such diffuse infiltration with fat. Hemangiopericytoma with adipose tissue does not form fascicles and is desmin negative.20 Lipoblastomatosis exhibits infiltration of adjacent muscle at the periphery. Those that have undergone maturation lack significant lipoblasts and may be composed entirely of mature adipose, mimicking myolipoma. The age of the patient and the presence of an adjacent conventional lipoblastoma are helpful in this instance.

Angiomyolipoma smaller (~5 cm) and well circumscribed. The tumor is an intimate mixture (in varying proportions) of mature adipose tissue interspersed with well-differentiated smooth muscle, resembling a sieve (Fig. 32-8). The muscle cells form only short, irregular fascicles, in contrast to the long fascicles present in leiomyomas.

The smooth muscle is reactive for both actin and desmin. No recurrences have been reported.5 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes spindle cell lipoma, liposarcoma, smooth muscle hamartoma, leiomyomas with fatty infiltration, and

 FIGURE 32-8 Myolipoma. Admixture of mature adipocytes and smooth muscle.

Angiomyolipomas are deeply seated lesions that usually occur in the kidney but rarely may be located in other organs or in deep soft tissue. Approximately half are associated with tuberous sclerosis. The tumor is a member of the PEComa family, which is a group of related mesenchymal neoplasms that include angiomyolipoma, lymphangiomyomatosis, and clear cell “sugar” tumor of the lung. These tumors all share a distinctive cell type—the perivascular epithelioid cell, which has no known normal tissue counterpart.28 Angiomyolipomas exhibit a distinctive triphasic histology, with thickwalled blood vessels, lipid-distended tumor cells (so-called adipocytes), and epithelioid to spindled cells (Fig. 32-9). The epithelioid, spindled, and lipid-distended cells have a distinctive “myomelanocytic” immuno-phenotype with coexpression of smooth muscle actin and melanocytic markers such as HMB-45 or Melan-A. Some early reports of extremity angiomyolipomas in the literature may represent mixed smooth muscle and adipocytic neoplasms, such as myolipoma, rather than PEComas based on provided illustrations and the absence of documented HMB-45 positivity.29-31 Recently, however, several bona fide cases of PEComas involving the extremities have been reported.28,32-34 These occur predominately in the lower extremities of females, with rare incidence of malignant transformation.35

DIFFERENTIAL DIAGNOSIS Although angiomyolipoma is characterized by a triphasic histology, occasionally, one of these components may predominate with exclusion of one ore more other elements. This may give the tumor a biphasic, or rarely monophasic, appearance. Immunohistochemical staining for melanocytic markers can be useful in this instance.

(mean, 10 cm). Occasional examples are intramuscular. These tumors are benign. HISTOPATHOLOGIC FEATURES The tumor usually has a yellow-brown, lobulated cut surface.5 Three cell types are present. Intermediate-sized polygonal cells with

DIFFERENTIAL DIAGNOSIS Diagnosis is usually straightforward. Focal areas of brown fat can be present in an otherwise typical mature lipoma. Hibernomas may be mistaken for liposarcomas, but the uniformity of the lesion, lack of mitoses, lack of atypia, and (most important) lack of true lipoblasts (defined by their indented hyperchromatic nuclei) argue against the diagnosis. Granular cell tumors

Hibernoma CLINICAL FEATURES Hibernomas are tumors of brown fat.36 They arise usually in young to middle-aged adults (average age, 36 years) and are commonly located in the thigh, shoulder, and axilla (Table 32-7). They are most often subcutaneous, well circumscribed, and measure up to 19 cm in diameter

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

 FIGURE 32-9 Angiomyolipoma. Typical triphasic histology exhibiting mature adipocytes, smooth muscle, and thick-walled blood vessels.

abundant granular, eosinophilic cytoplasm, and centrally placed nuclei are often most common (see Table 32-6). Slightly larger cells with multiple cytoplasmic vacuoles that do not indent the centrally placed nucleus are also present. The third cell type resembles a mature adipocyte with a large, solitary vacuole displacing the nucleus off to the side (Fig. 32-10). Four histologic variants are recognized. The typical hibernoma is composed of the aforementioned three cell types in varying proportions. The lipoma-like variant consists of only scattered hibernoma cells among white fat. The spindle cell variant combines the features of hibernoma and spindle cell lipoma. Last, the myxoid variant exhibits hibernoma cells in a myxoid matrix. The importance of these variants lies only in their recognition, not in their clinical behavior.37 The ultrastructural features differ from those of mature adipose tissue and include abundant mitochondria, basal lamina, and micropinocytotic vesicles.

Table 32-7 Hibernoma

Clinical Features Young adults Upper back Histopathologic Features Granular cells Vacuolated cells Mature adipose tissue Differential Diagnosis Lipoma

 FIGURE 32-10 Hibernoma. Mixture of granular eosinophilic cells, multivacuolated cells, and mature adipocytes.

863

and adult rhabdomyomas do not contain adipocytes.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Multiple Symmetric Lipomatosis (Madelung Disease) Multiple symmetric lipomatosis is characterized by unencapsulated masses of adipose tissue symmetrically located in the neck, shoulders, chest, abdomen, groin, or buttocks.38,39 These lesions arise in subcutaneous tissue but spread deeply. Although generally asymptomatic, compression of airways and vital organs has been described. This condition is most common in adult men (20-52 years) and may be familial. Histologically, the adipocytes are said to be smaller than normal and relatively uniform in size. Definitive diagnosis requires clinical correlation.

Lipoblastoma or Lipoblastomatosis CLINICAL FEATURES Lipoblastoma or lipoblastomatosis is rare and occurs almost exclusively in children younger than 7 years old, predominantly in those younger than age 3 years.40 Boys are affected more commonly (2:1). The lesions can be localized or diffuse and usually occur in the extremities. Localized forms are termed lipoblastoma and diffuse forms lipoblastomatosis. In subcutaneous sites, localized lobulated lesions smaller than 5 cm in diameter are most common. Although 15% to 20% of lesions recur (usually of the diffuse type), no metastases or deaths have been reported. HISTOPATHOLOGIC FEATURES Histologically, the lesions mimic and may be almost identical to well-differentiated or myxoid liposarcomas (Table 32-8). At low power, the tumor is distinctly lobulated or nested (Fig. 32-11). At high power, numerous lipoblasts, a rich plexiform

Table 32-8 Lipoblastoma

864

Clinical Features Children Boys > girls Extremities Localized or diffuse Histopathologic Features Lipoblasts Lobular growth pattern Mature adipose tissue Differential Diagnosis ALT/WDL

 FIGURE 32-11 Lipoblastoma. Fibrous septae dividing the fatty tumor into lobules with varying degrees of maturation.

capillary network, and a myxoid matrix resemble myxoid liposarcoma. Lesions with mature adipocytes interspersed with lipoblasts and spindled or stellate mesenchymal cells resemble WDL. In general, however, nuclear atypia is absent in contrast to that in liposarcoma. Maturing lipoblastomas display few lipoblasts but still have distinct lobularity and possibly increased vascularity.41 Fibrous septa may be pronounced. Signet ring and multivacuolated lipoblasts are both present. In contrast to liposarcomas, rearrangements of chromosome 8 are often found cytogenetically.42 Although lipoblastomas are asymptomatic and lack metastatic potential, they may cause dysfunction of other organ systems due to mass effect. Complete surgical excision with clinical follow-up is the preferred therapy.43 DIFFERENTIAL DIAGNOSIS The primary differential diagnosis is with WDL/ALT. Liposarcoma is rare in children, and the diagnosis must be made with caution. Liposarcomas in children occur at an older age, are more common in girls, are often located in the thigh, and usually involve deep soft tissues rather than subcutaneous sites.44 Histologically, they are less uniformly lobular than lipoblastoma, often show increased cellularity at the periphery of tumor lobules, and have more nuclear atypia. As previously mentioned, lipoblastomas exhibit maturation with time. Cytogenetic analysis may be of value in difficult cases.

Malignant Neoplasms Malignant adipocytic tumors as a group exhibit considerable morphologic and genetic heterogeneity. Histologic observation and genetic studies over the past decade have been successfully integrated. This has resulted in significant changes to the way these tumors are categorized, as reflected in the most recent WHO classification (Table 32-9). New concepts regarding their relationship to one another as well as their biologic potential pose controversial questions and are a source of considerable debate.

Liposarcoma Liposarcoma is the most common soft tissue sarcoma in adults and accounts for approximately 20% of all mesenchymal malignancies.45 Liposarcomas are most common in deep soft tissues, especially the thigh and retroperitoneum;

Table 32-9 WHO Classification of Malignant Adipocytic Tumors ALT/WDL Myxoid liposarcoma Round cell liposarcoma Pleomorphlic liposarcoma Dedifferentiated liposarcoma Mixed-type liposarcoma

Well-Differentiated Liposarcoma/Atypical Lipomatous Tumor WDL of deep soft tissues is a wellrecognized entity. When the same lesion occurs subcutaneously or in an intramuscular location, the preferred term is ATL. This distinction is made to indicate the markedly better prognosis of the latter, perhaps related to earlier detection and easier wide excision.49,50 However,

A

Table 32-10 Atypical Lipomatous Tumor/ Well-Differentiated Liposarcoma

Clinical Features Adults Proximal extremities (for atypical lipomatous tumor) Histopathologic Features Mature adipose tissue with variably sized adipocytes Hyperchromatic stromal cells Lipoblasts Differential Diagnosis Lipoma Pleomorphic lipoma Lipoblastoma

both terms describe lesions identical both morphologically and karyotypically, thus the different terms are essentially synonyms. Terminologic preference depends heavily on liaison between surgeon and pathologist, and in most instances we prefer to use both terms in the histology report. In this chapter we will use the term ALT/WDL. CLINICAL FEATURES WDL occurs in adults of either gender, mainly in the fourth to eighth decades of life (Table 32-10). Subcutaneous tumors are well circumscribed, 2 to 20 cm in diameter (mean 10 cm), and have a predilection for the upper and lower limb girdles. In subcutaneous lesions, recurrence is relatively infrequent. Metastases do not occur in an otherwise conventional well-differentiated liposarcoma. However, dedifferentiation may

take place with subsequent metastatic potential in deep, and rarely superficial, lesions.51 HISTOPATHOLOGIC FEATURES Histologically, these lesions superficially resemble lipomas. However, the adipocytes vary in size, and fibrous septae containing hyperchromatic pleomorphic stromal cells are often present. A varying number of monovacuolated or multivacuolated lipoblasts may be seen (Fig. 32-12). It is important to emphasize that the presence of lipoblasts does not make, and is not required, for a diagnosis of liposarcoma. Lipoblasts are strictly defined by the presence of single or multiple discrete, optically clear, round and sharply demarcated cytoplasmic vacuoles that indent an enlarged hyperchromatic nucleus. When these atypical cells are identified among the adipocytes, the term lipoma-like liposarcoma is used. When the atypical cells are associated with a predominant diffuse pattern of fine fibrosis and a relatively sparse adipocytic component, the term sclerosing liposarcoma is used. Some tumors have areas with spindle cells and have been termed spindle cell liposarcoma.52 Cytogenetically, WDLs are associated with a ring or giant chromosome derived from the long arm of chromosome 12q13-15, leading to amplification of the protooncogenes MDM2 and CDK4.53,54 DIFFERENTIAL DIAGNOSIS It must be emphasized that a number of entirely benign adipocytic tumors, such as lipoblastoma and pleomorphic lipoma, may contain lipoblasts. Thus, the presence of

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

however, they also occur, albeit relatively infrequently, in subcutaneous sites and rarely even in the dermis.46 The current WHO classification includes one neoplasm in the intermediate category and five categories of malignant fatty neoplasms with incorporation of relevant genetic findings.47 The solitary entity within the intermediate (locally aggressive) category is ALT/WDL. Five distinct variants are recognized in the malignant category: myxoid liposarcoma, round cell liposarcoma, pleomorphic liposarcoma, dedifferentiated liposarcoma, and mixed liposarcoma.10 Despite this formal segregation, functionally, it is convenient to regard them as kindred entities, with dedifferentiated liposarcoma representing a unique biologic event occurring exclusively within ALT or WDL and myxoid or round cell liposarcoma representing a spectrum of the same entity. Taken together, most series show a male predominance and a mean age of 50 years (range, 30-80 years).48 However, myxoid or round cell tumors tend to occur 10 years earlier than welldifferentiated and pleomorphic tumors.

B

 FIGURE 32-12 Well-differentiated liposarcoma or atypical lipomatous tumor. (A) A variably-sized adipocytes with scattered hyperchromatic stromal cells. (B) A single multivacuolated lipoblasts (center of the field), hyperchromatic stromal cells, and adipocytes.

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lipoblasts does not equate to a diagnosis of malignancy.45 With this in mind, the differential diagnosis includes benign, reactive, and malignant processes. The differential diagnosis includes lipoma, pleomorphic lipoma, spindle cell lipoma, lipoblastoma, xanthomatous reactions, fat necrosis, diffuse neurofibroma, and dermatofibrosarcoma protuberans (DFSP). The hyperchromatic stromal cells distinguish this tumor from a lipoma. Pleomorphic lipomas have a rather well-defined clinical context (see the preceding text), and floret cells are usually noted rather than the smudgy atypical cells observed in WDL. Spindle cell lipomas have distinctive ropey (thick bundles of) collagen and usually lack lipoblasts. Lipoblastomas may be identical but generally occur in children younger than 7 years of age, when the diagnosis of liposarcoma is rare, indeed. Xanthomatous reactions have numerous foamy cells rather than cells with large, fat vacuoles (adipocytes); are associated with inflammation; and lack atypia. Likewise, fat necrosis shows aggregates of foamy histiocytes and lacks atypia. Spindle cell liposarcoma may be confused with either diffuse neurofibroma or DFSP. Recognition of the atypical adipocytes is most important for the correct diagnosis. Immunoreactivity for S-100 protein in neurofibroma and CD34 in DFSP may be helpful. Detection of MDM2-CDK4 amplification by varying techniques, including fluorescence in situ hybridization, immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR), may be helpful in difficult cases.53

A

B  FIGURE 32-13 Dedifferentiated liposarcoma. (A) Abrupt transition from well-differentiated liposarcoma/atypical lipomatous tumor (right) to a dedifferentiated liposarcoma (left). (B) The dedifferentiated component is nonlipogenic. Immunohistochemistry for MDM2 is confirmatory (inset).

Dedifferentiated Liposarcoma CLINICAL FEATURES Dedifferentiated liposarcoma usually presents as a longstanding, painless mass exhibiting a recent increase in size.10 Dedifferentiation may occur in either the primary tumor (90%) or in a recurrence (10%) generally in deep soft tissues, though rarely in superficial anatomic sites.55 Although up to 50% recur and at least 15% metastasize, patients with these dedifferentiated tumors may have a better prognosis than patients with other “pleomorphic” sarcomas, even in the presence of heterologous differentiation.56 HISTOPATHOLOGIC FEATURES Dedifferentiated liposarcoma is a malignant adipocytic neoplasm that morphologically exhibits an abrupt transition from WDL to nonlipogenic sarcoma (Fig. 32-13). The dedifferentiated component is often a high-grade sarcoma

but may also be a low-grade spindle cell or myxoid sarcoma. Some are composed mainly of dedifferentiated areas with a largely obscured or absent a welldifferentiated component. The dedifferentiated component may display heterologous differentiation, generally toward rhabdomyosarcoma, osteosarcoma, or chondrosarcoma. Recently, the degree of cellularity and mitotic activity required for the diagnosis of dedifferentiation has come under question. Traditionally, dedifferentiated liposarcoma consists of a combination of WDL and a cellular nonlipogenic sarcoma having significant mitotic activity (at least 5 mitotic figures per 10 highpower fields [hpf]).57 A diagnostic dilemma arises when WDLs contain areas whose cellularity and mitotic rate are increased but lower than in the classically defined dedifferentiated component of dedifferentiated liposarcoma. Although some

consider this finding to represent “lowgrade dedifferentiation,” this term has come under recent scrutiny because it has no effect on patient survival and may be best regarded as part of the spectrum of findings within ALT/WDL.58,59 DIFFERENTIAL DIAGNOSIS Several studies have shown that many sarcomas previously diagnosed as malignant fibrous histiocytomas, fibrosarcomas, and malignant hemangiopericytomas likely represented dedifferentiated liposarcomas.60,61 This serves to underscore the wide morphologic spectrum of dedifferentiated liposarcoma and the subsequent need to include this entity when considering the differential diagnosis of many malignant mesenchymal neoplasms. The potential for heterologous differentiation within dedifferentiated liposarcoma further complicates this matter. Those with more low-grade appearance may

be confused for leiomyosarcoma and dermatofibrosarcoma, but those with more high-grade histology should be differentiated from pleomorphic rhabdomyosarcoma and metastatic melanoma. Identification of a well-differentiated component or immunohistochemistry for MDM2 and CDK4 can be key to the diagnosis.62

Myxoid Liposarcoma

HISTOPATHOLOGIC FEATURES Pure myxoid liposarcoma consists of a uniform myxoid matrix, a characteristic “chicken wire”–like plexiform capillary network; numerous small relatively bland spindle cells; and a variable number of small lipoblasts, commonly of signet ring or bivacuolated type (Fig. 32-14 and

A

Clinical Features Adults Proximal extremities (for atypical lipomatous tumor) Histopathologic Features Mature adipose tissue Myxoid matrix Lipoblasts, often signet ring–like Chicken wire–like capillary network Differential Diagnosis Myxofibrosarcoma

Table 32-11). The most characteristic feature is the capillary network. The capillaries are evenly spaced, thin-walled, and slightly curved. Frequently, the myxoid matrix may coalesce to form acellular pools with an alveolar appearance. Round cell change in myxoid liposarcoma is characterized by a significant increase in cellularity, with nuclear overlapping and obscuring of the capillaries (Fig. 32-14B). The cells are smaller than adipocytes and have enlarged hyperchromatic nuclei and prominent nucleoli. The cytoplasm may be scant or vacuolated. Despite the aggressive nature of the lesion (including eventual metastasis in more than 50% of patients), mitoses are usually sparse. Myxoid liposarcoma may display areas of increased cellularity in which the cells remain spindled, do not have overlapping nuclear borders, and retain an easily discernible plexiform

vascular pattern. This histologic finding, termed transitional areas, should not be confused for a round cell component because it carries no effect on prognosis.63,66 Pure round cell liposarcoma is a rare neoplasm in which round cell differentiation accounts for more than 80% of the tumor.45 Cytogenetically, myxoid or round cell liposarcoma almost always has a t(12;16) (q13;p11) translocation that fuses the transcription factor gene CHOP on chromosome 12 to the TLS/FUS gene on chromosome 16.67 Rarely, a t(12;22) translocation linking the EWSR1 gene with the DDIT3 gene occurs.68 DIFFERENTIAL DIAGNOSIS Myxoid liposarcoma may be confused with soft tissue myxoma, superficial angiomyxoma, and myxofibrosarcoma. Myxomas are less cellular, lack the vascular network, and do not contain lipoblasts. Angiomyxomas lack lipoblasts and are characterized by numerous isolated vessels rather than a plexiform network of capillaries. Myxofibrosarcoma, similar to myxoid liposarcoma, is characterized by a prominent vascular network and spindle cells. However, the vessels are not as profuse and are typically thicker and straighter than those in myxoid liposarcoma, and the spindle cells are more atypical in myxofibrosarcoma. In addition, lipoblasts are not present, and the lesion often has a distinctly multinodular growth pattern. When a tumor is purely round cell, the diagnosis may be very difficult and requires a thorough search for lipoblasts. This type of liposarcoma also distinctively shows S-100 protein

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

CLINICAL FEATURES The clinical presentation of myxoid liposarcoma is similar to that of WDL, although it usually occurs at an earlier age and arises in the lower limb (particularly the thigh) in the vast majority of cases. Similar to WDL, pure myxoid liposarcoma is a low-grade tumor. Myxoid liposarcoma is unique in that metastases tend to occur in unusual soft tissue sites, such as the extremities and chest wall, rather than the visceral organs. Transformation to a higher-grade lesion with a variably prominent round cell component may occur (round cell liposarcoma), conferring a poorer prognosis.63,64 The quantity of round cell differentiation has prognostic significance, with tumors exhibiting 5% to 25% round cell component displaying a lower rate of metastasis than those exceeding 25% (metastasis rate, 35% versus 58%).65

Table 32-11 Myxoid Liposarcoma/Round Cell Liposarcoma

B

 FIGURE 32-14 Myxoid liposarcoma. (A) Arborizing “chicken wire” vasculature and bland mesenchymal cells characterize the typical myxoid liposarcoma. No lipoblasts are seen in this field. (B) Nodules of round cell differentiation (round cell liposarcoma) confer a poor prognosis. A few lipoblasts can be identified.

867

Table 32-12 Pleomorphic Liposarcoma

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Clinical Features Adults Deep soft tissues Histopathologic Features Pleomorphic cells Spindle cells Lipoblasts Differential Diagnosis Myxofibrosarcoma Pleomorphic lipoma Pleomorphic rhabdomyosarcoma

868

positivity in the nonlipogenic cells in most cases. Fluoresence in situ hybridization may be useful in diagnostically challenging cases.69

Pleomorphic Liposarcoma CLINICAL AND HISTOPATHOLOGIC FEATURES Pleomorphic liposarcomas are the least common type of liposarcoma, they occur most often in elderly individuals, and subcutaneous examples are especially rare (Table 32-12). These tumors generally exhibit three morphologic pictures: a high-grade pleomorphic spindle cell sarcoma containing scattered multivacuolated lipoblasts, a cellular neoplasm containing sheets of bizarre pleomorphic monovacuolated as well as multivacuolated lipoblasts (Fig. 32-15), and an epithelioid variant composed of sheets of pleomorphic epithelioid cells with distinct cell borders.70 The prognosis for patients with dermal pleomorphic liposarcomas appears to be substantially better than that of patients with more deeply seated lesions, based on a small number of reported cases.46 Cytogenetically, the majority of pleomorphic liposarcomas display complex karyotypes.71 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other pleomorphic high-grade sarcomas, such as pleomorphic rhabdomyosarcoma. The identification of lipoblasts is key. The epithelioid morphology in these pleomorphic tumors may closely simulate other malignant epithelial neoplasms, mainly adrenal cortical carcinoma.72 In this context, immunohistochemical stains must be interpreted prudently because overlap between these two entities may be seen, with focal expression of Melan-A and pan-keratin. Inhibin immunoreactivity, however, has not been reported in pleomorphic liposarcoma.72 The immunohistochemical profile of pleomorphic

 FIGURE 32-15 Pleomorphic liposarcoma. Numerous pleomorphic multivacuolated lipoblasts.

liposarcoma in nonlipogenic regions is heterogeneous; however, reactivity with S-100 protein in lipoblasts also may be helpful.73,74

TUMORS OF MUSCLE

Smooth Muscle Smooth muscle tumors occur mainly but not exclusively in adults (Tables 32-13 and 32-14). Determining the prognosis of these lesions may be a difficult task for the pathologist. Prognosis is very dependent on site. Extremely bland lesions in

Table 32-13 WHO Classification of Smooth Muscle Tumors Angioleiomyoma Deep leiomyoma Genital leiomyoma Leiomyosarcoma

Table 32-14 Generalized Approach to Tumors of Smooth Muscle Smooth Muscle No other features Vessels Mitoses, necrosis, atypia

Leiomyoma Angioleiomyoma Leiomyosarcoma

some sites may still carry a risk for recurrence, although this may occur late.

Congenital Smooth Muscle Hamartoma CLINICAL AND HISTOPATHOLOGIC FEATURES Smooth muscle hamartoma of the skin is a rare congenital lesion presenting in children up to 18 years old.75,76 Clinically, they are most common on the torso; measure up to 10 cm in diameter; and may or may not occur in association with Becker nevus (melanosis), an epidermal hamartoma exhibiting hyperpigmentation and hypertrichosis. Histologically, the lesion is composed of well-ordered noncohesive fascicles of smooth muscle arranged in various directions within the dermis and subcutaneous tissue (Fig. 32-16). Adipocytes may also be present unusually high in the dermis. There may be an artifactual cleft between the lesion and the surrounding dermis. DIFFERENTIAL DIAGNOSIS Diagnostically, the lesion may be associated with or distinct from Becker nevus, which may have similar smooth muscle hyperplasia. However, Becker nevus is usually not congenital, and the distinction is primarily clinical. Leiomyomas are also composed of smooth muscle, but the muscle bundles tend to form a single mass; in hamartoma, the bundles are discrete and surrounded by ordered collagen.

 FIGURE 32-16 Congenital smooth muscle hamartoma. Irregularly arranged smooth muscle bundles in the reticular dermis are interspersed with collagen, adipocytes, and adnexae.

Leiomyoma CLINICAL FEATURES Smooth muscle tumors of the skin and subcutaneous tissues are uncommon and can be divided into pure leiomyomas and those arising in association with vascular structures, namely angioleiomyomas.77 Pure leiomyomas have no gender preference and generally arise in early adulthood. They can be separated into those that arise in the skin and those associated with the external genitalia (including the nipple, vulva, and scrotum). Leiomyomas of the skin arise from the erector pilae muscles and tend to occur on the extensor surface of the extremities and the trunk (Table 32-15). They are often multiple, painful, firm reddish-brown papules or nodules, commonly smaller than 2 cm in diameter. Familial leiomyomatosis, in which multiple cutaneous and uterine leiomyomas occur, is an autosomal dominant condition, with a predisposition to an aggressive form of renal cell carcinoma.78 Nipple lesions are similar and arise from areolar smooth muscle. Genital leiomyomas arise from dartos or vulvar smooth muscle. They are solitary, painless, wellcircumscribed masses that may grow up to 15 cm in diameter and may be located in the subcutaneous tissue.77

Separation of dermal and genital leiomyomas is most important for prognosis. Small, solitary dermal leiomyomas tend not to recur. Patients with multiple dermal leiomyomas often experience recurrence (50%) and tend to develop subsequent lesions. Patients with genital leiomyomas tend usually to be disease free after 5 years of follow-up, but longer follow-up has shown the development of recurrences after periods as long as 15 years.79

Table 32-15 Pilar Leiomyoma

Clinical Features Adults Skin, nipple Painful, often multiple Histopathologic Features Fasiculated Spindle shaped (sometimes epitheloid) Boxcar-shaped nuclei Eosinophilic cytoplasm Differential Diagnosis Leiomyosarcoma Benign fibrous histiocytoma Dermatofibrosarcoma protuberans

DIFFERENTIAL DIAGNOSIS The differential diagnosis for these lesions includes dermatofibroma, DFSP, neurofibroma, fibromatosis, and leiomyosarcoma. Dermatofibroma is less fascicular, the cells tend to be rounder and more polymorphic and may surround collagen, and foamy macrophages may be present. DFSP has spindle cells, but these tend to be wavy rather than straight, have pale rather than eosinophilic cytoplasm, form storiform patterns rather than fascicles, and are CD34 positive. Neurofibroma also has wavy nuclei, does not form fascicles, and is immunoreactive for S-100 protein and neurofilament. Fibromatosis tends to have cells with more variable nuclei and paler cytoplasm and generally a less well-developed fascicular pattern. Low-grade leiomyosarcoma may be difficult to distinguish. Tumors larger than 2 cm that extend deep into the subcutis always should raise the suspicion of malignancy. The presence of nuclear atypia, mitotic activity of 1 or more per 50 hpf or necrosis should prompt the diagnosis of leiomyosarcoma.82

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

HISTOPATHOLOGIC FEATURES Histologically, dermal pilar leiomyomas are composed of numerous fascicles of smooth muscle and variable amounts of collagen arranged randomly throughout the dermis or subcutaneous tissue (Fig. 32-17). They are unencapsulated and infiltrative; involvement of hair follicles and adnexal glands is typical. The cells have abundant eosinophilic cytoplasm that may have a perinuclear vacuole; the nuclei are oval with blunt ends and evenly dispersed chromatin. Genital tumors are larger, usually better circumscribed, and centered in the subcutaneous tissues. They may have a pseudocapsule, focal calcifications, stromal myxoid change, and focal mitotic activity.79 Any mitotic activity in a smooth muscle tumor with any degree of nuclear atypia should raise the suspicion of malignancy.80,81

Angioleiomyoma (Angiomyoma, Vascular Leiomyoma) CLINICAL FEATURES Angioleiomyomas are solitary, often painful tumors of adults (average age, 47 years) with a predilection for women (Table 32-16). They occur mainly in the lower extremities, especially the lower leg and foot.83 The lesion is benign and only rarely recurs. HISTOPATHOLOGIC FEATURES Histologically, angioleiomyomas are well-circumscribed solid masses composed of coalesced vessels with prominent walls

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A

B

 FIGURE 32-17 Pilar leiomyoma. (A) Short, intersecting fasicles of bland spindled cells with eosinophilic cytoplasm and boxcar-shaped nuclei. (B) At the deep aspect, the tumor entraps adnexal structures.

consisting of smooth muscle and collagen (Fig. 32-18). They are commonly located in the subcutis. They have been divided into three types, termed solid, cavernous, and venous.83 The vascular lumina are usually compressed, but they are occasionally large and dilated in the cavernous angioleiomyoma. The muscle of the vessel walls forms irregular, often concentric bundles that merge with those of their neighbors. Stromal hyalinization or myxoid change is common. Rarely, mature adipose tissue is present. Small nerve fibers are detectable immunohistochemically.84 Atypia, mitoses, and necrosis are not seen.

poorly circumscribed and lacks the vascular spaces, and the muscle does not emerge from vascular walls. Most leiomyosarcomas also lack the vascular spaces, although vascular leiomyosarcomas have also been described.85 Most important, leiomyosarcomas have cytologic atypia, mitoses, and necrosis. Cutaneous angiolipoleiomyomas (also reported as angiomyolipomas) are rare tumors composed of mature adipose tissue, smooth muscle, and vessels.86 They lack expression of melanocytic markers and

likely represent involutional metaplasia in an angioleiomyoma. Myopericytomas may exhibit immunohistochemical and morphologic overlap with angioleiomyoma. The perivascular concentric arrangement of cells, which is a salient feature of myopericytoma, is a useful feature.87

Leiomyosarcoma CLINICAL FEATURES Superficial (ie, dermal and subcutaneous) leiomyosarcoma is most common between the ages of

DIFFERENTIAL DIAGNOSIS The lesion should be distinguished from pilar leiomyoma and leiomyosarcoma. Leiomyoma is

Table 32-16 Angioleiomyoma

Clinical Features Adults; female predominance Lower extremities Painful, often solitary Histopathologic Features Well-circumscribed Blood vessels Smooth muscle of vessel walls in irregular concentric bundles Three variants: solid, cavernous, venous Stromal hyalinization Myxoid change Differential Diagnosis Leiomyoma Leiomyosarcoma Hemangioma

 FIGURE 32-18 Angioleiomyoma. Bland smooth muscle fibers intimately merge with smooth muscle cells in the wall of blood vessels.

HISTOPATHOLOGIC FEATURES Histologically, leiomyosarcomas, particularly of the dermis, may closely resemble their benign counterparts with well-formed fascicles of spindle cells with abundant eosinophilic cytoplasm and elongated, blunt-ended nuclei (Table 32-17 and Fig. 32-19). The nuclei may be more vesicular and have nucleoli. The fascicles typically run at right angles to each other. Unlike leiomyomas, most tumors display some pleomorphism, mitotic activity, or necrosis;

Table 32-17 Leiomyosarcoma

Clinical Features Adults Extremities Dermal or subcutaneous Histopathologic Features Smooth muscle Mitoses Atypia Necrosis Differential Diagnosis Leiomyoma Benign fibrous histiocytoma Dermatofibrosarcoma protuberans Spindle cell rhabdomyosarcoma Malignant melanoma Granular cell tumor Metastasis

however, well-differentiated tumors may be difficult to differentiate from leiomyomas. Some tumors are epithelioid and are composed of rounded cells that do not form fascicles and often have clear cytoplasm. These are more common in the head and neck.93 Rarely, these tumors may exhibit cells with abundant granular cytoplasms.94 As with leiomyomas, the matrix may undergo myxoid degeneration or become desmoplastic, obscuring

 FIGURE 32-19 Leiomyosarcoma. Fascicles of spindled cells with eosinophilic cytoplasm and hyperchromatic nuclei. Brisk mitotic activity is present (inset).

the diagnosis.95,96 Dermal lesions are often highly infiltrative; by contrast, subcutaneous lesions appear more circumscribed. Immunohistochemically, these tumors are typically reactive for actin and often desmin, and some (<10%) express keratin. 97,98 Granular cell variants of leiomyosarcoma are negative for S-100 protein but, in addition to muscle markers, stain for NKIC3.94 DIFFERENTIAL DIAGNOSIS The distinction from leiomyoma can be difficult. In general, leiomyosarcomas occur in an older age group and more commonly in the proximal extremity. Certainly, tumors that extend widely into the subcutis, are larger than 2 cm, have more than 1 mitosis per 10 hpf, or necrosis at all should be diagnosed as benign with great trepidation. All of these features are more common in leiomyosarcomas (Table 32-18). In some cases, absolute distinction may not be possible, and in these cases, this uncertainty should be expressed in the report using such terms as uncertain malignant potential. Distinction from dermatofibroma is based on more prominent fascicular growth, more eosinophilic cytoplasm, lack of cytologic polymorphism, the presence of foam and inflammatory cells, and the finding of desmin reactivity. Fibromatoses have more poorly formed fascicles and paler cytoplasms and generally are desmin negative. Distinction from myxofibrosarcoma is based on fascicle formation, lack of mucin-containing vacuolated cells, and reactivity for actin or desmin. DFSP has a storiform pattern rather than fascicles, more wavy nuclei, and reactivity for CD34. Spindle cell carcinoma exhibits varying degrees of keratin positivity, as well as immunoreactivity for p63.99,100 The spindle cell variant of embryonal rhabdomyosarcomas is exceedingly rare in superficial soft tissue, although metastases to the skin have been documented.101-104 True rhabdomyoblasts are generally not seen in spindle cell embryonal rhabdomyosarcoma, so the diagnosis is dependant on demonstration of specific markers of skeletal muscle differentiation, such as myo-D1 or myogenin. The granular, myxoid, and epithelioid variants may be confused with granular cell tumor, malignant melanoma, cellular neurothekeoma, epithelioid sarcoma, and metastatic carcinoma. Classic-type granular cell tumors are often associated with pseudoepitheliomatous hyperplasia, do not form fascicles as frequently, are S-100 protein positive and desmin and actin negative, and have characteristic

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

40 and 80 years, although it has also been described in teenagers and children.88,89 These lesions are most common in the proximal extremities, especially the lower extremity, and generally are smaller than 5 cm in maximum diameter.90,91 Dermal tumors are believed to arise from erector pilae muscles and subcutaneous tumors from blood vessels. The prognosis is highly dependent on the size and depth.81 In general, tumors smaller than 5 cm in diameter have a much better prognosis. Up to 40% of dermal tumors recur, but metastasis is extremely rare. In contrast, one-third of subcutaneous lesions metastasize and cause death.90 For subcutaneous lesions, aneuploidy may be an additional unfavorable prognostic feature.92 Epithelioid change, granular cell change, and myxoid change, all of which are occasional features, are not prognostically important.

871

Table 32-18 Features Useful In Distinguishing Cutaneous Leiomyoma from Leiomyosarcoma

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Peak age (years) Size Number Depth Size Necrosis Mitoses

LEIOMYOMA

LEIOMYOSARCOMA

20-50 Trunk, extensor surfaces Often multiple More superficial Usually < 2cm Rare Rare (<1/10 hpf)

30-80 Proximal lower extremities Solitary Usually extend deep Often larger Common Often (>3/10 hpf)

ultrastructural features. S-100 protein or HMB45 reactivity in melanoma is typical, and such lesions tend also to have prominent nucleoli. Neurothekeoma has a distinctive lobular growth pattern and usually some myxoid alteration and is actin negative. Epithelioid sarcoma tends to have a multinodular growth pattern and central areas of degenerate collagen or necrosis. In addition, they exhibit immunoreactivity for keratin, epithelial membrane antigen (EMA), and CD34. Metastatic carcinoma should be suspected in patients with an appropriate clinical history and keratin reactivity. Primary cutaneous leiomyosarcoma should be distinguished from metastatic leiomyosarcoma originating in deeper visceral tissues, which is one of the more common deep tissue sarcomas to metastasize to skin. Cutaneous metastases typically present as painless firm nodules under an intact, normal-appearing epidermis. The scalp is the most common cutaneous site of involvement of metastatic leiomyosarcoma; metastases are generally of higher histologic grade.105

more common than benign tumors, and benign tumors may have immature features suggesting a malignant lesion.

Rhabdomyomatous Mesenchymal Hamartoma Rhabdomyomatous mesenchymal hamartoma is a rare congenital lesion, predominantly affecting boys, that may be associated with other developmental anomalies of the head and neck.106,107 It usually presents as a small, soft polyp in the head and neck region. Histologically, fascicles of mature striated myofibers are seen at all levels of the dermis, interdigitating with hair follicles and adnexal structures (Fig. 32-20). The fibers may form a central mass that rarely can ossify. Cross-striations can be seen. Although both nevus lipomatosis superficialis and fibrous hamartoma of infancy have a variety of abnormally placed dermal tissues, they do not contain skeletal muscle. Benign Triton

tumors contain muscle but are associated with nerves. Rhabdomyomas in childhood show relatively immature skeletal muscle differentiation rather than wellformed muscle fibers.

Rhabdomyoma Rhabdomyomas of cardiac origin are hamartomas and associated with tuberous sclerosis. However, rhabdomyomas of skin and soft tissue are benign neoplasms and are not associated with any clinical syndromes. These rhabdomyomas can be divided into fetal and adult types. Regardless of the histologic subtype, rhabdomyomas do not exhibit mitotic activity, nuclear atypia, or necrosis. Lesions are cured by complete excision without local recurrence.

Fetal Rhabdomyoma CLINICAL FEATURES Fetal rhabdomyomas (F-RM) typically occur as a solitary mass in the subcutaneous tissue of the head and neck region of boys younger than 5 years of age (Table 32-20).108-110 Somewhat more mature but similar lesions occur in the genital areas of adult women.111 They measure up to 12 cm in diameter and are well circumscribed but not encapsulated. Some case are associated with nevoid basal cell syndrome in patients with mutations in the hedgehog receptor PTCH gene.112 HISTOPATHOLOGIC FEATURES Traditionally, F-RMs have been divided into two

Skeletal Muscle Tumors showing skeletal muscle differentiation are most common in childhood (Table 32-19). Malignant tumors are far

Table 32-19 WHO Classification of Skeletal Muscle Tumors

872

Benign Rhabdomyoma Adult type Fetal type Genital type Malignant Embryonal rhabdomyosarcoma Spindle cell Botryoid Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma

 FIGURE 32-20 Rhabdomyomatous mesenchymal hamartoma. Irregular bundles of skeletal muscle underlie abnormal dermis.

Table 32-20 Fetal-Type Rhabdomyoma

Clinical Features Boys <5 years and men >60 years Head and neck Histopathologic Features Immature skeletal muscle No mitoses or atypia Differential Diagnosis Rhabdomyosarcoma Granular cell tumor

rhabdomyosarcoma (botyroid type) and benign vaginal polyps. Botryoid embryonal rhabdomyosarcoma is a rapidly growing tumor of young girls that exhibitis the histologic features of embryonal rhabdomyosarcoma and is characterized by a subepithelial cambium layer. Benign vaginal polyps lack the characteristic strap cells of rhabdomyoma and are composed of atypical stromal cells in a myxoid background.

Table 32-21 Adult-Type Rhabdomyoma

Clinical Features Boys <5 years and men >60 years Head and neck Histopathologic Features Immature skeletal muscle No mitoses or atypia Differential Diagnosis Rhabdomyosarcoma Granular cell tumor

Adult Rhabdomyoma

DIFFERENTIAL DIAGNOSIS Atypical nuclei, hyperchromasia, and necrosis should raise the suspicion of rhabdomyosarcoma. Rhabdomyosarcomas have alternating hypercellular and hypocellular areas, are less circumscribed, do not “mature” peripherally, and may have a cambium layer if submucosal. Adult rhabdomyoma has a uniform population of large polygonal cells with abundant, deeply eosinophilic cytoplasm. Infantile fibromatosis may closely mimic rhabdomyoma by invading normal skeletal muscle; however, whereas fibromatosis is an infiltrative process, rhabdomyomas are circumscribed. Rhabdomyomatous mesenchymal hamartoma is described in the preceding text.

adult and fetal types. Adult rhabdomyomas may recur, but aggressive behavior has not been seen. DIFFERENTIAL DIAGNOSIS Adult rhabdomyomas may be confused with several entities, including benign, malignant, and nonneoplastic conditions, such as granular cell tumor, hibernoma, paraganglioma, pleomorphic rhabdomyosarcoma, and crystalstoring histiocytosis. Granular cell tumors are composed of slightly smaller cells with much smaller nuclei and nucleoli. The cytoplasm is generally paler and more granular. They are reactive for S-100 protein, and electron microscopy will show characteristic autophagocytic lyzosomes. Hibernomas may resemble rhabdomyoma due to their vacuolated cytoplasms.

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

subtypes, the “classic,” which has a predilection for postauricular soft tissue, and the “intermediate,” which tends to involve mucosal sites. Histologically, “classic” F-RM is composed of bland, elongated spindle cells representing fetal myotubules in a myxoid background. Occasional rhabdomyoblasts with crossstriations are present. In contrast, “intermediate” F-RM exhibits more advances stages of muscle differentiation, with broad fascicles of spindled rhabdomyoblasts and interlacing straplike cells. Some cases may be quite cellular, and areas resembling adult rhabdomyoma with large ganglion-like cells may be present.

CLINICAL AND HISTOPATHOLOGIC FEATURES Adult rhabdomyomas also occur in the head and neck of men, with a predilection for the upper respiratory tract (see Table 32-21).109 The average age at presentation, however, is the sixth decade of life. Most are solitary, but multiple lesions have been reported.115 They are well circumscribed and composed of large polygonal or round cells with abundant eosinophilic cytoplasm, a large nucleus, and prominent nucleolus (Fig. 32-21). The nucleus may be eccentric or multiple. Occasional spider cells with clear cytoplasm and thin strands of material extending from the nucleus to the cytoplasmic membrane are present. Cross-striations, disorderly filamentous arrays, and crystalline material may be present in the cytoplasm. Mitoses are rare. Some cases have features of both

Genital Rhabdomyoma CLINICAL AND HISTOPATHOLOGIC FEATURES Genital rhabdomyomas present as polypoid masses in the vulvovaginal region of middle-aged women. These tumors display round or straplike rhabdomyoblasts within a vascularized fibrous stroma.113,114 DIFFERENTIAL DIAGNOSIS The main differential diagnosis includes embryonal

 FIGURE 32-21 Adult rhabdomyoma. Polygonal tumor cells with abundant eosinophilic and focally vacuolated cytoplasm.

873

However, these tumors are more densely eosinophilic and are generally seen in a younger age group than adult rhabdomyoma. Paragangliomas exhibit an organoid pattern and express neuroendocrine markers such as synaptophysin and chromogranin. Pleomorphic rhabdomyosarcomas typically occur in the extremities, are more infiltrative, and have far more cytologic atypia and mitoses. Crystal-storing histiocytosis is immunoreactive for the histiocyte marker CD68 and negative for myogenic markers.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Rhabdomyosarcoma

874

Rhabdomyosarcomas arise most commonly in children but are rarely primary in the skin (Table 32-22). Although several histologic variants have been described, tumors are classified within three main subtypes: embryonal, alveolar, and pleomorphic.

Embryonal Rhabdomyosarcoma CLINICAL FEATURES Embryonal rhabdomyosarcoma is the most common type of rhabdomyosarcoma. It occurs most frequently in the head and neck and urogenital regions in patients younger than 8 years of age.116 HISTOPATHOLOGIC FEATURES Histologically, noncohesive spindle- to round-shaped cells with a variable amount of cytoplasm are present in a myxoid background (Fig. 32-22). The cells have round to oval nuclei with open chromatin and inconspicuous nucleoli. Small amounts of eosinophilic cytoplasm may be present to one side of the cell, or cytoplasm may be more profuse, giving rise to round, tadpole-, or strap-shaped rhabdomyoblasts.

Table 32-22 Rhabdomyosarcoma

Clinical Features Infants to young adults Males > Females Head and neck, urogenital region, extremities Histopathologic Features Small, round, blue cells Eosinophilic cytoplasm Strap or tadpole cells Solid or alveolar pattern Differential Diagnosis Ewing sarcoma/PNET Lymphoma Neuroblastoma Poorly differentiated synovial sarcoma Rhabdomyoma

 FIGURE 32-22 Embryonal rhabdomyosarcoma. Primitive small, round, blue cells with scattered ovoid and spindled rhabdomyoblasts exhibiting more abundant eosinophilic cytoplasm.

Mitoses and necrosis may be present. When submucosal, the lesion may present as a polypoid mass protruding into the lumen, and there may be a so-called cambium layer characterized by increased cellularity immediately beneath the epithelium. This subtype is termed botryoid. Another subtype, predominantly in the paratesticular region, has spindle cells in a fascicular or storiform pattern and is termed spindle cell rhabdomyosarcoma.101,102 Immunohistochemically, reactivity for muscle actin, desmin, myo-D1, and myogenin are characteristic.117 Ultrastructurally, alternating thin and thick filaments with occasional Ζ bands can be demonstrated. Focal anaplastic features may be seen, as well as bizarre multipolar mitotic figures. Whether these findings portend a worse outcome is still unclear.118 Allelic loss in chromosomal region 11p15 is seen in most embryonal rhabdomyosarcomas.119 Patients with Beckwith-Wiede-mann syndrome exhibit similar genetic losses, and not surprisingly, are at increased risk of developing embryonal rhabdomyosacoma, among other tumors. 120 Recently, a peculiar type of adult rhabdomyosarcoma characterized by prominent hyaline sclerosis and a pseudovascular growth pattern has been described. This variant has been termed sclerosing rhabdomyosarcoma.121,122 The relationship between sclerosing rhabdomyosarcoma

and conventional rhabdomyosarcoma remains uncertain, although cytogenetic studies suggest a link with embryonal rhabdomyosarcoma.123 DIFFERENTIAL DIAGNOSIS The differential diagnosis is long and encompasses a variety of malignant round cell tumors. Both Ewing sarcoma/primitive neuroectodermal tumor (PNET) and lymphoma usually display more uniformity in cellular size and shape than the majority of rhabdomyosarcomas and obviously lack muscle markers (desmin, myo-D1, myogenin). CD99, a highly sensitive marker of Ewing sarcoma/PNET, is also present focally in rhabdomyosarcomas and thus potentially represents a diagnostic pitfall to those unfamiliar with this fact. Neuroblastoma is distinguished by a background of neutropils, focal or partial ganglionic differentiation, and reactivity for neural markers. The spindle cell subtype of rhabdomyosarcoma may be confused with a leiomyosarcoma or fibrosarcoma. Both lesions are uncommon in children. Leiomyosarcoma does not have cross-striations by light microscopy and does not express myoD1 or myogenin. Rhabdomyoblastic heterologous differentiation may be seen in a variety of neoplasms, generally as a focal histologic finding. These include germ cell tumors, malignant peripheral nerve sheath tumor (malignant Triton tumor), metastatic Wilms

tumor, and congenital melanocytic nevus. Care must be taken when interpreting myogenic markers because they may be expressed in entrapped atrophic muscle.124 Due to the presence of heavily hyalinized collagenous matrix and occasional pseudovascular growth pattern, sclerosing rhabdomyosarcoma is frequently misdiagnosed as angiosarcoma, chondrosarcoma, or osteosarcoma.121

Alveolar Rhabdomyosarcoma

HISTOPATHOLOGIC FEATURES The initial descriptions emphasized the alveolar pattern, with cells lining up against thin fibrous septa to produce small spaces resembling lung tissue (Fig. 32-23). The cells may have a hobnail appearance and are discohesive, with isolated cells lying free within these spaces. In contrast to embryonal rhabdomyosarcoma, the cells tend to be round rather than oval with larger nuclei and sometimes with more abundant eosinophilic cytoplasm. Multinucleated cells with the nuclei forming a peripheral wreath are a characteristic finding, and some cases have strap cells as well. Greater emphasis has been placed on the nuclear rather than the architectural features.127 Cases with a solid pattern without any evidence of alveolar septa but containing cells with larger, more pleomorphic nuclei, coarse chromatin, and prominent nucleoli may occur. ARMS is associated with t(2;13) or t(1;13) chromosomal translocations, which generate PAX3FKHR and PAX7-FKHR fusion products, respectively. Distinction from Ewing’s sarcoma/PNET can be made by cytogenetic analysis or reverse transcriptase polymerase chain reaction.129,130 DIFFERENTIAL DIAGNOSIS The alveolar pattern may suggest a vascular or epithelial neoplasm. Markers for CD31, CD34, and keratin are most helpful in these situations. As with embryonal rhabdomyosarcoma in fact, more so in view of the larger nuclear size, Ewing sarcoma/PNET is also in the differential. The more prominent eosinophilic cytoplasm, the eccentric

 FIGURE 32-23 Alveolar rhabdomyosarcoma. Aggregates of small, round, blue cells exhibiting a central loss of cohesion separated by hyalinized fibrous septae.

nuclei, and desmin staining are again helpful. Lymphoma is ruled out by reactivity for CD45.

Pleomorphic Rhabdomyosarcoma CLINICAL AND HISTOPATHOLOGIC FEATURES Pleomorphic rhabdomyosarcoma is a

 FIGURE 32-24 Pleomorphic rhabdomyosarcoma.

high-grade sarcoma that occurs almost exclusively in older adults (median, sixth decade of life). The limbs and limb girdles are the most common locations. Histologically, the tumor is composed of bizarre large polygonal and spindle cells with abundant eosinophilic cytoplasms forming irregular fascicles (Fig. 32-24).131

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

CLINICAL FEATURES Alveolar rhabdomyosarcomas (ARMs) are most common in adolescent boys and young men. The average age at presentation (12 years) is distinctly older than that of embryonal tumors (6 years) and younger than that of the pleomorphic subtype (50 years).125-127 Most tumors arise in the extremities, usually intramuscularly. ARMS carry a poorer prognosis compared with embryonal rhabdomyosarcoma.128

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Cytogenetically, these tumors have complex karyotypes. Increasing age and stage and deep location are poor prognostic factors.10 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes pleomorphic leiomyosarcoma. Myo-D1 and myogenin are somewhat less often positive in pleomorphic rhabdomyosarcoma than in other types of rhabdomyosarcoma.132 Demonstration of myoid differentiation should be sought, as clinically, pleomorphic rhabdomyosarcomas carry a worse prognosis compared with undifferentiated pleomorphic sarcomas.133 Ultrastructural demonstration of Z bands may be necessary for definitive separation. As mentioned previously, focal heterologous rhabdomyoblastic differentiation may be seen with a variety of tumors, including dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, and carcinosarcoma.

TUMORS OF CARTILAGE Cartilage tumors in the skin and subcutaneous sites are infrequent (Table 32-23). Most occur in the hands and feet and are benign despite worrisome histologic features. In large cartilaginous masses occurring in superficial sites and showing significant cytologic atypia, the possibility of local spread or metastasis from a primary bone tumor always should be considered. Extraskeletal mesenchymal chondrosarcoma virtually never involves skin or subcutaneous tissue and is not discussed further here.

Extraskeletal Chondroma CLINICAL AND HISTOPATHOLOGIC FEATURES Extraskeletal chondromas are uncommon and present mainly in the hands and feet of adults in their fourth and fifth decades.134-136 They are solitary, well circumscribed, and usually smaller than 2 cm in greatest diameter, although large tumors have been reported occasionally. They are composed of variably cellular but generally mature hyaline

Table 32-23 WHO Classification of Chondro-Osseous Tumors

876

Soft tissue chondroma Mesenchymal chrondrosarcoma Extraskeletal osteosarcoma

 FIGURE 32-25 Soft tissue chondroma. A pseudoencapsulated cartilaginous tumor with focal hypercellularity.

cartilage that may calcify and even ossify (Fig. 32-25). Plump chondroblasts and giant cells may be present. Myxoid areas and fibrosis may occur. In one series, all lesions had areas with marked nuclear pleomorphism, hyperchromasia, binucleation, and myxoid change. The lesion may appear more mature peripherally. Although these lesions may recur, multiple recurrences and metastases have not been reported in cases occurring in typical sites. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes osteochondroma, fibroosseous pseudotumor, synovial chondromatosis, giant cell tumor of tendon sheath, tumoral calcinosis, extraskeletal chondrosarcoma of myxoid or mesenchymal types, and mixed tumor (chondroid syringoma). Osteochondromas, as well as periosteal and juxtacortical chondromas, can be distinguished radiographically. Fibroosseous pseudotumor is discussed in the following pages. Calcifying aponeurotic fibroma occurs in the hands of young adults and exhibits small foci of cartilaginous metaplasia within a densely fibrous background. Synovial chondromatosis is located within a joint or synovial tissue and usually consists of multiple nodules. Giant cell tumor of tendon sheath does not contain cartilage. Tumoral calcinosis contains abundant basophilic debris, and although it may show vaguely chondroid

foci, it does not contain true hyaline cartilage. Extraskeletal myxoid chondrosarcoma has more prominent myxoid rather than cartilagenous areas, is less circumscribed, has cells in chains and nests rather than isolated in lacunae, is more cellular, and has smaller cells. Mesenchymal chondrosarcoma may present in soft tissue and rarely in the hands and feet. Diagnosis requires identification of the generally predominant small cell undifferentiated component that rarely may be missing in small biopsies. Mixed tumors usually show a significant epithelial component that often contains ducts. Rarely, mixed tumors contain a single-cell dispersion of epithelium indistinguishable from chondroma. However, the epithelial cells are positive for cytokeratin or EMA. Epitheloid hemangioendothelioma enters the differential diagnosis due to the presence of myxohyaline matrix; however, this tumor is positive for the vascular markers CD31 and CD34.

Extraskeletal Myxoid Chondrosarcoma CLINICAL FEATURES Extraskeletal myxoid chondrosarcoma is uncommon and occurs mainly in adults, with a peak incidence in the fifth decade of life.137-139 Men are affected more commonly (2:1). It favors the lower extremity and may present in subcutaneous tissue. Rare

TUMORS OF BONE Primary bone-forming lesions in the skin and soft tissues are unusual; the most common lesion is myositis ossificans, a reactive lesion that can mimic osteosarcoma histologically (see Table 32-21). Metaplastic bone formation in other lesions, such as pilomatrixoma or intradermal nevus, is probably more frequent and referred to as osteoma cutis.

Osteoma Cutis

cases may present in children.140 There is a 5-year survival of approximately 85%. However, the lesion is persistent, and long-term follow-up is not as favorable.141 HISTOPATHOLOGIC FEATURES Histologically, the tumor is lobulated and consists of isolated strands, ribbons, or small nests of cells in a myxoid background (Fig. 32-26). The cells are oval and small and have scant amounts of eosinophilic cytoplasm and round nuclei. Occasional cytoplasmic vacuoles can be found, but extensive vacuolization, as in the physalliphorous cells of chordoma, is not seen. Lacunae formation occurs rarely. Some areas can be quite cellular, and focal areas of true cartilage and rarely metaplastic bone can be found. Some cases have cytoplasmic rhabdoid inclusions. Mitotic activity is low (<2 per 10 hpf). Immunohistochemically, the tumors may be reactive for S-100 protein, but this is not a consistent finding.142 Despite the rare chondroid formation and focal S-100 staining, these tumors do not show a chondrocytic phenotype. Absence of proteoglycan aggrecans and collagen type X supports the notion that extraskeletal myxoid chondrosarcoma is a primitive mesenchymal neoplasm rather than a chondrosarcomatous entity.143 Further studies have shown that many of these tumors express neuroendocrine differentiation, both at an immunohistochemical

level as well as ultrastructually.144 For these reasons, the most recent WHO classification places this tumor not within tumors of cartilage, but rather in the category of tumors of uncertain differentiation.10 Extraskeletal myxoid chondrosarcoma is characterized by a reciprocal t(9;22) translocation involving EWS and NOR1, although rarely others, such as t(9;17) or t(9;15), may be seen.145,146 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes intramuscular myxoma, myxoid liposarcoma, myxofibrosarcoma, chordoma, chondroid syringoma, and cellular neurothekeoma. Intramuscular myxoma is much less cellular. Myxoid liposarcoma has a characteristic vascular pattern and lipoblasts. Myxofibrosarcoma has a characteristic curvilinear vascular pattern and significantly more atypia. Chordoma contains physalliphorous cells and is keratin and EMA positive. Chondroid syringoma has nests of cells, can display overt tubular differentiation, and is typically strongly positive for keratin and S100 protein. Ultrastructural examination reveals true epithelial and myoepithelial differentiation. Cellular neurothekeoma frequently occurs in adolescents of young adults, involves the head and neck most commonly, is superficial (ie, dermal), does not show chondroid differentiation, and often has a distinct lobular pattern.

Fibroosseous Pseudotumor Synonyms: Parosteal fasciitis, florid reactive periostitis CLINICAL AND HISTOPATHOLOGIC FEATURES Fibroosseous pseudotumor is a painful, reactive lesion occurring usually in the hands and less commonly the feet of young adults (with a female predominance) and rarely in children.150-152 A history of trauma usually is lacking, and the lesion may be related to the periosteal surface of bone. It is a multinodular partially circumscribed mass smaller than 3 cm in diameter. Microscopically, spindle cell areas, myxoid areas, irregular trabeculae of bone with osteoblastic rimming, areas of vascularity and giant cells, and (occasionally) cartilage can be seen (Fig. 32-27). Mitoses are common. The zonation of myositis ossificans is not seen. The combination of fibrous areas, myxoid areas, and increased vascularity often are similar to nodular fasciitis. The cellularity, mitoses, and osteoblastic activity may suggest a malignant neoplasm; however, the lesion is benign. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes myositis ossificans, nodular fasciitis, osteochondroma, and

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

 FIGURE 32-26 Extraskeletal myxoid chondrosarcoma. These tumors display a multinodular growth pattern exhibiting peripheral hypercellularity with cords of small hyperchromatic cells within a myxoid matrix.

CLINICAL AND HISTOPATHOLOGIC FEATURES Ossification in the skin occurs commonly with trauma or as a component of a variety of other neoplasms. It is classified as primary when it occurs in the absence of a demonstrable preexisting lesion. Secondary lesions, which make up the majority of cases, are generally seen occurring with pilomatricoma, basal cell carcinoma, acne vulgaris, and melanocytic nevi.147,148 They occur at any age and at any site. The bone appears mature in all cases and may be accompanied by marrow elements and inflammation.149 Cartilage and amorphous calcifications are rare. An underlying tumor should be excluded. Calcinosis cutis is characterized by the absence of mature bone.

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are not as atypical. The bone varies from mature to immature and is usually surrounded by abundant osteoblasts. Lacelike patterns of osteoid can be seen rarely, as well as areas of cartilage. In subcutaneous sites, the zonal phenomenon may not be as apparent. In these cases (sometimes known as fasciitis ossificans), the resemblance of the spindle cell component to nodular fasciitis is critical for accurate diagnosis. It is important to note that the zonal pattern is not apparent in early lesions and is usually appreciated after 3 weeks after onset.

878

 FIGURE 32-27 Fibroosseous pseudotumor. Irregular bony trabeculae with osteoblast rimming admixed with spindled cells. The orderly zonal pattern of myositis ossificans is absent.

DIFFERENTIAL DIAGNOSIS The principal differential diagnosis is osteosarcoma. The history of rapid onset is helpful, as well as the zonal pattern and resemblance to nodular fasciitis. Osteosarcoma generally has more atypia, atypical mitoses, and an infiltrative pattern. Myositis ossificans is more likely to contain fibrinous material and edematous lymphangioma-like areas.156 In difficult cases, rebiopsy at a later time may be useful.

Extraskeletal Osteosarcoma osteosarcoma. Anatomic location, a close association with bone, and a lack of zonation distinguish it from myositis ossificans. Bone formation distinguishes it from nodular fasciitis. Osteochondroma has an orderly appearance with cartilage on the surface and underlying mature bone, often with marrow. Osteosarcoma of the hand or foot is rare and typically has more pleomorphism, with lacelike areas of osteoid rather than the thicker seams of woven bone present in fibroosseous pseudotumor.

centrally (Fig. 32-28). The immature area has a loose myxoid to fibrous background with spindle cells that can become highly cellular and mitotically active. This can mimic nodular fasciitis or fibromatosis. Some cells are epithelioid, particularly in areas associated with bone. Osteoblasts are plump and can simulate malignant osteoblasts but

CLINICAL AND HISTOPATHOLOGIC FEATURES Extraskeletal osteosarcoma is a rare neoplasm of adults (mean age, 59 years) with a predilection for the extremities, especially the thigh. 157 Some cases are associated with prior radiation.158 Although most are deep-seated lesions, cases confined to the dermis and subcutaneous tissue have been described.

Myositis Ossificans CLINICAL FEATURES Myositis ossificans is a reactive lesion most commonly presenting in muscle but also arising in or extending into subcutaneous tissue (panniculitis ossificans) of the extremities.153,154 Cutaneous involvement is not a feature. It occurs mainly in young, active men and may be related to trauma in up to 50% of cases. Rapid onset is characteristic. Grossly, the lesion is well circumscribed, usually smaller than 6 cm, and is often stone hard. Immunohistochemical and histologic similarities support fibroosseous pseudotumor of the digit being a cutaneous variant of myositis ossificans.155 HISTOPATHOLOGIC FEATURES Histologically, the lesion is zonal, with mature bone at the periphery and immature elements

 FIGURE 32-28 Myositis ossificans. Zonation; the lesion forms more mature bone toward the periphery and is more cellular toward the center.

6. 7. 8.

9.

10.

 FIGURE 32-29 Extraskeletal osteosarcoma. The tumor is composed of an admixture of malignant bone (irregular trabeculae of osteoid) and cartilage.

12. 13. 14.

All show at least focal areas of infiltration. By definition, the lesions contain osteoid intimately associated with atypical cells (Fig. 32-29). All of the major subtypes of conventional osteosarcoma that are observed in primary bone lesions may be seen in extraskeletal osteosarcoma. These include, most commonly, the osteoblastic variant followed by the fibroblastic and chondroid types. Rare cases of telangiectatic osteosarcoma consisting of large, dilated, blood-filled spaces have been described.159 Up to two-thirds recur, and at least two-thirds of patients develop metastases and die.160 DIFFERENTIAL DIAGNOSIS In contrast to osteosarcoma, myositis ossificans has a zoning phenomenon with more mature bone at the periphery and more immature areas centrally. The lack of markedly atypical cells in myositis ossificans may also be helpful. Distinction from fibroosseous pseudotumor is discussed in the preceding text. The small cell variant of extraskeletal osteosarcoma consists of sheets of small round blue cells and may mimic Ewing/PNET or lymphoma. Histologic identification of lacelike osteoid formation is critical in some cases because CD99 expression may be observed in all three tumors. Immunohistochemically, extraskeletal osteosarcomas have a broad immunohistochemical profile, with reactivity for vimentin and variable expression

of smooth muscle actin, desmin, and S-100.161 Focal heterologous osseous differentiation may be seen in several tumors, including malignant peripheral nerve sheath tumors, synovial sarcoma, and dedifferentiated liposarcoma.

15.

16.

ACKNOWLEDGMENT The authors wish to thank Drs. Christopher, DM Fletcher, Andrew Folpe, and Andrew Renshaw for their contributions to previous editions of this text. We also acknowledge Dr. Christopher Fletcher’s contribution of selected histologic slides that were photographed and used to illustrate the current chapter.

17.

18.

19.

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42. Fletcher JA, Kozakewich HP, Schoenberg ML, et al: Cytogenetic findings in pediatric adipose tumors: consistent rearrangement of chromosome 8 in lipoblastoma. Genes Chromosomes Cancer. 1993;6(1):24-29. 43. Hicks J, Dilley A, Patel D, et al: Lipoblastoma and lipoblastomatosis in infancy and childhood: histopathologic, ultrastructural, and cytogenetic features. Ultrastruct Pathol. 2001;25(4):321333. 44. Shmookler BM, Enzinger FM: Liposarcoma occurring in children. An analysis of 17 cases and review of the literature. Cancer. 1983;52(3):567-574. 45. Dei Tos AP: Liposarcoma: new entities and evolving concepts. Ann Diagn Pathol. 2000;4(4):252-266. 46. Dei Tos AP, Mentzel T, Fletcher CD: Primary liposarcoma of the skin: a rare neoplasm with unusual high grade features. Am J Dermatopathol. 1998;20(4): 332-338. 47. Hameed M: Pathology and genetics of adipocytic tumors. Cytogenet Genome Res. 2007;118(2-4):138-147. 48. Enzinger FM, Winslow DJ: Liposarcoma. A study of 103 cases. Virchows Arch Pathol Anat Physiol Klin Med. 1962;335:367-388. 49. Azumi N, Curtis J, Kempson RL, et al: Atypical and malignant neoplasms showing lipomatous differentiation. A study of 111 cases. Am J Surg Pathol. 1987;11(3):161-183. 50. Evans HL, Soule EH, Winkelmann RK: Atypical lipoma, atypical intramuscular lipoma, and well differentiated retroperitoneal liposarcoma: a reappraisal of 30 cases formerly classified as well differentiated liposarcoma. Cancer. 1979; 43(2):574-584. 51. Weiss SW, Rao WK: Well-differentiated liposarcoma (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum, and miscellaneous sites. A follow-up study of 92 cases with analysis of the incidence of “dedifferentiation”. Am J Surg Pathol. 1992;16(11):10511058. 52. Dei Tos AP, Mentzel T, Newman PL, et al: Spindle cell liposarcoma, a hitherto unrecognized variant of liposarcoma. Analysis of six cases. Am J Surg Pathol. 1994;18(9):913-921. 53. Sirvent N, Coindre JM, Maire G, et al: Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol. 2007;31(10):1476-1489. 54. Dal Cin P, Kools P, Sciot R, et al: Cytogenetic and fluorescence in situ hybridization investigation of ring chromosomes characterizing a specific pathologic subgroup of adipose tissue tumors. Cancer Genet Cytogenet. 1993; 68(2): 85-90. 55. Toro JR, Travis LB, Wu HJ, et al: Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer. 2006;119(12):2922-2930. 56. Tos AP: Classification of pleomorphic sarcomas: where are we now? Histopathology. 2006;48(1):51-62.

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CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

71. Meis-Kindblom JM, Sjogren H, Kindblom LG, et al: Cytogenetic and molecular genetic analyses of liposarcoma and its soft tissue simulators: recognition of new variants and differential diagnosis. Virchows Arch. 2001; 439(2):141-151. 72. Huang HY, Antonescu CR: Epithelioid variant of pleomorphic liposarcoma: a comparative immunohistochemical and ultrastructural analysis of six cases with emphasis on overlapping features with epithelial malignancies. Ultrastruct Pathol. 2002;26(5):299-308. 73. Hashimoto H, Daimaru Y, Enjoji M: S100 protein distribution in liposarcoma. An immunoperoxidase study with special reference to the distinction of liposarcoma from myxoid malignant fibrous histiocytoma. Virchows Arch A Pathol Anat Histopathol. 1984;405(1): 1-10. 74. 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(5):601-616. 75. Berger TG, Levin MW: Congenital smooth muscle hamartoma. J Am Acad Dermatol. 1984;11(4, pt 2):709-712. 76. Johnson MD, Jacobs AH: Congenital smooth muscle hamartoma. A report of six cases and a review of the literature. Arch Dermatol. 1989;125(6):820-822. 77. Fisher WC, Helwig EB: Leiomyomas of the skin. Arch Dermatol. 1963;88:510-520. 78. Grubb RL 3rd, Franks ME, Toro J, et al: Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol. 2007;177(6):2074-2079; discussion 2079-2080. 79. Newman PL, Fletcher CD: Smooth muscle tumours of the external genitalia: clinicopathological analysis of a series. Histopathology. 1991;18(6):523-529. 80. Billings SD, Folpe AL, Weiss SW: Do leiomyomas of deep soft tissue exist? An analysis of highly differentiated smooth muscle tumors of deep soft tissue supporting two distinct subtypes. Am J Surg Pathol. 2001;25(9):1134-1142. 81. Miettinen M, Fetsch JF: Evaluation of biological potential of smooth muscle tumours. Histopathology. 2006;48(1):97105. 82. Hornick JL, Fletcher CD: Criteria for malignancy in nonvisceral smooth muscle tumors. Ann Diagn Pathol. 2003;7(1): 60-66. 83. Hachisuga T, Hashimoto H, Enjoji M: Angioleiomyoma. A clinicopathologic reappraisal of 562 cases. Cancer. 1984; 54(1):126-130. 84. Fox SB, Heryet A, Khong TY: Angioleiomyomas: an immunohistological study. Histopathology. 1990;16(5): 495496. 85. Varela-Duran J, Oliva H, Rosai J: Vascular leiomyosarcoma: the malignant counterpart of vascular leiomyoma. Cancer. 1979;44(5):1684-1691. 86. Makino E, Yamada J, Tada J, et al: Cutaneous angiolipoleiomyoma. J Am Acad Dermatol. 2006;54(1):167-171. 87. Matsuyama A, Hisaoka M, Hashimoto H: Angioleiomyoma: a clinicopatho-

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122. Mentzel T, Katenkamp D: Sclerosing, pseudovascular rhabdomyosarcoma in adults. Clinicopathological and immunohistochemical analysis of three cases. Virchows Arch. 2000;436(4):305-311. 123. Croes R, Debiec-Rychter M, Cokelaere K, et al: Adult sclerosing rhabdomyosarcoma: cytogenetic link with embryonal rhabdomyosarcoma. Virchows Arch. 2005; 446(1):64-67. 124. Cessna MH, Zhou H, Perkins SL, et al: Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol. 2001;25(9):1150-1157. 125. Enterline HT, Horn RC Jr: Alveolar rhabdomyosarcoma: a distinctive tumor type. Am J Clin Pathol. 1958;29(4):356-366. 126. Enzinger FM, Shiraki M: Alveolar rhabdomyosarcoma. An analysis of 110 cases. Cancer. 1969;24(1):18-31. 127. Tsokos M, Webber BL, Parham DM, et al: Rhabdomyosarcoma. A new classification scheme related to prognosis. Arch Pathol Lab Med. 1992;116(8): 847-855. 128. Meza JL, Anderson J, Pappo AS, et al: Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children’s Oncology Group. J Clin Oncol. 2006; 24(24):3844-3851. 129. Galili N, Davis RJ, Fredericks WJ, et al: Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet. 1993;5(3): 230-235. 130. Shapiro DN, Sublett JE, Li B, et al: Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res. 1993;53(21):5108-5112. 131. Gaffney EF, Dervan PA, Fletcher CD: Pleomorphic rhabdomyosarcoma in adulthood. Analysis of 11 cases with definition of diagnostic criteria. Am J Surg Pathol. 1993;17(6):601-609. 132. Folpe AL: MyoD1 and myogenin expression in human neoplasia: a review and update. Adv Anat Pathol. 2002;9(3):198203. 133. Deyrup AT, Haydon RC, Huo D, et al: Myoid differentiation and prognosis in adult pleomorphic sarcomas of the extremity: an analysis of 92 cases. Cancer. 2003;98(4):805-813. 134. Chung EB, Enzinger FM: Chondroma of soft parts. Cancer. 1978;41(4):1414-1424.

135. Dahlin DC, Salvador AH: Cartilaginous tumors of the soft tissues of the hands and feet. Mayo Clin Proc. 1974;49(10): 721-726. 136. Humphreys S, Pambakian H, McKee PH, et al: Soft tissue chondroma—a study of 15 tumours. Histopathology. 1986;10(2):147-159. 137. Dardick I, Lgace R, Carlier MT, et al: Chordoid sarcoma (extraskeletal myxoid chondrosarcoma). Virchows Arch A Pathol Anat Histopathol. 1983;399(1):6178. 138. Enzinger FM, Shiraki M: Extraskeletal myxoid chondrosarcoma. An analysis of 34 cases. Hum Pathol. 1972;3(3):421435. 139. Meis-Kindblom JM, Bergh P, Gunterberg B, et al: Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol. 1999;23(6):636-650. 140. Hachitanda Y, Tsuneyoshi M, Daimaru Y, et al: Extraskeletal myxoid chondrosarcoma in young children. Cancer. 1988;61(12):2521-2526. 141. Saleh G, Evans HL, Ro JY, et al: Extraskeletal myxoid chondrosarcoma. A clinicopathologic study of ten patients with long-term follow-up. Cancer. 1992;70(12):2827-2830. 142. Fletcher CD, Powell G, McKee PH: Extraskeletal myxoid chondrosarcoma: a histochemical and immunohistochemical study. Histopathology. 1986;10(5):489499. 143. Aigner T, Oliveira AM, Nascimento AG: Extraskeletal myxoid chondrosarcomas do not show a chondrocytic phenotype. Mod Pathol. 2004;17(2):214-221. 144. Goh YW, Spagnolo DV, Platten M, et al: Extraskeletal myxoid chondrosarcoma: a light microscopic, immunohistochemical, ultrastructural and immuno-ultrastructural study indicating neuroendocrine differentiation. Histopathology. 2001;39(5):514-524. 145. Panagopoulos I, Mertens F, Isaksson M, et al: Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer. 2002;35(4):340-352. 146. Subramanian S, West RB, Marinelli RJ, et al: The gene expression profile of extraskeletal myxoid chondrosarcoma. J Pathol. 2005;206(4):433-444. 147. Cottoni F, Dell’ Orbo C, Quacci D, et al: Primary osteoma cutis. Clinical, mor-

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CHAPTER 33 Neural and Neuroendocrine Tumors Zsolt B. Argenyi Chris H. Jokinen

CLASSIFICATION Cutaneous neural tumors represent either primary tumors of the peripheral nerves or ectopic-heterotopic tissues from the CNS or sympathetic ganglionic chain. Further classification is usually based on their assumed histogenetic differentiation. Table 33-1 contains one of the currently used classifications of cutaneous neural tumors.

REACTIVE OR HAMARTOMATOUS LESIONS OF PERIPHERAL NERVE

Neuromas Synonyms: Spontaneous neuroma, solitary circumscribed neuroma, palisaded

Table 33-1 Classification of Cutaneous Neural Tumors PERIPHERAL NERVE SHEATH TUMORS

Tumor-like lesions (reactive or hamartomatous) Neuromas Traumatic Spontaneous Solitary, encapsulated Multiple, nonencapsulated Variants True nerve sheath neoplasms Neurofibromas Superficial Deep Diffuse Pigmented Plexiform Variants Perineuriomas Soft tissue type Intraneural type Schwannomas Common, solitary Ancient Cellular Plexiform Variants Nerve sheath myxoma Classic Cellular (neurothekeoma) Malignant peripheral nerve sheath tumor Variants Miscellaneous Granular cell tumor Neuroendocrine carcinoma of the skin (Merkel cell carcinoma)

NEURAL HETEROTOPIAS

Meningothelial Meningocele Rudimentary meningocele Meningioma Neuroglial Nasal glioma Neuroblastic/ganglionic Metastatic neuroblastoma Primary primitive neuroectodermal tumor Ganglioneuroma Miscellaneous Pigmented neuroectodermal tumor of infancy

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

During their histogenesis, cutaneous neural tumors either recapitulate or retain to a variable extent the architectural arrangement and cytologic components of the normal peripheral nerve. Therefore, familiarity with the normal histology of the peripheral nerve is essential for the correct characterization of neural tumors.1 In short, the structural organization of the peripheral nerve follows a hierarchical arrangement of different compartments. The basic unit is the nerve fiber, which is composed of an axon (neurite) and the surrounding Schwann cells.2 Axons are cytoplasmic extensions of neurons that are located in the central nervous system (CNS) or in the sympathetic ganglionic chain. Axons become myelinated by multiple periaxonal rotation of the surrounding Schwann cells, thus creating a concentric layer of cytoplasmic membranes. Unmyelinated nerve fibers develop by invagination of the axons into the cytoplasm of the Schwann cells. In the next architectural compartment, several nerve fibers form nerve fascicles that are surrounded by a sheath, called a perineurium. The space within the perineurium is referred to as the endoneurium.2 The perineurium is composed of a specialized cell type, the perineurial cell, that is in continuity with the pia-arachnoidal lining of the CNS. Besides the nerve fibers, the endoneurium also contains fibroblasts, capillaries, and mast cells. In the final organizational compartment, numerous nerve fascicles are grouped into nerve bundles that are held together by a protective sheath referred to as the epineurium.2 The epineurium is made up of fibroblasts, collagen, and adipose tissue, but fine vascular structures also penetrate its wall. The sensory nerves are connected to various types of sensory corpuscles (eg, pacinian, meissnerian, Vater-Pacini, and Krause) that are differentiated to specific sensory perceptions.

encapsulated neuroma, true neuroma, amputation neuroma, traumatic neuroma, supernumerary digit Neuromas represent hamartomatous proliferation of the nerve sheath components in which there is an approximate recapitulation of the normal structural arrangements of the peripheral nerve.3,4 The constituent fibers have an axon-toSchwann cell ratio close to the normal 1:1, which makes this group of tumors distinct from other nerve sheath neoplasms. From an etiologic standpoint, neuromas can be classified as spontaneous and traumatic types. The spontaneous type has two main forms: a solitary, encapsulated type (solitary palisaded encapsulated neuroma) and a multiple, nonencapsulated type.3,4 Spontaneous neuromas are

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considered to be a form of primary hyperplasia of the nerve fibers without apparent antecedent tissue injury.4 Traumatic neuromas develop after sharp or blunt trauma of the peripheral nerve, resulting in a partial or complete transection of the continuity of the nerve fibers.1,3 After transection of the nerve fiber, the distal end undergoes Wallerian degeneration, and the fibers from the proximal end try to regenerate and reunite with the distal end. This attempt at regeneration often fails due to the severity of the damage and results in an unorganized, irregular overgrowth of regrowing nerve fibers from the proximal end of the nerve. Traumatic neuromas developing after a complete transection of the nerves are called amputation neuromas and are reactive proliferations rather than true hamartomas or neoplasms.1,3 CLINICAL FEATURES Palisaded encapsulated neuroma develops in adults (mean age, 45.5 years) with an approximately equal ratio of both genders. Most lesions (close to 90%) manifest on the face, but they can occur anywhere on the body. The lesions are solitary, small (2-6 mm), skincolored, firm or rubbery, dome-shaped, asymptomatic papules.5,6 There is no known association with neurofibromatosis or multiple endocrine neoplasia. Multiple, nonencapsulated neuromas on the other hand usually manifest as part of multiple endocrine neoplasia syndrome type 2B.7-10 In this syndrome, there are numerous soft, skin-colored or pink papules and nodules around the mucosal orifices, mainly around the lips, but also in the oral cavity as well. This manifestation is also referred to as multiple mucosal neuromas. Other components of this syndrome include pheochromocytoma and medullary thyroid carcinoma.7-10 Traumatic neuromas can occur at any age or in either gender but are obviously more prevalent in people working certain professions that make the individual prone to acute and chronic injuries. Thus, there is some predilection for the extremities. They are usually solitary, skin-colored, often broad-based, firm papules and nodules at the sites of previous injury or trauma.1,3,11 They may be asymptomatic, but older lesions often become sensitive and painful on pressure. Lancinating pain is considered characteristic for amputation neuromas.11 A special form of traumatic neuroma is the supernumerary digit, which occurs on the lateral-volar aspect of the hand in newborns and young infants. These lesions represent amputation neuromas at the site of an extranumerary

digit separated in utero. Despite the term, they do not contain bone or cartilage of a true digit.12,13 HISTOPATHOLOGIC FEATURES Palisaded encapsulated neuroma is a well-circumscribed, round or oblong nodule located in the dermis that occasionally has a polypoid configuration (Tables 33-2 and 33-3). The tumor is composed of tightly woven fascicles often separated by clear clefts5,6 (Fig. 33-1A). The cells in the fascicles are uniformly spindle-shaped with eosinophilic cytoplasm and ovoid or wavy nuclei. Mitotic figures are rare or absent. There is often parallel arrangement of the nuclei in a given fascicle suggestive of a palisading pattern, although this is not a constant feature14,15 (Fig. 33-1B). Classic Verocay bodies are not present. There is no appreciable fibrosis, chronic inflammation, or granulomatous reaction within the tumor.14 A thin, capsule-like structure separates the tumor from the surrounding dermis. However, this capsule is often incomplete near the epidermal aspect of the lesion. A connection with adjacent nerves can usually be demonstrated on serially sectioned specimens. Variants of palisaded encapsulated neuroma with a plexiform or multinodular growth pattern and highly vascular stroma have been reported.16 The morphologic features of spontaneous neuromas, in either solitary or multiple settings, are similar, with the exception of histologic encapsulation.4 Traumatic or amputation neuromas are usually well-defined nodular lesions located in the dermis or subcutis (see Tables 33-2 and 33-4). The tumors are encased by a fibrous sheath, which is often incomplete at the distal end, where the regenerating fibers may infiltrate the adjacent stroma (Fig. 33-2). The tumor nodules are composed of a chaotic tangle of regenerating nerve fascicles of various sizes and shapes separated by fibrous tissue; variable chronic inflammation; or less often, granulomatous reaction1,3,4 (see Fig. 33-1). Mucinous changes are common in early lesions, especially in the regenerating perineurial spaces.14 The regenerated individual fibers have a nearly normal structural organization of typical Schwann cells, perineurial cells, and centrally located axons. Immunohistochemically, palisaded encapsulated neuroma and traumatic neuroma share several features.14 The constituent cells of the fascicles stain for S-100 protein. In traumatic neuroma, the perineurial cells in the surrounding sheaths are positive for epithelial membrane antigen (EMA). In palisaded

encapsulated neuroma, only the outer capsule reacts for this antigen, confirming a perineurial cell participation.14 Silver impregnation and neural filament stains reveal that the fascicles are rich in axons in both lesions. In traumatic neuroma, the axons follow the normal longitudinal arrangement in the proximal part of the tumor, but they become haphazardly and irregularly arranged toward the distal end.6,14,17 Prominent myelinization is often present, as detected by antibodies to myelin basic protein and CD57.17 DIFFERENTIAL DIAGNOSIS Palisaded encapsulated neuroma must be differentiated from other peripheral nerve sheath tumors, particularly schwannoma, as well as non-nerve sheath proliferations such as angioleiomyoma. Solitary schwannomas contain Antoni A and B type tissues with Verocay bodies and are most often devoid of axons by special stains. Neurofibroma may also be considered on cytologic grounds; however, the haphazard architecture contrasts the orderly appearance of palisaded encapsulated neuroma. Angioleiomyomas are well-circumscribed smooth muscle tumors that may occasionally mimic palisaded encapsulated neuroma, but the cytologic features of each are distinct. Smooth muscle cells of angioleiomyoma have a more eosinophilic, fine fibrillary cytoplasm and bluntended nuclei with a “bubbly” chromatin pattern. Thick-walled vessels are usually present. Axons are not absent. Plexiform or multinodular variants of palisaded encapsulated neuromas should be differentiated from plexiform variants of neurofibroma, schwannoma, and fibrohistiocytic tumors. Traumatic neuroma can be differentiated easily from the other variants of neuromas based on the presence of scar and chronic inflammation and a history of previous trauma. Painful plantar nodules, often referred to as Morton neuromas, are no longer considered true neuromas but rather localized forms of interdigital neuritis with a complex etiology.

PERIPHERAL NERVE SHEATH NEOPLASMS

Neurofibromas Synonyms: Solitary neurofibroma, solitary nerve sheath tumor, plexiform nerve sheath tumor, multiple neurofibromatosis Neurofibromas are complex proliferations of the various components of the neuromesenchyme, including Schwann cells, endoneurial fibroblasts, perineurial

Table 33-2 Histopathologic Diagnostic Features of Common Cutaneous Neural Neoplasms SOLITARY SUPERFICIAL NEUROFIBROMA

SOLITARY SCHWANNOMA

CLASSIC NERVE SHEATH MYXOMA

CELLULAR NEUROTHEKEOMA

Well circumscribed, nodular, rarely plexiform Yes, by perineurium Compactly arranged fascicles, separated by clefts

Relatively well defined, but with infiltrative margins None

Well circumscribed, nodular

Lobulated or plexiform

Yes, perineurium

Yes, partially by perineurium Hypocellular, myxoid matrix

Fascicular or irregular sheaths and nests None

Spindled cells with tapered, wavy nuclei

Spindled cells with tapered, wavy nuclei

None

Variable palisading

Spindled cells with tapered, wavy nuclei, plump fibroblasts, mast cells Rarely

Irregularly arranged axons Extensive fibrosis, rarely inflammation, macrophages

Relatively wellorganized axons No fibrosis or inflammation

FEATURE

TRAUMATIC NEUROMA

Growth pattern

Well circumscribed at the proximal end, irregular at the distal end Partially by fibrous sheath Unorganized tangles of regenerating fascicles

Cytologic features

Nuclear palisading and Verocay bodies Nerve fibers

Encapsulation Architecture

Other important features

PALISADED, ENCAPSULATED NEUROMA

Variable matrix from the fine fibrillary to dense fibrotic

Rare, scattered axons Fibrosis, myxoid, and vascular changes

Antoni A type: hypercellular Antoni B type: hypocellular Spindled cells with tapered, wavy nuclei, mast cells

Solid proliferation of epithelioid or spindled cells

Stellate, spindled, and giant cells

Large epithelioid or spindled cells

Yes

None

None

None or only at the origin Hemorrhage, thrombosis, hyalinization, cytologic atypia (ancient changes)

None

None

Mild cytologic atypia

Variable atypia, rare mitotic figures

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Table 33-3 Palisaded and Encapsulated Neuroma

886

Clinical Features Usually solitary Predilection for the face of adults Nondescript skin-colored papule or nodule suggesting a dermal nevus Histopathologic Features Well-circumscribed nodule with incomplete encapsulation Spindled cells arranged in short fascicles Well-developed palisading of nuclei is usually not present Differential Diagnosis Schwannoma Leiomyoma Neurotized nevus Other spindle cell melanocytic tumors

cells, and mast cells.1,3,4 In this complex proliferation, however, the proportion of each cell type varies, giving rise to broad histologic appearances. Because axons do not duplicate, their relative proportion to the other cell components is less than the usual 1:1 axon-toSchwann cell ratio of the normal nerve. The main histopathologic types of neurofibromas include the sporadic cutaneous type, deep-seated encapsulated type, diffuse type, pigmented type, and plexiform type. Furthermore, other rare variants also exist, including atypical (cellular), sclerosing, and lipomatous types. Neurofibromas containing dendritic cells and hyperplastic pacinian corpuscles have also been described.1,3,4,18-30 CLINICAL FEATURES Sporadic neurofibromas are relatively common lesions in adults and affect both genders equally (Table 33-5). They are soft or rubbery, dome-shaped or polypoid, skin-colored or tan papules or nodules (Fig. 33-3A). They may display a “button hole” sign on pinching.3,19 They are usually asymptomatic, but the pedunculated forms may become irritated.20 A few lesions in a single patient, provided there are no other stigmata present, do not indicate neurofibromatosis; however, they still can be part of this syndrome. Contrary to this, the plexiform variant is considered pathognomonic for neurofibromatosis type 1.1,3 The diffuse, deep-seated, and pigmented variants may also be more common in neurofibromatosis.1,23 Whereas common solitary neurofibromas grow slowly and follow a benign course, the deep-seated, diffuse, and

A

B  FIGURE 33-1 Palisaded, encapsulated neuroma. (A) Well-delineated, encapsulated dermal nodule. (B) The individual fascicles are compactly and relatively uniformly arranged and are separated by narrow artificially produced clefts. Focal palisading of the nuclei is present.

plexiform variants may cause local infiltration and organ displacement. The plexiform type also has an increased probability of malignant transformation.1,3 The typical presentation of plexiform neurofibroma is a baglike or twisted ropelike dermal or subcutaneous mass, often associated with redundant skin folds, hyperpigmentation, and hirsutism.1,3,30,31 Besides plexiform neurofibroma, the other important clinical stigmata of neurofibromatosis include conjunctival Lisch nodules, café-au-lait spots, bilateral axillary freckling, numerous superficial and deeply located diffuse neurofibromas, and various soft tissue, bone, endocrine, and other types of neoplasms. 31 For a detailed description of the various types of neurofibromatoses, readers are referred to the specific literature on this subject.31-36 HISTOPATHOLOGIC FEATURES Common solitary cutaneous neurofibromas are round, oblong, or polypoid nodules in the dermis. Although they are well

circumscribed, they are not encapsulated (Fig. 33-3B). The tumor is composed of proliferating delicate spindle cells with indistinct cytoplasmic membranes (see Tables 33-2 and 33-5). The nuclei are wavy, with tapered ends and an evenly distributed chromatin pattern.1,3,4 Mitotic figures should not be

Table 33-4 Traumatic Neuroma

Clinical Features May occur at any site after trauma Small skin-colored nodule or mass Often painful Histopathologic Features Circumscribed but unencapsulated Mass composed of axons and Schwann cells admixed with fibrous tissue Differential Diagnosis Neurofibroma Perineurioma

A

B

present. The cells are embedded in a fibrillary pale-pink collagenous stroma (see Fig. 33-3C). The cellularity varies from densely cellular to a loosely arranged pattern. The stroma can be markedly fibrotic, edematous, myxomatous, and even vascular. Compression of surrounding fibrous tissue may mimic the presence of a true capsule; however, the fibrous tissue is often less organized and prominent compared with the capsule of schwannoma. The cutaneous adnexa are surrounded but spared by the tumor. Mast cells are present in variable numbers

Table 33-5 Neurofibroma

Clinical Features Skin-colored or tan polypoid papule or nodule Soft or rubbery May involve any cutaneous site Plexiform pattern—pathognomonic of neurofibromatosis Histopathologic Features Spindle cell proliferation, wavy nuclei with tapered ends Often significant fibrosis Occasional mucinous stroma In general, not encapsulated Mast cells are common Plexiform variant is similar but with complex “wormlike” growth pattern Differential Diagnosis Neurotized nevus Schwannoma Trichodiscoma and related tumors Dermatofibroma Smooth muscle neoplasms Hypertrophic scar

throughout the lesion. Entrapped small nerve twigs, tactile body-like structures, or pigmented dendritic cells may be observed. Although nuclear palisading can occur, Verocay bodies are not characteristic findings.1,3 When neurofibromas develop in the deeper and larger nerves, they initially remain encapsulated due to confinement by the perineurium. These types are sometimes referred to as intraneural neurofibromas.4 In the deep-seated and diffuse types, the spindle cell proliferation is poorly defined and usually involves the subcutaneous fat. The tumor otherwise has similar features to the solitary type. The intraneural and diffuse (extraneural) growth patterns may be present in the same lesion.4 Plexiform neurofibromas (Fig. 33-4) are composed of interconnecting bundles and fascicles of markedly expanded nerves that are usually surrounded by a fibrous encapsulation of the epineurium and adjacent connective tissue.1,3,30 The superficial part, however, is usually not encapsulated, and the proliferating fascicles blend into the surrounding dermis. The individual fascicles display variable cellularity and often show edematous and mucinous changes. Cytologically, the cells are similar to those described in the solitary superficial form. In neurofibromatosis type 1, plexiform and diffuse growth patterns may coexist.1,3 Cytologic atypia in neurofibroma is a rare but often troubling finding. If not associated with increased cellularity or mitotic activity, isolated pleomorphism appears to have little clinical significance.24 An increased density of atypical cells, including areas of organized fascicular growth, necrosis, or mitotic activity, should raise concern for transformation

to malignant peripheral nerve sheath tumor (MPNST).34,37,38 Although the determination of malignant transformation in principally a morphologic exercise, strong expression of p53 or Ki-67 by the atypical cells may also favor development of MPNST.39,40 Immunohistochemically, the cells in neurofibroma variably express antigens, depending on the predominant cell types. These include S-100 protein and collagen type IV for Schwann cells, EMA for perineurial cells, vimentin for fibroblasts and Schwann cells, and neurofilament and myelin basic protein for axons and myelin sheaths, respectively.18 Axons may be scattered singly within the tumor, or clustered with similarity to small nerve twigs. Pigmented neurofibroma contains HMB-45-positive cells, and the dendritic cells of the peculiar variant of dendritic cell neurofibroma with pseudorosettes express CD57.21-24 DIFFERENTIAL DIAGNOSIS The solitary superficial type of neurofibroma must be differentiated from other spindle cell neoplasms that are not encapsulated, such as dermatofibroma, hypertrophic scar, neurotized intradermal melanocytic nevus, and traumatic neuroma. The diffuse deep-seated type and the pigmented variant may be confused with dermatofibrosarcoma protuberans and common blue nevus. The plexiform variant, which has the greatest clinical relevance because of its common association with von Recklinghausen disease and the increased possibility of malignant transformation, should be separated from plexiform schwannoma and plexiform fibrohistiocytic tumor. Each of these can be differentiated relatively easily with the help of immunohistochemical markers.41

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

 FIGURE 33-2 Traumatic neuroma. (A) The regenerating nerve fascicles have haphazard arrangement and are embedded in a markedly fibrotic stroma. (B) There is prominent variation in the size and shape f the fascicles, which are separated by scar tissue.

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A

C  FIGURE 33-3 Neurofibroma. (A) Rubbery, polypoid, skin-colored papules and nodules in a patient with neurofibromasis. (B) Solitary, cutaneous neurofibroma. A well-defined but non-encapsulated dermal nodule, which on occasion becomes pedunculated. (C) The slender spindle cells are haphazardly arranged in a fine fibrillary matrix.

A

888

B

B

 FIGURE 33-4 Plexiform neurofibroma, superficial type. (A) Interconnecting nerve fascicles of various size and shape are infiltrating the dermis. (B) The spindle cells in a whorling pattern are embedded in variably fibromatous stroma.

Perineuriomas

CLINICAL FEATURES Soft tissue perineurioma arises mainly in middle-aged patients, typically on the extremities and trunk.42 The tumor is predominantly located in the subcutis; exclusive dermal manifestation is rare. A definitive association with neurofibromatosis type 1 or 2 has not been established. However, mutations involving the NF2 gene locus in perineuriomas have been described.43-45 The usual biologic course is benign.42,46-48 Sclerosing perineurioma usually presents a painless mass on the hands of young adults, particularly young men. Similar to the soft tissue variants, sclerosing perineurioma usually involves the subcutis.47 Fibrous perineuriomas appear closely related to the sclerosing form but are located in the dermis.48 HISTOPATHOLOGIC FEATURES Soft tissue perineurioma is usually well circumscribed by condensation of surrounding fibrous tissue but lacks a true capsule. The bulk of the tumor is composed of the proliferation of delicate spindle cells arranged in interwoven fascicles, often in a partial storiform pattern42,46 (Fig. 33-5). Perivascular whorls may be present.42 The stroma may be collagenous, hyalinized, hypocellular with a myxoid appearance, or a combination of these. The constituent cells are elongated, slender cells with disk-shaped or wavy nuclei and bipolar extensions of eosinophilic cytoplasm.42 Most lesions lack significant atypia. Mitotic figures are most often absent or rare.42,49 Sclerosing perineurioma is also well circumscribed and composed of epithelioid or spindle cells arranged in small whorls, cords, or chains intermixed

 FIGURE 33-5 Soft tissue perineurioma. Interweaving fascicles with a vague storiform pattern composed of elongated, slender spindle cells with dissecting collagen fibers.

between thick bundles of collagen. Mitotic activity is low.47 Immunohistochemically, the cells are positive for EMA, and claudin-1, CD34, Glut-1, collagen type IV, laminin, and vimentin are also usually expressed.42,46,47,50,51 A subset of sclerosing perineuriomas express smooth muscle actin and muscle-specific actin.47 Perineuriomas are negative for S-100 protein, GFAP, and neurofilaments.42,47-50 DIFFERENTIAL DIAGNOSIS Soft tissue perineurioma should be distinguished from variants of neurofibroma, the latter of which is positive for S-100 protein and neurofilaments. Lesions with an extensive storiform pattern may be confused with dermatofibrosarcoma protuberans, in which case the lack of epithelial membrane positivity and strong CD34 reaction should be helpful to make the diagnosis. Myoepithelioma may exhibit a whorling pattern but immunohistochemically is positive for cytokeratin and actin. Finally, sclerosing fibroma can occasionally be difficult to separate from perineuriomas with abundant collagen. The former, however, are negative for EMA and positive for factor XIIIa and focally CD34. Lesions with essentially identical light microscopic features of sclerosing fibroma but with S-100 protein positivity most likely represent burnt-out neurofibromas.

Schwannomas Synonyms: Neurilemoma, neurolemmoma, neurinoma, Schwann cell tumor, acoustic neuroma, perineurial fibroblastoma Schwannomas are considered true nerve sheath neoplasms because they are composed almost entirely of proliferating Schwann cells. The Schwann cell proliferation takes place within the confines of the perineurium and displaces the remainder of the normal nerve fibers to the periphery of the tumor.1,3 This histogenesis explains the three main features of schwannomas: the exclusive Schwann cell component, encapsulation, and the virtual lack of axons within the tumor. There are four main types of schwannomas: (1) the common solitary type,52-55 which is almost invariably a benign neoplasm; (2) the ancient type, which represents a degenerated variant of the common type56; (3) the plexiform type, which displays cytologic features similar to the common type but that has a distinct growth pattern57-61; (4) and the cellular type, a benign, hypercellular lesion that mimics a malignancy and is prone to recurrence.3,62-64 Malignant transformation of a benign schwannoma (malignant schwannoma) is extremely rare.65,66 This lesion is now usually designated as MPNST. Other less common variants, such as pigmented (psammomatous melanotic),67-69 glandular,70,71

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

Synonyms: Storiform perineurial fibroma, fibrolamellar nerve sheath tumor, localized hypertrophic neuropathy Perineurial tumors encompass a morphologically diverse group of lesions that, by definition, are composed of predominantly perineurial cells.1,3 Recent immunohistochemical and molecular biologic studies have helped to better clarify these lesions and have considerably simplified the previously confusing terminology. Based on the current view, these tumors can be divided into four main types: soft tissue, sclerosing, reticular, and intraneural.1,3,42 The previously designated localized hypertrophic neuropathy is now considered an intraneural perineurioma. Although all forms are considered rare, the soft tissue and sclerosing types are most relevant for dermatopathologists and are therefore discussed herein.

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epithelioid,72-75 and neuroblastoma-like,76-78 have also been reported.

890

CLINICAL FEATURES Common solitary schwannomas are tumors of adulthood; however, although rare, unusual congenital variants have been documented. There is no significant predilection for either gender.1,3,52,55 The lesions are usually solitary tumors, but rarely they can occur as multiple lesions, designated as neurilemmomatosis (schwannomatosis).79-83 Whereas cutaneous solitary schwannoma rarely can be part of neurofibromatosis type 1, bilateral schwannomas of the vestibular nerve are more common in the type 2 manifestation of neurofibromatosis.80,82,84 The tumors have a predilection for the flexor aspects of the extremities, followed by the head and neck and mediastinum, but even the internal organs can be involved. The average size of the tumors ranges between 1.5 and 3 cm, but extreme growth may occur, especially in body cavities. The usual appearance is that of a skin-colored or pink-yellow, deep dermal or subcutaneous well-defined nodule that may be partially movable. Although the lesion in general is asymptomatic, it may be slightly painful or tender on palpation. Sensory or motor impairment may occur, but it is extremely rare.1,3,52 The cutaneous tumors grow slowly after an almost invariably benign course, but they may encompass adjacent tissues and organs, necessitating their removal. Pigmented (melanotic) schwannomas are a rare variant that may occur sporadically or in association with lentigenes, cutaneous and visceral myxomas, blue nevi, and endocrine hyperactivity in patients with Carney complex.67-69 A subset of pigmented melanotic schwannomas carry a risk of metastatic potential.67 HISTOPATHOLOGIC FEATURES Common solitary schwannomas are ovoid or round tumors located in the deep dermis or subcutis (see Tables 33-2 and 33-6). They are well delineated by a thin, fibrous capsule. Two main histologic patterns are considered characteristic of schwannomas: the Antoni type A and type B patterns1,3 (Fig. 33-6A). The Antoni type A pattern refers to a solid proliferation of Schwann cells forming compactly arranged fascicles and cords. The ovoid nuclei of the spindled Schwann cells are often arranged in a parallel fashion, referred to as palisading. When two rows of palisaded nuclei are separated by an acellular collagen-rich matrix, the resulting structures are designated as Verocay bodies1,3 (Fig. 33-6B). Although nuclear palisading

Table 33-6 Soft Tissue Perineurioma

Clinical Features Middle-aged adults Predilection for extremities and trunk Skin-colored soft tissue nodules and tumors Histopathologic Features Dermal or subcutaneous mass Well circumscribed, but without thin capsules Interweaving fascicles and whorls Delicate, elongated spindle cells Cracking or lamination of collagen fibers Differential Diagnosis Neurofibroma Dermatofibrosarcoma protuberans Myoepithelioma Sclerotic fibroma

is nonspecific and may occur in other soft tissue tumors (eg, neurofibroma, dermatofibroma, leiomyoma), it is quite common in schwannomas. Verocay bodies superficially resemble tactile bodies, but they do not have a sensory innervation. The cells constituting Antoni type A areas do not display significant cytologic atypia, and mitotic figures are absent or extremely rare. Antoni type B tissue shows various degrees of cystic, edematous, or myxoid degeneration associated with vascular changes, namely thickened and hyalinized vessel walls, and fibrosis.1,3 Thrombosis of the vessels, hemosiderin deposition, adjacent chronic inflammatory infiltrate, and increased numbers of mast cells are common. The degenerating cells often display variable nuclear atypia and pleomorphism, but mitotic figures are usually absent. If the tumor is thoroughly sampled, its nerve origin can be recognized, as a rule, around the periphery of the lesion.1,3 Ancient schwannoma is composed almost entirely of Antoni type B tissue (Fig. 33-7). The degenerating cells may display prominent cytologic atypia, but no other features of malignancy are present.53,56 Cellular schwannoma is usually a tumor of the mediastinum, retroperitoneum, or deep soft tissue. It is exceedingly rare in the skin. The tumor is a hypercellular mass of spindle-shaped cells that form intertwining fascicles and cords (Fig. 33-8). Mild to moderate cytologic atypia and low mitotic rate (5 per 20 high-power fields [hpf]) are characteristic. Atypical mitotic figures, necrosis, and invasion are absent.62-64 Plexiform schwannoma is predominantly composed of Antoni type A tissue.57,58 The

proliferating cells form interconnecting fascicles and nodules extensively involving the dermis and subcutis (Fig. 33-9). The proliferation, however, remains mainly within the confines of the capsule. Mild to moderate cytologic atypia is common, but mitotic figures are rare or absent.57 In contrast to the plexiform neurofibroma, this tumor is not considered pathognomonic of neurofibromatosis even though it has been reported in association with neurofibromatosis type 2.61 Its malignant transformation is uncommon.58 Schwannoma intermixed with true epithelial glands are rare.70-71 Whether these changes represent divergent differentiation of the schwannian cells or entrapped adnexal structures is unclear. Pigmented (melanotic) schwannomas contain melanin pigment, often in abundance.67 The lesional cells may be epithelioid, spindled, or enlarged with prominent nucleoli. The marked atypia characteristic of most melanomas is absent. Tumors of the Carney complex usually have psammoma bodies and admixed adipose tissue.67-69 Epithelioid variants of schwannoma are uncommon but can mimic a malignancy due to the unusual morphologic features and lowlevel mitotic activity. The circumscribed growth pattern, relative uniform cytology, absence of atypical mitotic figures and lack of necrosis favor a benign lesion.72-75 Collagen, especially type IV, is commonly produced by both spindled and epithelioid schwannoma cells and may provide a clue to the histogenesis.1 In rare cases, collagen production may manifest as rosettelike structures,76-78 or large, obscuring nodules.75 Malignant transformation of an ordinary solitary schwannoma is considered an exceedingly rare phenomenon.1,3,65,66,85 When present, however, the malignancy may manifest as epithelioid MPNST or angiosarcoma.85 Immunohistochemically, schwannomas stain strongly for S-100 protein and type IV collagen in the Antoni type A areas. The capsule is positive for EMA, supporting perineurial cell participation.1,3 Stains for axons either by silver impregnation or by immunohistochemistry usually show residual parent nerve fibers in the capsule and a lack of axons in the tumor itself except at the periphery if the nerve of origin is present.3 DIFFERENTIAL DIAGNOSIS Common solitary schwannoma must be differentiated from the encapsulated, palisaded neuroma and amputation neuroma, both of which contain abundant axons, as opposed to schwannoma. Angioleiomyomas are

composed of spindle cells with more eosinophilic cytoplasm and characteristic nuclei. Because vascular and degenerative changes may mimic ancient schwannoma, immunohistochemical stains for smooth muscle–specific actin and desmin may be necessary to render a specific diagnosis. Plexiform schwannomas can be separated from plexiform neurofibromas by the virtual absence of axons. The plexiform fibrohistiocytic tumor may represent a diagnostic problem, but it contains histiocytic cells and often multinucleated giant cells and does not stain for S-100 protein.41

B  FIGURE 33-6 Solitary schwannoma. (A) The tumor is an encapsulated nodule consisting of hypercellular Antoni A and hypocellular Antoni B types of tissues. (B) Characteristic nuclear palisading and Verocay bodies with adjacent edematous stroma are present.

 FIGURE 33-7 Ancient schwannoma. The lesion is composed of extensive areas of degenerative changes with stromal edema, vascular abnormalities, chronic inflammation, and foamy macrophages.

Nerve Sheath Myxoma

CLINICAL FEATURES Nerve sheath myxoma is most common on the extremities, especially the hands and fingers.88 There is no definite gender predilection, and these tumors may present at any age. Individual lesions are skin-colored or pink, soft to rubbery papules and nodules. The clinical differential diagnoses include ganglions, myxoid cysts, dermal nevi, fibrolipomas, or adnexal neoplasms. Nerve sheath myxoma may recur if not completely excised.

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

A

HISTOPATHOLOGIC FEATURES Nerve sheath myxoma is a well-delineated tumor composed of interconnecting lobules and fascicles within the dermis, subcutis, or both (Fig. 33-10A; see also Tables 33-2 and 33-7). The lobules or fascicles contain abundant myxomatous stroma that is only sparsely cellular.86-89 The component cells are variable and may be plump, spindle shaped, slender, elongated with bipolar cytoplasmic extensions, stellate, or multinucleate (see Fig. 33-10B). Ringlike vacuolated forms mimicking adipocytes may be observed.88 The nuclei are slightly hyperchromatic without prominent nucleoli. Mitotic figures are sparse or absent. The myxoid nodules are often separated by a partially preserved capsule or by condensation of the surrounding collagenous tissue. Although adjacent nerve twigs often can be identified, direct connection with nerves usually is not readily discernible.

891

Synonyms: Pacinian neurofibroma, cutaneous lobular neuromyxoma, myxomatous perineurioma, bizarre cutaneous neurofibroma Nerve sheath myxoma is a cutaneous peripheral nerve sheath tumor characterized by the proliferation of schwannian cells in a variably myxomatous stroma.1,3,86,87,88

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

 FIGURE 33-8 Cellular schwannoma. A compact fascicular proliferation of spindle cells with variable cytologic atypia and rare mitotic figures are seen.

Immunohistochemically, the lesional cells react strongly to S-100 protein and collagen type IV, variably to GFAP, and less intensely to neuron-specific enolase and CD57.88,89 When the capsule is preserved, a reaction to EMA is often present. Neurofilament stain for axons is usually negative. The myxomatous stroma is strongly positive for acidic mucopolysaccharides.89,90 DIFFERENTIAL DIAGNOSIS Focal cutaneous mucinosis and ganglion cysts may resemble nerve sheath myxomas superficially but do not display a plexiform or fascicular growth pattern, and their cells do not stain for S-100 protein.88,89

A

892

Strong, uniform S-100 expression favors nerve sheath myxoma over myxoid variants of neurothekeoma.

Neurothekeoma Synonyms: Mature (classical, myxoid) neurothekeoma, immature (cellular) neurothekeoma The term neurothekeoma refers to a spectrum of neoplasms of uncertain histogenesis, which despite the name, usually do not display definitive features of nerve sheath lineage. At one end of the spectrum are hypocellular neurothekeomas associated with abundant myxomatous stroma. In the past, these have been

referred to as classic nerve sheath myxomas89-91 or mature nerve sheath myxomas because ultrastructurally and immunohistochemically, some displayed characteristics of nerve sheath differentiation. At the other end of the spectrum are hypercellular tumors composed of immature cells in a collagenous stroma with only either minimal or absent myxoid quality. Such lesions displayed distinctly different features and were often designated cellular neurothekeomas or immature nerve sheath myxomas.91,92 As more studies of these lesions have become available, the emerging concept is that although a spectrum of myxoid (hypocellular), cellular, and mixed variants of neurothekeoma exist, the myxoid variants may be histogenetically different from nerve sheath myxoma (described in a prior section) despite their morphologic similarities. This conceptual paradigm shift still awaits confirmation. It appears, however, that many tumors previously described as classical nerve sheath myxoma, but with definitive nerve sheath features (eg, S-100 protein expression) are actually best classified as ordinary nerve sheath myxoma.93,94 Neurothekomas (hypocellular, mixed, and cellular forms) may demonstrate multiple lines of mesenchymal differentiation, including histiocytic, myoid, and myofibroblastic, but only rudimentary or indirect markers of peripheral nerve sheath lineage. Thus, their histogenesis remains controversial.90-100 CLINICAL FEATURES Neurothekeomas show a predilection for younger adults (second to third decades of life), with a female preponderance, and are found at any body site but mainly in the head and neck areas.92 These tumors are firm,

B

 FIGURE 33-9 Plexiform schwannoma. (A) Interconnecting hypercellular nodules and fascicles infiltrating the dermis. (B) The individual fascicles are composed mainly of Antoni A type of tissue with common nuclear palisading and Verocay bodies.

Table 33-7 Schwannoma

pink or red-brown papules and nodules that usually are smaller than 3 cm in diameter. All variants are commonly asymptomatic, but on occasion, they may become sensitive or tender. They are benign lesions but may recur if they are incompletely removed. HISTOPATHOLOGIC FEATURES Neurothekeoma is composed of nests or small clusters of spindled or epithelioid cells embedded in a variably myxoid or collagenous matrix. The myxoid ground substance may be abundant, similar to nerve sheath myxoma, relatively sparse, or intermediate.93 Many neurothekeomas are ill-defined, often infiltrative lesions occupying much of the dermis and even extending to the subcutis. The

A

are less frequently observed.89,90,97 GFAP is negative.90 The cells do not or only focally and weakly express S-100, a feature that distinguishes neurothekeoma from nerve sheath myxoma.89,90,93-96,102 DIFFERENTIAL DIAGNOSIS Neurothekeomas commonly show variable amounts of myxoid matrix and dense collagen within the same histologic section, and strict criteria for defining highly myxoid and cellular variants do not exist. Additionally, the distinction between nerve sheath myxoma and highly myxoid variants of neurothekeomas may be difficult in some cases. Myxoid-rich forms of neurothekeoma must be differentiated from the myxoid variant of neurofibroma. The latter frequently contains axons demonstrable by special stains, and some usually retain the architecture of a neurofibroma. Cellular neurothekeomas have a wider differential diagnosis, including epithelioid Spitz nevus, deep-penetrating nevus, plexiform spindle cell nevus, and fascicular variants of cellular blue nevi. With the exception of the latter, these entities usually show epidermal melanocytic hyperplasia, often contain distinct pigmented cells, and stain strongly for S-100 protein.89,92 One must also consider fibrohistiocytic lesions such as dermatofibroma, epithelioid cell histiocytoma, and juvenile xanthogranuloma. However, careful study of histologic features and the adjunctive use of immunostaining should facilitate this discrimination. Epithelioid variants of piloleiomyoma can be excluded based on their fine cytomorphologic features, their connection with existing pilar muscles, and the strong reaction with both smooth muscle–specific actin and

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

Clinical Features Deep dermal or subcutaneous nodule Up to 3 cm May be painful Predilection for flexor surface of extremities and head and neck Histopathologic Features Well-circumscribed, encapsulated, spindle cell proliferation Alternating Antoni A and B areas Palisaded nuclei Cystic or myxoid degeneration is common Thickened hyalinized vessel walls Differential Diagnosis Neuromas Smooth muscle neoplasms Melanocytic neoplasms with spindle cell phenotype

growth patterns are fascicular, plexiform, nodular, or nested, but a combination of these patterns may also occur89,91,92,95 (Fig. 33-11A; see also Tables 33-2 and 33-8). The tumor is mainly composed of epithelioid cells with large, ovoid nuclei; ample eosinophilic cytoplasm; and indistinct cytoplasmic membranes. The chromatin is often concentrated around the nuclear membrane, and there is a small, prominent nucleolus (see Fig. 33-11B). Spindle-shaped cells with plump or ovoid nuclei are also common, especially when the cells form nests or whorls.94,96 When present, myxoid material is usually accumulated around the individual cell nests. In cellular variants, individual cells or larger nests may be separated by thick bundles of hyalinized collagen. Alternatively, fascicles of cells may surround collagen bundles, mimicking dermatofibroma. Other stromal changes, including lymphocytic inflammation and angioplasia, may occur. Occasionally, the overlying epidermis shows mild to moderate melanocytic hyperplasia. A direct association with nerve twigs is difficult to demonstrate.89 Mitotic figures are usually present, and varying degrees of cytologic atypia are not infrequently seen.94,98 Although increased tumor size, nuclear pleomorphism, and mitotic activity may generate concern, these features do not appear predictive of recurrence.94 True malignant variants are rare, if they exist. Immunohistochemically, myxoid and cellular forms of neurothekeoma show a variable and inconsistent reaction pattern. Whereas NKI/C3 is commonly positive, PGP9,5 microphthalmia transcription factor (MiTF), neuron-specific enolase, and collagen type IV are positive in many tumors.90,93,94,101 Expression of smooth muscle actin and CD57 (Leu-7)

B

 FIGURE 33-10 Nerve sheath myxoma. (A) Well-defined dermal nodules and fascicles with myxomatous stroma. (B) The mucinous stroma contains scattered spindle, polygonal, and stellatelike cells.

893

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 33-8 Nerve Sheath Myxoma (Neurothekeoma)

Clinical Features Young to middle-aged adults Female predominance Predilection for head and neck and upper extremities Skin-colored papules or nodules Histopathologic Features Lobules and fascicles of spindled cells within myxoid matrix Cells may be epithelioid or multinucleated Cellular variant is much more densely cellular with less myxoid matrix Atypia and mitoses may be present Differential Diagnosis Neurofibroma Melanocytic neoplasms (especially Spitz tumor) Melanoma, especially neurotropic and myxoid variants Fibrohistiocytic neoplasms: juvenile and adult xanthogranuloma Smooth muscle neoplasms

desmin. In cases in which the predominant cell type is spindle shaped, plexiform fibrohistiocytic tumors must be excluded.

Granular Cell Tumor Synonyms: Granular cell nerve sheath tumor, granular cell myoblastoma, granular cell schwannoma, Abrikossoff tumor

A

894

Granular cell tumor has a disputed histogenesis. A neural origin is postulated based on the observation that granular cells similar to those composed of these tumors are often observed within or adjacent to normal peripheral nerves.103-105 The granular cells also express S-100 protein, CD57 (Leu-7), and myelin basic protein, as do normal peripheral nerves.106 However, morphologically identical granular cells also have been described in various other nonneural neoplasms.107 CLINICAL FEATURES Granular cell tumors usually present in adults with a 1:3 male-to-female ratio. In about 90% of cases, the tumor is solitary (Table 33-9). In the remaining 10%, multiple lesions are present, predominantly in blacks.103 The most common site is the tongue, followed by the skin, various organs (eg, the gastrointestinal and upper respiratory tract), and skeletal muscle.105,108 In the skin, granular cell tumor presents as a skin-colored, firm, often verrucous or ulcerated nodule ranging in size from 0.5 to 3.0 cm. The lesion is usually asymptomatic, but mild pruritus or tenderness may occur. Malignant granular cell tumor is a rare entity that presents as a rapidly growing nodule with frequent ulceration.109-112 Extensive local involvement and lymph node metastasis have been described. HISTOPATHOLOGIC FEATURES Granular cell tumors form an ill-defined, often infiltrative mass in the dermis, frequently

involving the subcutis (see Table 33-9). The relatively large, polygonal cells are arranged in nests and cords, but infiltration as single cells or peculiar plexiform growth patterns also have been documented (Fig. 33-12A). The cells have an abundant, finely granular, faintly eosinophilic cytoplasm with small, round, centrally located nuclei103,108 (see Fig. 33-12B). Occasional tiny intracytoplasmic spherules with halos are present. Mitotic figures are rare or absent. The surrounding dermis is frequently fibrotic or hyalinized. Association with a peripheral nerve is extremely uncommon. The overlying epidermis often displays prominent pseudoepitheliomatous hyperplasia. Occasionally, prominent nucleoli or “degenerative” nuclear features may be present in clinically benign forms and do not necessarily connote a malignancy. Histopathologically, in fact, the malignant variant103 may be indistinguishable from the benign lesion; in other cases, distinct cytologic atypia, increased mitotic activity, abnormal mitotic forms, and areas of necrosis are present.109-112 In the former case, only the clinical presentation, including rapid growth, large size, and ulceration, permits prediction of the malignant nature of the tumor.112 The intracytoplasmic granules stain positively with the periodic acid–Schiff (PAS) reaction, but they are diastase resistant. Ultrastructurally, the intracytoplasmic granules are membrane-bound lysosomes and autophagosomes.105,113 Immunohistochemically, the cells are positive for S-100 protein, CD57 (Leu-7),

B

 FIGURE 33-11 Cellular neurothekeoma. (A) The tumor is composed of fascicles and nests infiltrating the dermis and subcutis without prominent myxomatous changes. (B) The tumor cells have eosinophilic cytoplasm, large, vacuolated nuclei, often with prominent nucleoli. Mitotic figures are scant.

Table 33-9 Granular Cell Tumor

peripheral nerve myelin proteins, neuronspecific enolase, and vimentin.106,108,113 Although MiTF is usually expressed, other melanocytic markers, such as HMB-45 and Melan-A, should be absent.114 DIFFERENTIAL DIAGNOSIS Granular cell tumors often are associated with prominent pseudoepitheliomatous hyperplasia

A

Malignant Peripheral Nerve Sheath Tumor Synonyms: Malignant schwannoma, neurofibrosarcoma, neurogenic sarcoma The current prevailing view on MPNSTs s is that they originate either de novo from a peripheral nerve or arise from a sporadic type or a neurofibromatosis-1–associated neurofibroma. However, exceedingly rarely, they may develop from schwannoma, ganglioneuroma, ganglioneuroblastoma, or pheochromocytoma.3,115 MPNST is usually a tumor of the deep soft tissues, head and neck areas, or retroperitoneum.3,115 Nevertheless, it carries a great relevance for the dermatologist and dermatopathologist because approximately 50% of MPNSTs are associated with neurofibromatosis type 1.116 Cutaneous involvement is often the result of direct extension from a deeply located tumor. Primary cutaneous MPNST are much more rare and likewise represent malignant transformation of a preexisting neurofibroma, usually of the plexiform type, or are associated with a peripheral nerve.38 The more generic term MPNST is favored

over malignant schwannoma. Because the vast majority of MPNSTs arise from neurofibroma3,115 malignant schwannoma would imply incorrectly the histogenesis in most cases.117,118 Although uncommon, MPNSTs arising in schwa-nnoma often have an epithelioid morphology.85 CLINICAL FEATURES MPNST is a tumor of adulthood; however, the cases that are associated with neurofibromatosis type 1 tend to occur in the younger age group. Whereas the sporadic form of MPNST is roughly equally common in both genders, it is more common in males when the tumor is associated with neurofibromatosis (Table 33-10). The tumor presents as a gradually growing, asymptomatic soft tissue mass, but pain, paresthesia, or weakness may occur at any stage of development.3,115 Whereas the sporadic type usually involves the main nerve trunks of the extremities, tumors associated with neurofibromatosis are more common on the trunk.118-121 Sudden enlargement of a preexisting plexiform or solitary neurofibroma is always suspicious for malignant transformation. The overall clinical course is poor, especially in patients with associated neurofibromatosis; it is manifested by aggressive local recurrence, distant metastasis usually to the lung, and eventual death.119 HISTOPATHOLOGIC FEATURES The predominant histopathologic type of MPNST is composed of spindle cells arranged in

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

Clinical Features Adults, predilection for women May occur at almost any site, predilection for tongue Extremely rare malignant counterpart is often large, deep seated, and unlikely to be encountered by dermatopathologist Histopathologic Features Ill-defined infiltrative tumors Large cells with abundant finely granular eosinophilic cytoplasm Often associated with pseudoepitheliomatous hyperplasia, particularly in mucosal locations Criteria for malignancy are not well established but include large size and mitotic activity Differential Diagnosis Xanthoma Reticulohistiocytoma Adult-type rhabdomyoma Alveolar soft part sarcoma Metastatic Leydig cell tumor and granular cell variant of renal cell carcinoma

and may be misdiagnosed as squamous cell carcinoma. Cells of xanthomas contain fine cytoplasmic vacuoles rather than granules and are PAS negative. Various other tumors, including basal cell carcinoma, leiomyoma, leiomyosarcoma, and dermatofibroma, may also contain granular cells.

B

 FIGURE 33-12 Granular cell tumor. (A) Indistinct, eosinophilic tumor cells forming nests and cords infiltrate the dermis and subcutis. The overlying epidermis is often acanthotic. (B) The tumor cells have polygonal shape; indistinct cytoplasmic membranes; and uniformly small, round nuclei. The cytoplasm has a characteristic fine granular appearance.

895

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 33-10 Malignant Peripheral Nerve Sheath Tumor

896

Clinical Features Only rarely involves skin Often associated with neurofibromatosis Histopathologic Features Spindle cells with wavy nuclei Cellular areas alternating with less cellular myxoid zones is characteristic Increased cellularity adjacent to blood vessels Only 50% of tumors are immunoreactive for S-100 protein Tumors may show heterogeneous differentiation (i.e., rhabdomyoblastic, cartilaginous, osseous) Differential Diagnosis Spindle cell melanoma, especially neurotropic melanoma Monophasic synovial sarcoma Fibrosarcoma

sweeping fascicles38,120-123 (see Table 33-10). This pattern is also referred to as a herringbone pattern and often is composed of alternating hyper- and hypocellular areas (Fig. 33-13A). Although MPNST may bear resemblance to fibrosarcoma, the constituent cells differ from fibroblasts by their slender, wavy nuclei and indistinct cytoplasmic membranes. In addition, focal whorling, nuclear palisading, or tactile body-like structures may be present. Cytologic pleomorphism and nuclear atypia are variable (see Fig. 33-13B). Mitotic activity greater than 4 per 10 hpf is common.3 Intratumoral hemorrhage and geographic necrosis are particularly common in high-grade tumors.115 Rare subtypes include elements of divergent differentiation, including skeletal muscle (socalled Triton tumor), cartilaginous, and osteoid, but glandular, epithelioid, and neuroblastic components have also been described.3,115 Immunohistochemically, only about 50% to 65% of spindle cell MPNSTs stain for S-100 protein, which may be focal and weak.3,38,115 In the remainder, the diagnosis can be quite difficult, especially if a direct connection with a peripheral nerve or existing neurofibroma cannot be established. Other markers, including vimentin, CD57, myelin basic protein, laminin, collagen type IV, and neuron-specific enolase and neural filaments115,122 are even less specific but in the appropriate context can help to corroborate neural differentiation. Frequently, immunohistochemical evaluation of a suspected MPNST relies

B

A  FIGURE 33-13 Malignant peripheral nerve sheath tumor. (A) The tumor is composed of intersecting and “sweeping” fascicles of spindle cells. (B) The tumor cells show marked cytologic pleomorphism, nuclear atypia, and increased mitotic figures.

more on the absence of markers commonly expressed by morphologically similar spindle cell tumors (eg, smooth muscle actin in leiomyosarcoma, HMB45 in melanoma) as opposed to confirming expression of a specific antigen. Unlike most neurofibromas, the majority of MPNSTs strongly overexpress p53, which may be etiologically related to malignant development.40 DIFFERENTIAL DIAGNOSIS Conventional MPNST should be differentiated from monophasic synovial sarcoma, leiomyosarcoma, and spindle cell variants of melanoma. Although synovial sarcoma is unusual in the skin, molecular testing to exclude the presence of t(X;18) may be warranted. Clinical history, identification of an associated nerve of origin, cytologic features (especially the nuclear features), and thorough exclusion of other spindle cell neoplasms by immunohistochemistry should be helpful for making the definite diagnosis.

PRIMARY NEUROENDOCRINE CARCINOMA OF THE SKIN Synonyms: Merkel cell carcinoma, trabecular carcinoma of the skin, primary small cell carcinoma of the skin, cutaneous APUDoma Although the cells of primary neuroendocrine carcinoma of the skin (PNECS) and the normal Merkel cell, which is a specialized receptor cell of touch located in the basal layer of the epidermis, share several morphologic, immunohistochemical, and ultrastructural features, there is little evidence for a direct histogenetic relationship between the two.124 Furthermore, other extracutaneous neuroendocrine tumors also display similar features; therefore, the conceptually more unifying term PNECS is preferred over Merkel cell carcinoma.124 CLINICAL FEATURES PNECS is most common in late adulthood, and it is slightly

Table 33-11 Neuroendocrine (Merkel Cell) Carcinoma of Skin

more prevalent in women. The tumor involves mainly the head and neck areas, followed by the extremities and the buttocks (Table 33-11). The usual appearance is a pink-red or violaceous, firm, dome-shaped solitary nodule that grows rapidly (Fig. 33-14A).125 Ulceration may occur. Although rare spontaneous regression has been reported, the usual biologic course is that of an aggressively growing, quickly metastasizing tumor with a usually fatal outcome.126-129 Recent studies suggest genomic integration of a polyomavirus may be linked to the pathogenesis of these neoplasms.130 HISTOPATHOLOGIC FEATURES PNECS appears as a poorly defined dermal mass, frequently infiltrating the subcutaneous fat, fascia, and muscle. Although it may show various growth patterns, a sheetlike growth is the most common, followed by the nested and trabecular types (Fig. 33-14A; see also Table 33-11). Characteristically, the edge of the tumor shows a trabecular infiltrating pattern.124,125 The tumor is composed of monotonously uniform, small, round to oval cells that are about two to three times larger than mature lymphocytes. The nuclei are ovoid with finely dispersed chromatin and distinct nuclear membranes. Nucleoli are usually not prominent (see Fig. 33-14B). Mitotic figures are abundant. The cytoplasm is scant and faintly amphophilic. Extensive necrosis, including individual cell necrosis, and characteristic crush artifact are common in PNECS.124,125 Various peculiar morphologic patterns have been described in PNECS, including rosettelike structures resembling Homer Wright

DIFFERENTIAL DIAGNOSIS A broad spectrum of small, round, blue cell tumors of various histogeneses may be confused with PNECS. These include metastatic small cell carcinoma of the lung, poorly differentiated adnexal carcinoma, lymphoblastic lymphoma, primary or metastatic neuroblastoma, primary or metastatic Ewing sarcoma/PNET, melanoma, and poorly differentiated squamous cell carcinoma. These entities can usually be differentiated with the help of immunohistochemistry. In general, diffuse paranuclear reactivity for cytokeratin 20, absence of cytokeratin 7 and TTF-1, and expression of neurofilament favor PNECS over metastatic pulmonary small cell carcinoma.142,147 The main immunohistochemical differential diagnostic features are summarized in Table 33-12.

NEURAL HETEROTOPIAS AND RELATED TUMORS Cutaneous neural heterotopias are rare conditions that represent a broad spectrum of abnormalities of the cerebrospinal axis. Histogenetically, most of them are due to abnormal closure of the neural

tube and its associated components, representing dysraphic conditions. A less common etiology of neural heterotopia is abnormal migration and differentiation of neural crest cells despite a complete closure of the neural tube.148 There are three major histopathologic manifestations of neural heterotopias in the skin: meningeal, neuroglial, and neuroblastic or ganglionic abnormalities. Only the most common entities relevant to dermatopathologists are discussed here.

Heterotopic Meningeal Tissue Cutaneous heterotopic meningeal tissues either represent herniations of the meningeal linings, as in the classic and rudimentary meningoceles of congenital malformation, or autonomous proliferations of displaced meningothelial cells, defined as meningiomas.149 CLINICAL FEATURES Rudimentary meningoceles are most common on the scalp along the cranial closure lines as skin-colored papules and nodules associated with alopecia or abnormal hair growth.150-153 Cutaneous meningiomas have three main forms of histogenesis, which also explains their clinical presentations.154 In type I, the tumors are composed of arachnoid lining cells that are misplaced during embryogenesis. These lesions are usually congenital and are located on the scalp, forehead, and paravertebral regions. In type II, the tumors develop along the course of the cranial nerves and therefore are located mainly on the head, usually in adult patients. Type III lesions represent cutaneous metastasis or direct extension of primary meningiomas of the arachnoid lining, and these carry the worst prognosis of the three types.154

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

Clinical Features Predilection for head and neck of older adults Solitary rapidly growing nodule Histopathologic Features Small, round, blue cell tumor Often nested or trabecular growth pattern High mitotic rate and frequent single-cell necrosis, often zonal necrosis Squamous differentiation not infrequently seen Differential Diagnosis Metastatic small cell carcinoma of lung and other sites Lymphoma and leukemia Small cell melanoma

rosettes of neuroblastoma, epidermotropic involvement with pagetoid spread, and eccrine and squamoid differentiation, as well as lymphoepitheliomalike features.131-135 The adjacent stroma may show fibrosis, a lymphoplasmacytic infiltrate, and increased vascularity. Immunohistochemically, PNECS demonstrates a characteristic paranuclear, globular-appearing (so-called dotlike) reaction to low-molecular-weight keratins and cytokeratin 20. This staining pattern corresponds to the ultrastructurally seen distribution of paranuclear whorls of intermediate filaments.136-142 The cells also commonly express EMA. In addition, there is expression of various neuroendocrine markers, including chromogranin A, synaptophysin, somatostatin, calcitonin, vasoactive intestinal peptides, and others. These peptides are associated with the ultrastructurally demonstrable membrane-bound densecore secretory granules. The tumor may also express neuron-specific enolase, neurofilament, and CD56.143 S-100 protein expression is characteristically negative.138-142 p53 and p63 expression may also be present, the latter of which may portend a clinically aggressive course.144 Similar to Ewing sarcoma or primitive neuroectodermal tumor (PNET), CD99 and Fli-1 can be expressed in PNECS.145 A subset of PNECS stain for terminal deoxynucleotidyl transferase (TdT).146

HISTOPATHOLOGIC FEATURES Rudimentary meningocele is an ill-defined mass of cavernous pseudovascular spaces embedded in a markedly collagenous stroma. The spaces may be lined by elongated meningoendothelial cells characterized by eosinophilic cytoplasm, round or ovoid nuclei, and a fine chromatin pattern (Fig. 33-15). Similar cells dissect or wrap around collagen fibers, producing “collagen bodies.”150 Significant cytologic atypia or mitotic activity is not present. Focal calcifications and psammoma bodies may occur.150-153 Immunohistochemically, the meningoendothelial cells are positive for EMA and vimentin.150 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes cellular neurothekeoma, vascular neoplasms (particularly

897

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

A

B

 FIGURE 33-14 Primary neuroendocrine carcinoma of the skin, Merkel cell carcinoma. (A) Pinkish-red, firm, dome-shaped solitary nodule on the arm. (B) The tumor forms irregular sheets and cords of hyperchromatic cells infiltrating the dermis. (C) The tumor cells have a relatively uniform size, round to ovoid shape, with scant cytoplasm and fine “dusky” chromatin pattern.

angiosarcoma), hemangiopericytoma, and giant cell fibroblastoma.

Cutaneous Meningioma

898

C

HISTOPATHOLOGIC FEATURES Cutaneous meningioma is composed of a multinodular mass in the deep dermis or subcutis, often with an infiltrative growth pattern.154-156 Depending on their histogenesis, the cells may show a variable degree of differentiation. In the most common form, the spindle cells show a concentric, whorl-like arrangement154 (Fig. 33-16). The cells have oval nuclei with vesicular chromatin. Cytologic

atypia may be predominant in type III lesions. Mitotic figures are rare in types I and II and variably increased in type III. Psammoma bodies are often present.154,157 Immunohistochemically, the constituent cells are positive for EMA and vimentin, but other antigen expression, such as S-100 protein, neuronspecific enolase, and cytokeratins, has also been described in the various subtypes of meningioma.155,157-159 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes metastatic squamous cell carcinoma, cutaneous adnexal neoplasms, hemangiopericytoma, neu-

rothekeoma, and cellular blue nevus. Distinct immunohistochemical profiles help to differentiate these lesions from meningioma.

Heterotopic Neuroglial Tissue The three major forms of neuroglial tissue displacement from the CNS are meningomyeloceles, meningoencephaloceles, and heterotopic brain tissue.160 In the first two forms, there is some degree of connection retained between the herniated brain tissue and the underlying structures, but in completely heterotopic brain tissue, there is no apparent communication. The

Table 33-12 Immunohistochemical Differential Diagnostic Features of Small Round Cell Cutaneous Tumors CK

CEA

EMA

LCA

VIM

CHG

SYN-7

LEU-7

DES

AC

NSE

NF

CD99 (013)

CK2O

−

+

−

+

−

−

+

+

−

−

−

+

+/−

ΝΚ

+

−

−

−

−

−

+

+/−

+/−

+/−

−

−

+

+/−

+

−

−

−

−

−

+

+

−

−

−

−

−

−

−

+

−

+/−

+

+

+

−

−

−

−

−

−

−

−

−

NK

ΝΚ

+

−

−

−

−

+

−

−

−

−

−

+

−

NK

−

+/−

−

−

−

−

+

−

−

−

+

+

−

−

most −

−

− −

− +

− −

− +

− −

+ −

+/− +

+/− +

+/− −

− −

− −

+ +

+ −

− −

− −

Key: +, present; −, absent; +/−, variably present; NK, not known. PNECS = primary neuroendocrine carcinoma of the skin; PNET = primitive neuroectodermal tumor; NF = neural filaments; AC = actin; S-100 = S-100 protein; CK = cytokeratin; CEA = carcinoembryonic antigen; EMA = epithelial membrane antigen; LCA = leukocyte common antigen; VIM = vimentin; CHG = chromogranin; SYN = synaptophysin; DES = desmin; NSE = neuron-specific enolase.

heterotopic brain tissue has a predilection for the nasal and paranasal areas; therefore, it is commonly designated as nasal glioma.160 However, this is not a true neoplasm, so the term is incorrect.

CLINICAL FEATURES Nasal gliomas are firm, smooth-surfaced, skin-colored or pink, sometimes slightly vascularized nodules ranging in size between 1.0 and 5.0 cm. Approximately 60% of them are

 FIGURE 33-15 Rudimentary meningocele. The infiltrating meningoendothelial cells appear to dissect the dermal collagen, creating “pseudovascular spaces.” A psammoma body is present.

located extranasally on the bridge of the nose, and the remainder are located intranasally or in both locations.160-163 Occasionally, there may be some communication with the underlying CNS; therefore, thorough neuroradiologic imaging is mandatory before any cranial midline mass is biopsied to avoid cerebrospinal fluid leakage and possible consequent meningoencephalitis.161 HISTOPATHOLOGIC FEATURES Nasal glioma forms an ill-defined, unencapsulated neuropil-like mass in the dermis and subcutis. The adjacent stroma is usually markedly fibrotic and vascularized. On rare occasions, residual meningoendothelial cells may be present. The neuropil-like tissue is composed of nests and strands of pale-staining, finely vacuolated or fibrillary glial tissue in which various types of astrocytes can be found.161,162 Whereas normal astrocytes have a round nucleus, a distinct nuclear membrane, and a prominent nucleolus, fibrillary astrocytes are characterized by eosinophilic cytoplasmic processes. Gemistocytic astrocytes, with polygonal, eosinophilic cytoplasm and eccentric nuclei, as well as multinucleated giant cells, are also common (Fig. 33-17). Mature neurons with triangular cell bodies; large, open, eccentric nuclei; Nissl

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

PNECS (Merkel cell tumor) PNET (neuroblastoma) Malignant lymphoma Poorly differentiated eccrine carcinoma Small cell melanoma Embryonal rhabdomyosarcoma Neuroblastoma Small cell carcinoma

S-100

899

roblastoma, dermoid cyst, and hemangioma. Ganglion cells can be differentiated from glial cells by their characteristic oval shape, large size, and eccentric nuclei with prominent nucleoli. Dermoid cysts contain tissues of all three germ layers, and hemangiomas are devoid of neuropil-like tissue.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Heterotopic Neuroblastic Tissue and Their Tumors

900

 FIGURE 33-17 Nasal glioma. Gemistocytic astrocytes with abundant eosinophilic cytoplasm and multiple nuclei, and spindle-shaped fibrillary astrocytes are embedded in a foamy neuropil matrix.

Neuroblastoma, neuroganglioblastoma, and ganglioneuroma are neural crest–derived neoplasms that arise from the sympathetic chain, paraganglia, and adrenal medulla.165 These neoplasms comprise a family of related neoplasms with a wide spectrum of clinicopathologic manifestations, commonly referred to as neuroblastic tumors.165 In the past, some neoplasms of this group were described as PNETs. This term is now best reserved for soft tissue lesions, which comprise part of a spectrum known as the Ewing sarcoma family of neoplasms. These bear similar morphologic features to Ewing sarcoma of bone and harbor abnormalities of the EWS gene on chromosome 22q12.166 Because of limited cutaneous involvement, the reader is referred to the literature for a more detailed description of the neuroblastic tumor family.165 In brief, these tumors form a spectrum classified by the degree of neuroblast differentiation and amount of schwannian stroma. The most primitive tumors, neuroblastomas, form one end of the spectrum, and neoplasms with fully mature ganglion cells and stromal constituents, ganglioneuromas, form the other.165 Neuroblastoma of the skin most often represents metastasis of a primary adrenal or sympathetic chain neoplasm; however, some cutaneous neuroblastic tumors may develop de novo from heterotopic neural crest cells.167 Likewise, ganglioneuroma may arise de novo or represent maturation of a previous neuroblastoma.165 Ganglion cell choristomas are morphologically similar to ganglioneuroma but lack schwannian stroma.168

substance; and dendritic and axonal processes are present in variable numbers.162,164 Occasionally, ductlike structures with ependymal cells, choroid plexus–like structures, and pigmented cells can be identified. No mitotic activity or destructive growth pattern has been described.164

CLINICAL FEATURES Neuroblastoma is a common childhood neoplasm, and cutaneous metastasis is frequent. The metastases often manifest as multiple, blue or purple dermal papules or nodules resembling the “blueberry muffin” lesions of congenital rubella syndrome.169,170 These nodules may blanch on stroking. Serum and urine catecholamine levels are typically elevated. The prognosis depends on a variety of clinical, histopathologic,

 FIGURE 33-16 Primary cutaneous meningioma. The tumor has an infiltrative growth, and the epithelioid or spindle-shaped cells are often arranged in a whorl-like pattern.

Immunohistochemically, the glial tissue stains strongly for glial fibrillary acidic protein, the neurons react with neuronspecific enolase, and the axons label with antibodies to neural filaments.155 DIFFERENTIAL DIAGNOSIS Nasal glioma must be differentiated from ganglioneu-

carcinoma, non-Hodgkin lymphoma, acute lymphoblastic lymphoma, and leukemic infiltrates. Ganglioneuroblastoma should be distinguished from solitary reticulohistiocytoma, Spitz nevus, and neurofibroma. Ganglioneuroblastic differentiation in malignant melanoma is a rarely reported event.177 A summary of the cardinal differential diagnostic and immunohistochemical findings is provided in Table 33-12.

REFERENCES

and laboratory parameters, including the patient’s age and clinical stage. Spontaneous regression has been described in the stage IV-S type.167,171 Primary cutaneous neuroblastic tumors are exceedingly rare.172-175 They usually manifest in adults as rapidly growing dermal and subcutaneous nodules. These are highly aggressive neoplasms with an almost invariably fatal outcome. Cutaneous ganglioneuroma is likewise rare but is usually an asymptomatic, flesh-colored papule on the trunk or extremities. Both neuroblastoma and ganglioneuroma are encountered in the skin in patients with and without evidence of neuroblastic tumor elsewhere.168 HISTOPATHOLOGIC FEATURES Metastatic neuroblastoma is an ill-defined or infiltrative mass in the dermis, the subcutis, or both. The mass is composed of atypical, small, dark cells with scant cytoplasms. The cells have larger nuclei than mature lymphocytes, with “salt-andpepper”–type chromatin. The cells form irregular nests, cords, or poorly cohesive sheets.165,167 Rosette formation, by concentrically arranged tumor cells in double or multiple circles, is common. The center of the rosettes contains converging fine fibrillary material characteristic of Homer Wright rosettes (Fig. 33-18). Mitotic activity (including abnormal forms), karyorrhetic debris, necrosis, and hemorrhage are frequent.165,167 Histopathologically, cells of primary cutaneous neuroblastoma are similar to those metastatic lesions, but ganglionic

or neuromatous differentiation is not characteristic.172 Ganglion cell lesions are composed of mature ganglion cells that have a large polygonal or epithelioid shape, eccentric nuclei, fine to vesicular chromatin, and prominent nucleoli.165 Nissl substance may be present. In ganglioneuroma, the surrounding stroma is cellular and composed of bland spindle cells with wavy, slender nuclei, similar to cells of schwannoma or neurofibroma. Clusters of ganglion cells in the absence of a surrounding spindle cell stroma distinguishes ganglion cell choristoma.167 Immunohistochemically, neuroblasts and ganglion cells variably react with neural and neuroendocrine markers, depending on their state of differentiation. These include neuron-specific enolase, GFAP, S-100 protein (variable), neurofilaments, synaptophysin, chromogranin, and PGP9.5.167,169 Cytokeratin, CD99, CD45 and TdT expression are negative.165,176 Primary neuroblastomas share immunohistochemical features with those arising in the sympathetic nervous system.169,173 The schwannian-type stroma in ganglioneuroma is strongly positive for S-100.167 DIFFERENTIAL DIAGNOSIS Neuroblastoma must be differentiated from other rosette-forming, small, round, blue cell tumors that may involve the skin. These entities include PNECS (Merkel cell carcinoma), metastatic small cell carcinoma, Ewing sarcoma or PNET, rhabdomyosarcoma, poorly differentiated adnexal

CHAPTER 33 ■ NEURAL AND NEUROENDOCRINE TUMORS

 FIGURE 33-18 Cutaneous neuroblastoma. Poorly differentiated, small, round to ovoid, hyperchromatic cells form Homer Wright rosettes with characteristic central fibrillary material.

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of the skin: I. A clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol. 1985;9:95-108. Visscher D, Cooper PH, Zarbo RJ, et al: Cutaneous neuroendocrine (Merkel cell) carcinoma: an immunophenotypic, clinicopathologic, and flow cytometric study. Mod Pathol. 1989;2:331-338. Akhtar S, Oza KK, Wright J: Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol. 2000;43:755-767. Gollard R, Weber R, Kosty MP, et al: Merkel cell carcinoma: review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer. 2000;88:1842-1851. Yanguas I, Godáy JJ, González-Güemes M, et al: Spontaneous regression of Merkel cell (neuroendocrine) carcinoma of the skin. Br J Dermatol. 1997;137:296-298. Feng H, Shuda M, Chang Y, et al: Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319: 1096-1100. LeBoit PE, Crutcher WA, Shapiro PE: Pagetoid intraepidermal spread in Merkel cell (primary neuroendocrine) carcinoma of the skin. Am J Surg Pathol. 1992;16:584-592. Cerroni L, Kerl H: Primary cutaneous neuroendocrine (Merkel cell) carcinoma in association with squamous- and basal cell carcinoma. Am J Dermatopathol. 1997;19:610-613. Gould E, Albores-Saavedra J, Dubner B, et al: Eccrine and squamous differentiation in Merkel cell carcinoma: an immunohistochemical study. Am J Surg Pathol. 1988;12:768-772. Rosso R, Paulli M, Carnevali L: Neuroendocrine carcinoma of the skin with lymphoepithelioma-like features. Am J Dermatopathol. 1998;20:483-486. Rios-Martin JJ, Solorzano-Amoreti A, González-Campora R, et al: Neuroendocrine carcinoma of the skin with a lymphoepithelioma-like histological pattern. Br J Dermatol. 2000;143: 460-462. Layfield L, Ulich T, Liao S, et al: Neuroendocrine carcinoma of the skin: an immunohistochemical study of tumor markers and neuroendocrine products. J Cutan Pathol. 1986;13:268-273. Sibley RK, Dahl D: Primary neuroendocrine (Merkel cell?) carcinoma of the skin: II. An immunocytochemical study of 21 cases. Am J Surg Pathol. 1985;9: 109-116. Skelton HG, Smith KJ, Hitchcock CL, et al: Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol. 1997; 37:734-739. Scott MP, Helm KF: Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma. Am J Dermatopathol. 1999;21:16-20. Leech SN, Kolar AJO, Barrett PD, et al: Merkel cell carcinoma can be distinguished from metastatic small cell carcinoma using antibodies to cytokeratin 20 and thyroid transcription factor 1. J Clin Pathol. 2001;54:727-729. Allen PJ, Busam K, Hill ADK, et al: Immunohistochemical analysis of sentinel lymph nodes from patients with Merkel cell carcinoma. Cancer. 2001;92: 1650-1655.

142. Bobos M, Hytiroglou P, Kostopoulos I, et al: Immunohistochemical distinction between Merkel cell carcinoma and small cell carcinoma of the lung. Am J Dermatopathol. 2006;28:99-104. 143. McNiff JM, Cowper SE, Lazova R, et al: CD56 staining in Merkel cell carcinoma and natural killer-cell lymphoma: magic bullet, diagnostic pitfall, or both? J Cutan Pathol. 2005;32:541-545. 144. Asiolo S, Righi A, Volante M, et al: p63 expression as a new prognostic marker in Merkel cell carcinoma. Cancer. 2007;110:640-647. 145. Llombart B, Monteagudo C, LopezGuerrero JA, et al: Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology. 2005;46:622-634. 146. Sur M, AlArdati H, Ross C, et al: TdT expression in Merkel cell carcinoma: potential diagnostic pitfall with blastic hematological malignancies and expanded immunohistochemical analysis. Mod Pathol. 2007;20:1113-1120. 147. Ordónez NG: Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol. 2000;24:1217-1223. 148. Argenyi ZB: Cutaneous neural heterotopias and related tumors relevant for the dermatopathologist. Semin Diagn Pathol. 1996;13:60-71. 149. Berry AD III, Patterson W: Meningoceles, meningomyeloceles, and encephaloceles: a neuro-dermatopathologic study of 132 cases. J Cutan Pathol. 1991;18:164-177. 150. Marrogi AJ, Swanson PE, Kyriakos M, et al: Rudimentary meningocele of the skin: clinicopathologic features and differential diagnosis. J Cutan Pathol. 1991;18:178-188. 151. Chan HHL, Fung JWK, Lam WM, et al: The clinical spectrum of rudimentary meningocele. Pediatr Dermatol. 1998;15: 388-389. 152. El Shabrawi-Caelen L, White WL, Soyer HP, et al: Rudimentary meningocele: remnant of a neural tube defect? Arch Dermatol. 2001;137:45-50. 153. Sibley DA, Cooper PH: Rudimentary meningocele: a variant of “primary cutaneous meningioma.” J Cutan Pathol. 1989;16:72-80. 154. Lopez DA, Silvers DN, Helwig EB: Cutaneous meningiomas: a clinicopathologic study. Cancer. 1974;34:728-744. 155. Argenyi ZB, Thieberg MD, Hayes CM, et al: Primary cutaneous meningioma associated with von Recklinghausen disease. J Cutan Pathol. 1994;21:549-556. 156. Nochomovitz LE, Jannotta F, Orenstein JM: Meningioma of the scalp: light and electron microscopic observations. Arch Pathol Lab Med. 1985;109:92-95. 157. Gelli MC, Pasquinelli G, Martinelli G, et al: Cutaneous meningioma: histochemical, immunohistochemical and ultrastructural investigation. Histopathology. 1993;23:576-578. 158. Theaker JM, Fleming KA: Meningioma of the scalp: a case report with immunohistological features. J Cutan Pathol. 1987;14:49-53. 159. Peñas PF, Jones-Cabellero M, Garcia-Diez A: Cutaneous heterotopic meningeal nodules. Arch Dermatol. 1995;131:731.

160. Orkin M, Fisher I: Heterotopic brain tissue (heterotopic neural crest): case report with review of related anomalies. Arch Dermatol. 1966;94:699-708. 161. Yeoh GPS, Bale PM, DeSilva M: Nasal cerebral heterotopia: the so-called nasal glioma or sequestered encephalocele and its variants. Pediatr Pathol. 1989;9: 531-549. 162. Patterson K, Kapur S, Chandra RS: “Nasal gliomas” and related brain heterotopias: a pathologist’s perspective. Pediatr Pathol. 1986;5:353-362. 163. Skelton HG, Smith KJ: Glial heterotopia in the subcutaneous tissue overlying T-12. J Cutan Pathol. 1999;26:523-527. 164. Fletcher CDM, Carpenter G, McKee PH: Nasal glioma: a rarity. Am J Dermatopathol. 1986;8:341-346. 165. Shimada H, Ambros IM, Dehner LP, et al: Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International neuroblastoma Pathology Committee. Cancer. 1999;86:349-363. 166. Hasegawa SL, Davison JM, Rutten A, et al: Primary cutaneous Ewing’s sarcoma: immunophenotypic and molecular cytogenetic evaluation of five cases. Am J Surg Pathol. 1998;22:310-318. 167. Joshi VV, Silverman JF: Pathology of neuroblastic tumors. Semin Diagn Pathol. 1994;11:107-117. 168. Wallace CA, Hallman JR, Sangueza OP: Primary cutaneous ganglioneuroma: a report of two cases and literature review. Am J Dermatopathol. 2003;25:239-242. 169. Banerjee SS, Agbamu DA, Eyden BP, et al: Clinicopathological characteristics of peripheral primitive neuroectodermal tumour of skin and subcutaneous tissue. Histopathology. 1997;31: 355-366. 170. Shown TE, Durfee MF: Blueberry muffin baby: Neonatal neuroblastoma with subcutaneous metastases. J Urol. 1970; 104: 193-195. 171. Evans AE, Chatten J, D’Angio GD, et al: A review of 17 IV-S neuroblastoma patients at the Children’s Hospital of Philadelphia. Cancer. 1980;45:833-839. 172. Argenyi ZB, Bergfeld WF, McMahon JT, et al: Primitive neuroectodermal tumor in the skin with features of neuroblastoma in an adult patient. J Cutan Pathol. 1986;13:420-430. 173. Van Nguyen AV, Argenyi ZB: Cutaneous neuroblastoma: peripheral neuroblastoma. Am J Dermatopathol. 1993;15:7-14. 174. Tang CK, Hajdu SI: Neuroblastoma in adolescence and adulthood. NY State J Med. 1975;75:1434-1438. 175. Aleshire SL, Glick AD, Cruz VE, et al: Neuroblastoma in adults: pathologic findings and clinical outcome. Arch Pathol Lab Med. 1985;109:352-356. 176. Folpe AL, Hill CE, Parham DM, et al: Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing’s sarcoma/ primitive neuroectodermal tumor. Am J Surg Pathol. 2000;24:1657-1662. 177. Grayson W, Maré LR: Ganglioneuroblastic differentiation in a primary cutaneous malignant melanoma. Am J Dermatopathol. 2003;25:40-44.

CHAPTER 34 Lymphoid, Leukemic, and Other Cellular Infiltrates Cutaneous T-Cell Lymphoid Hyperplasia and Cutaneous T-Cell Lymphomas

Lymphoproliferative disease of the skin can be classified into benign reactive disorders—so-called pseudolymphoma (PSLs) or lymphoid hyperplasia—and malignant lymphomas. Primary cutaneous lymphomas (CLs) belong to the group of extranodal non–Hodgkin lymphomas (NHL) and can be defined as lymphoproliferative neoplasms that at the time of diagnosis are confined to the skin (ie, without detectable extracutaneous mani-

CLASSIFICATION OF CUTANEOUS LYMPHOMAS Many attempts have been made over the past decades to classify nodal and CLs. Due to a lack of knowledge about the etiology of most lymphomas, it has not been possible to develop an etiology-based classification. To emphasize the unique biologic aspects of CL, the EORTC classification for primary CLs was introduced in 1997.5 Conceptual differences in the EORTC classification versus the WHO classification6 were eliminated during consensus meetings in 2003 and 2004 and resulted in the WHO-EORTC classification for CLs that is now widely accepted.3,4 The entities listed in this classification will be part of the 2008 WHO classification for nodal and extranodal lymphomas. These lymphoma classifications define nosologic entities with distinct clinical and pathologic features. They replace the former classifications, such as the modifiediel classification and the Working Formulation, which defined lymphomas based almost exclusively on cytomorphologic features. Table 34-1 lists the nosologic entites of CL as recognized by the WHOEORTC classification.

Table 34-1 Entities of Primary Cutaneous T-Cell Lymphomas (CTCL) in the WHO (2001) and the EORTC (1997) Classifications EORTC CLASSIFICATION (1997) Indolent Mycosis fungoides (MF) MF-associated follicular mucinosis Pagetoid reticulosis Lymphomatoid papulosis Large T-cell lymphoma, CD30 + pleomorphic, anaplastic, immunoblastic Aggressive Sézary syndrome Large T-cell lymphoma, CD30+ pleomorphic, immunoblastic Provisional entities Pleomorphic medium-sized and large T-cell lymphoma, HTLV± Granulomatous slack skin Subcutaneous panniculitis-like T-cell lymphoma Not listed in EORTC classification Cytotoxic CD8 + cutaneous T-cell lymphoma NK and NK/T-cell lymphoma CD4+ CD56 + blastic NK-cell lymphoma Gamma/delta cutaneous lymphoma Juvenile granulomatous cutaneous T-cell lymphoma Syringolymphoid hyperplasia with alopecia

WHO CLASSIFICATION (2001) Mycosis fungoides MF-associated follicular mucinosis Pagetoid reticulosis Primary cutaneous CD30+ T-cell lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Werner Kempf Guenter Burg

festation at staging investigations). The overall frequency of CLs is about one per 100,000 inhabitants per year, similar to that of Hodgkin lymphoma.1,2 Cutaneous T-cell lymphomas (CTCLs) represent the largest proportion (65%) of all primary CLs. CTCL consists of several nosologic entities with distinct clinicopathologic, phenotypic, genotypic, and biologic features. The biology and prognosis of CL differ significantly from those of nodal lymphomas with the same cytomorphologic or phenotypic profile. This has an important impact on classification and therapy of CL, which has now been respected in the current lymphoma classifications such as the World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for CLs3,4 as well as for the treatment of CL. The histologic and phenotypic evaluation is of crucial value in the diagnostic workup of CL. Correlation of certain phenotypes with prognosis has been demonstrated for some forms of CTCL. However, a great number of CTCLs exhibit overlapping histologic and phenotypic findings. The final diagnosis of CL must always be based on a synthesis of clinical, histologic, cytologic, immunophenotypic, and molecular features as well as the results of staging examinations.2

Sézary syndrome Peripheral T-cell lymphoma, unspecified

Peripheral T-cell lymphoma, unspecified Granulomatous slack skin Subcutaneous panniculitis-like T-cell lymphoma Peripheral T-cell lymphoma, unspecified Extranodal NK/T-cell lymphoma, nasal type Blastic NK-cell lymphoma Peripheral T-cell lymphoma, unspecified Not listed Not listed

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Stem cell

In contrast to cutaneous B-cell lymphomas (CBCLs), in which the clinical presentation is usually relatively uniform with nodules, CTCLs display a broad and heterogeneous pattern of clinical features. Mycosis fungoides (MF) manifests with patches of various sizes, plaques, and tumors with or without ulceration, or erythroderma, the latter also being the hallmark of Sézary syndrome (SS). Primary cutaneous CD30-positive lymphoproliferative disorders (CD30+ LPD) and rare CTCL forms such as peripheral T-cell lymphoma, unspecified, are characterized by papular or nodular lesions often undergoing ulceration. Pruritus is a common feature in MF and SS.

NK cell Lymphoid progenitor

CD3 - CD56 TIA-1  TCR 

Thymocyte

CD1

T-cell

CD3

STAGING The staging of CL generally relies on the tumor, node, metastasis (TNM) classification.7 It was primarily intended to assess disease extent in patients with MF and SS but has some shortcomings for other forms of CTCL. Recently, new TNM staging schemes for MF and SS8 as well as CLs other than MF and SS9 have been proposed to document disease extent and evaluate efficacy of therapies in relation to tumor stage.

HISTOMORPHOLOGIC AND CYTOMORPHOLOGIC BASIS Malignant lymphomas are generally considered to be neoplastic proliferations of lymphoid cells that partly retain morphologic and functional properties of their normal counterparts, cells of the lymphoid series along the differentiation pathway from the stem cell to the peripheral postthymic, welldifferentiated T cell (Fig. 34-1). However, neoplastic cells can lose or acquire additional phenotypic and functional properties during tumorigenesis.

Principal Cell Types and Ontogeny of the T-Cell Series

906

CD34

Small lymphocytes correspond to the lymphocytes in the peripheral blood. In skin infiltrates, they appear as small cells with round chromatin-dense nuclei; the small rim of cytoplasm usually cannot be seen by conventional light microscopy. The small cerebriform lymphocyte is a variant of the well-differentiated peripheral T cell, also referred to as a Sézary cell or Lutzner cell. The characteristic hallmark is the increased nuclear folding and indentations, which can be roughly estimated in H&E-stained paraffin sections but are more precisely demonstrated in Giemsa (GMS)-

T helper cell CD4⫹ CD8

cytotoxic T-cell /  T-cell T/NK-cell CD4 CD8 CD4 CD8 CD3 CD56 TIA-1  TIA-1  TIA-1 

TCR / 

TCR /  TCR /  (rarely)

TCR /  TCR / 

TCR /  or / 

 FIGURE 34-1 Ontogeny of T-cell differentiation.

stained sections or semithin and ultrathin sections. These cells are mainly found in SS and in the patch and plaque stage of MF. Pleomorphism of cells indicates that the nuclei are of different sizes and shapes. The nuclei are irregularly shaped, folded, twisted, or serrated. Small, medium, and large variants can be distinguished. The chromatin—somewhat in contrast to the small cerebriform cells—is usually less dense. The cytoplasm is visible as a small rim in the small cell variants and abundant, often pale in the large cell pleomorphic variants. Pleomorphic tumor cells are characteristically found in PTL such as primary cutaneous pleomorphic small to medium or large T-cell lymphoma and during transformation in MF or SS. Anaplastic lymphoid cells morphologically do not correspond to any lymphoid cell in the normal or reactive lymph node. The tumor cells are of large or giant size with extreme irregularity of nuclear shapes and sizes and sometimes multinucleated. The chromatin is fine or coarse. The cytoplasm is abundant and gray or clear. These cells have been misinterpreted previously as cells of histiocytic origin. They are typically found in CD30-positive LPDs, where they are arranged in cohesive sheets, or are found as scattered tumor cells intermingled with reactive inflammatory cells. The morphologic hallmark of both T- and B-immunoblasts is a large round or

oval clear nucleus due to coarse chromatin and a prominent, centrally located nucleolus. The cytoplasm usually is abundant and gray (GMS stain) or pale. T-lymphoblasts are characterized by rounded nuclei with inconspicuous nuclei; the cells are intermediate in size. The skin may be involved secondarily in precursor T- or B-cell lymphoblastic lymphoma or leukemia.

Growth Patterns Two main growth patterns of tumor cell infiltrates in CTCL, namely, bandlike and nodular infiltrates, can be distinguished. A bandlike infiltrate spreads within the upper and middle dermis (Fig. 34-2). The clinical equivalent is infiltrated patches and plaques or an erythroderma if the entire skin surface is involved. It is a typical feature of early disease stages and most small cell types of CTCL. Epidermotropism of atypical lymphocytes is a characteristic finding of MF and SS and often associated with a bandlike infiltrate but is usually not found in CTCL with nodular infiltrates. Nodular infiltrates are located within the dermis (Fig. 34-3) and are mostly found in PTL and in latestage (i.e., transformation of MF or SS), MF, but also in CBCLs and the nodular form of cutaneous T-cell PSL.

lymphoid cells, as well as between large pleomorphic and anaplastic cells, poses considerable difficulties.

SPECIAL TECHNIQUES FOR THE DIAGNOSIS OF CTCL

Immunophenotyping  FIGURE 34-2 Bandlike growth pattern. Bandlike and perivascular lymphocytic infiltrates in the upper dermis (mycosis fungoides, patch stage).

 FIGURE 34-3 Nodular growth pattern. Circumscribed lymphocytic infiltrate in the middle dermis (T-cell pseudolymphoma).

There may be combinations of both growth patterns if tumorous lesions develop within preexisting patches of MF or erythroderma ie, MF. One has to keep in mind that a small biopsy such as punch biopsy from a nodular infiltrate exceeding the borders of the biopsy may simulate a diffuse infiltrate rather than revealing its nodular character. Thus, large representative biopsies are mandatory for an adequate diagnostic workup of CL.

Special Features Neoplastic proliferations of lymphocytes are mostly accompanied by varying

numbers of dendritic cells, macrophages, plasma cells, eosinophils, and reactive lymphocytes. Their presence may be partially due to the T-helper 2 (TH2) cytokines released by tumor cells.10,11

Phenotyping of lymphoid infiltrates allows to identify certain forms of CL such as cytotoxic CTCL and to assess prognosis in some forms of CTCL such as subcutaneous forms of CTCL. The most important T cell– and natural killer (NK) cell–associated antigens are listed in Table 34-2. The vast majority of these antigens can be detected by monoclonal or polyclonal antibodies in formalin-fixed, paraffin-embedded archival tissue. The basic panel of antibodies includes CD3 (pan Tcell marker), CD4, CD8, CD43, and CD45RO for evaluation of T-cell infiltrates. CD2, CD5, and CD7 are useful to assess loss of T-cell antigens of tumor cells, as well as prognostically relevant information in cytotoxic CD8+ lymphomas. CD30 is an activation marker and represents the phenotypic hallmark of primary cutaneous CD30+ LPDs of the skin, which are characterized by a favorable prognosis. CD56 allows identification of NK cells and NK/T cells. The expression of cytotoxic markers such as TIA-1, granzyme B, and perforin is useful in the recognition and evaluation of CL with a cytotoxic phenotype. The most common form of CTCL, MF, represents a neoplastic proliferation of monoclonal T cells with a T-helper memory cell phenotype (CD3+, CD4+, CD8-) in the vast majority of cases.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

H&E-stained sections have always been and probably will remain a crucial element in the diagnostic workup of CTCL. However, lineage- and cell-type identification by immunohistochemical phenotyping and molecular techniques for clonality assays and to detect genetic alterations are essential for an adequate diagnostic approach.2

Genotyping Reproducibility of Morphologic Criteria in Lymphoproliferative Skin Infiltrates Significant interaobserver and intraobserver variabilities have been reported,12,13 especially in early stages of CTCL.14 In particular, the differentiation between small, cerebriform, and small pleomorphic

Clonal rearrangement of the T-cell receptor genes as a sign of clonal outgrowth of neoplastic cells can be demonstrated by various molecular techniques.15 The Southern blot technique is considered to be the gold standard but can only be applied if sufficient cells can be harvested from fresh or cryopreserved material. In contrast, the polymerase chain reaction (PCR)–based

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 34-2 Antigens and Antibodies for the Immunophenotypic Evaluation of Cutaneous T-Cell Lymphoproliferative Disorders CD

ANTIBODY

SPECIFICITY

CD2 CD3

Leu5, OKT11 Leu4, OKT3

CD4

Leu3, OKT4

CD5

Leul, OKT1, Lyt2

CD7 CD8 CD30

Leu9, WT1 Leu2, OKT8 Ki1, BerH2

CD 43

MT-1

CD45RO

UCHL-1

CD56 TIA-1

NCAM Granule-associated cytotoxic molecule T-cell receptor α/β chain T-cell receptor γ/δ chain

T-lymphocytes Mature thymocytes, peripheral T-lymphocytes Helper/inducer T cells, some macrophages T-Iymphocytes; less than 5% of B-lymphocytes T-lymphocytes Suppressor/cytotoxic T cells Reed-Sternberg cells, Hodgkin cells, large cell anaplastic lymphoma, plasma cells T-lymphocytes, monocytes, myeloid cells T-lymphocytes, monocytes, myeloid cells Natural killer (NK) cells Cells with cytotoxic activity

βF1 TCR δ

amplification of DNA is more widely used and reveals a clonal T-cell population in cases in which only a few tumor cells are present or when only archival (ie, formalinfixed, paraffin-embedded) material is available for analysis. The sensitivity of PCR-based methods can be increased by denaturating (DGGE) or temperature gradient gel electrophoresis (TGGE) or high-resolution fragment analysis.16 Recently, standardized PCR-based protocols to assess T-cell clonality such as BIOMED217 have been introduced and have been shown to be useful in CTCL.18,19 The detection of clonal rearrangement of T-cell receptor genes by molecular biologic methods is of value in the differentiation of early forms of CTCL from reactive inflammatory disorders. However, the detection of clonality per se cannot be regarded as synonymous with malignancy.20 In addition, the identification of clonal T cells in early MF is challenging because of the subtle infiltrates and the admixture of reactive cells. Thus, the results of molecular studies should always be interpreted in the context of clinicopathologic and phenotypic findings.

Cytogenetic Findings in CTCL

908

Tumorigenesis is associated with and accompanied by chromosomal aberrations that can be detected by appropriate karyotyping or comparative genomic

T-lymphocytes T-lymphocytes

hybridization. Malignant T cells of patients with CTCL often demonstrate multiple and complex chromosome aberrations with translocations of genes regulating cell proliferation or programmed cell death (apoptosis). Thus, certain common but not fully distinct patterns of genetic alterations have been detected in CTCL.21 Some alterations are of differential diagnostic or prognostic value.22,23

lymphocytes27) are activated and stimulated to reactive proliferation by an infectious or noninfectious antigens. Genetic alterations such as translocations and mutations contribute further to the disease progression. The number of mutations in the genotraumatic cell clone increases during tumor progression. The unlimited neoplastic expansion of cells is usually limited by control mechanisms leading to cell death to prevent the accumulation of cells with chromosomal aberrations. Such control mechanisms include the induction of programmed cell death (apoptosis). Tumor cells of CTCL commonly overexpress the antiapoptotic bcl-2 gene.28 In addition, the enzyme telomerase shows a significant increase of activity in CTCL 29 and may be responsible for the prevention of cell death in tumor cells with unlimited proliferation and accumulation of mutations. The persistence of abnormal T cells rather than proliferation seems to be an important pathogenetic factor at least in the early stages of CTCL.28 These and other factors finally promote the expansion of a highly abnormal tumor cell clone that is maintained by autocrine or paracrine growth stimulation and over time becomes independent of external antigenic stimulation.10,30 Many systemic and laboratory changes found in CTCL patients can be explained by secretion of a cytokine pattern of TH2 cells.10,11

BENIGN T-CELL LYMPHOPROLIFERATIONS

T-Cell Pseudolymphomas ETIOPATHOGENESIS OF CTCL The etiology of most CLs is still unknown. Increasing evidence suggests that lymphomagenesis is a multistep process, during which normal lymphocytes develop into tumor cells under the influence of exogenous or endogenous antigens (eg, viruses or bacteria) and growthstimulating factors (ie, cytokines). No definite association with an oncogenic virus has been established. The role of human T-lymphotropic virus I (HTLV-I) in the pathogenesis of CTCL has been proposed but has not been proven.24 More recent theories hypothesize that tumor cells in CL are derived from bone marrow stem cells undergoing genetic alterations during lymphomagenesis.25 The authors favor the following hypothesis for the pathogenesis of CTCL26: abnormal lymphocytes with chromosomal instability (ie, genotraumatic

Synonyms: atypical lymphocytic or lymphoid hyperplasia PSLs are benign lymphoproliferative processes that clinically or histologically simulate CL (Table 34-3).2,31,32 PSLs are characterized clinically by spontaneous healing and a lack of recurrences after cessation of the causative factor (eg, drugs or infections) or treatment, absence of systemic spread, and transformation to highgrade malignant lymphoma. CLINICAL FEATURES There is a broad spectrum of clinical presentations of T-cell PSL.31-33 They may manifest as solitary, eczematous, patchy, papular, or nodular lesions or as erythroderma.33 HISTOPATHOLOGIC FEATURES Two main histologic types of cutaneous T-cell PSLs can be distinguished: a bandlike pattern that simulates MF and a nodular pattern

Table 34-4 Mycosis Fungoides

Clinical Features Broad spectrum: patchy or nodular lesions, erythroderma No progression, no extracutaneous spread Histopathologic Features Two main patterns: band like infiltrate with or without epidermotropism Nodular infiltrate Small lymphocytes, nuclear pleomorphism possible, but not prominent Admixture of eosinophils Immunohistologic Features CD3 +, CD4+ T cells intermingled with CD3+, CD4–, CD8 +T cells No loss of T-cell antigens Few CD30+ T cells can be present in some cases Differential Diagnosis Small cell pleomorphic T-cell lymphoma CTCL: mycosis fungoides, Sézary syndrome Chronic eczema

Clinical Features Irregular patches with pityriasiform scaling in early stage Evolution to plaques and nodular tumors in later stages Disease progression over years, in some patients with involvement of lymph nodes and internal organs Histopathologic Features Early stage: perivascular lymphocytic infiltrate with small lymphocytes with round or cerebriform nuclei Subepidermal edema and proliferation of postcapillary venules Admixture of eosinophils and plasma cells Plaque stage: dense subepidermal infiltrate with significant epidermotropism of single cells or cell clusters forming Pautrier microabscesses Tumor stage: nodular dense infiltrate, blast transformation, often loss of epidermotropism Immunohistologic Features CD4+, CD2+, CD3+, CD5+, CD7+, CD8 −, CD30 −, CD45RO+ Loss of T-cell antigens in plaque and tumor stages Differential Diagnosis MF patch stage: Small and large plaque parapsoriasis Chronic eczema MF plaque stage: Sézary syndrome Pagetoid reticulosis Cutaneous CD8+ cytotoxic lymphoma MF tumor stage: CD30+ or CD30− pleomorphic large T-cell lymphoma

(see Fig. 34-3) mimicking PTL or CD30+ lymphomas.34 T-cell PSLs are composed of small lymphocytes without significant nuclear atypia, but small numbers of medium-sized pleomorphic T cells may be observed. Admixture of eosinophils is a common but not a specific finding in T-cell PSL. IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES In most cases, lymphoid cells display a CD3+, CD4+, and CD8- phenotype. There is no antigen loss of CD2, CD5, and CD7.35 However, there may be a reduction in CD7 expression, although the striking decrement in staining typical for some cases of cutaneous T cell lymphoma is not seen. CD8+ cases have been reported in HIV-infected individuals.36 In some cases, especially in drug-induced T-cell PSL or pseudolymphomatous reactions to infectious agents (molluscum contagiosum, scabies), CD30-positive activated medium-sized lymphocytes may be observed.37 Clonal rearrangement of TCR genes may be found. DIFFERENTIAL DIAGNOSIS The differential diagnosis between T-cell PSL and CTCL is based on an overall assessment of clinical, histologic, phenotypic (ie, no loss of T-cell antigens), and molecular (ie, absence of T-cell clonality) data.

Mycosis Fungoides MF is a peripheral T-cell NHL initially and preferentially presenting in the skin with distinct clinical and histopathologic

features (Table 34-4). MF is the most common subtype of CL. CLINICAL FEATURES Usually, individuals in the fifth to seventh decades of life are affected, with a male preponderance, but MF may also develop in children. The disease starts with irregular, wellcircumscribed, yellowish-red patches with pityriasiform scaling, mostly located on the trunk or buttocks (Fig. 34-4A). It usually takes several years until the lesions develop into elevated plaques and tumors in the advanced stage (Fig. 34-4A). Progression to a large-cell morphology and formation of nodular tumors that may undergo ulceration is referred to as transformation of MF. It is associated with an aggressive clinical course. Moreover, extracutaneous spread to lymph nodes and visceral organs may occur in advanced stages. The sudden multifocal eruption of tumors without preceding patches or plaques was formerly referred to as the d’emblée form of MF. According to the WHO-EORTC and WHO classifications, this form belongs to the group of PTL that is unspecified due to the lack of preceding patches and plaques. HISTOPATHOLOGIC FEATURES In the early patch stage of MF, a perivascular or bandlike subepidermal or periadnexal

infiltrate is observed.39 The infiltrate may be relatively scant. In addition to lymphocytes, eosinphils and a few plasma cells may be present. Fibroplasia of the papillary dermis, resulting in what has been termed “wiry” collagen, is often present. Epidermotropism, mostly of single cells or small clusters of lymphoid cells, is present to a variable degree.40 The presence of halo cells—that is, intraepidermal (epidermotropic) lymphocytes with a clear cytoplasmic rim—is an useful feature but is not always present. Single or small clusters of lymphocytes disposed along the junctional zone is a common finding and is referred to as lining up (see Fig. 34-4). Spongiosis is usually minimal or absent, but it may be present, and this finding should not exclude a diagnosis of MF.41 Interface changes may also be present.39 Patchstage lesions in otherwise advanced MF show typical features with epidermotropism of clearly atypical cells.2 In the plaque stage, there is usually a dense, bandlike subepidermal infiltrate with significant epidermotropism of single cells or cell clusters forming Pautrier microabscesses (Fig. 34-5).23 The term microabscesses is a misnomer and could be replaced by collections or aggregations. In the tumor stage, the infiltrate is nodular, and in addition to the predominantely horizontal spread seen in the earlier stages,

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Table 34-3 T-Cell Pseudolymphoma

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poikiloderma or the presence of epidermal effacement and atrophy, telangiectasia, pigment incontinence, and papillary dermal thickening and fibroplasia. Such morphologic changes may be the defining histologic findings in treated lesions of MF. In addition, after light and psoralen therapy, focal keratinocyte necrosis and other changes associated with photo irritation may be observed. Cytomorphologically, the infiltrates in MF are composed of predominantly small lymphocytes with round or cerebriform nuclei in the patch and plaque stages. With tumor progression, overtly neoplastic medium-sized to large lymphoid cells with pleomorphic nuclei account for an increasingly larger percentage of the infiltrate.42,43 Immunoblasts and anaplastic cells may be observed in transformed MF.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

A

CLINICOPATHOLOGIC VARIANTS AND SUBTYPES OF MF MF exhibits a broad spectrum of clinical, histologic, and immu-nophenotypic variants.44 Most variants behave in a clinically comparable fashion to classic MF. Folliculotropic and granulomatous MF as well as pagetoid reticulosis (PR) differ clinically in terms of presentation and prognosis and thus are discussed in more detail.

B  FIGURE 34-4 Mycosis fungoides, patch stage. (A) Confluent patches and plaques on the trunk. (B) Lining up of haloed lymphoid cells along the junctional zone and epidermotropism of lymphoid cells.

 FIGURE 34-5 Mycosis fungoides, plaque stage. Bandlike dense lymphocytic infiltrate in the upper and middle dermis. Significant epidermotropism with formation of Pautrier microabscesses.

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vertical growth takes place, sometimes with progressive loss of epidermotropism (Fig. 34-6). Common features of patch and plaque MF are subepidermal fibrosis and the

admixture of eosinophils, plasma cells, macrophages, and dermal dendritic cells. In transformation, clusters of B cells may be found. The regression of lesions of MF may result in a nonspecific picture of

FOLLICULOTROPIC MF Folliculotropic MF is a subtype of MF that is defined by the perifollicular localization and folliculotropism of neoplastic lymphocytes that may or may not be accompanied by mucin deposits in the hair follicles (follicular mucinosis). Patients with follicular MF often are older than 40 years of age and present with erythematous papules, plaques, and comedo-like lesions involving the upper trunk and head and neck (most commonly the face).45 The neoplastic lymphocytes are small to medium sized and demonstrate prototypic cerebriform and hyperchromatic nuclei. In general, the number of lymphocytes infiltrating the follicular epithelium is limited46 (Fig. 34-7). The perifollicular infiltrates often consist of small- to medium-sized lymphocytes admixed with plasma cells and eosinophils. A granulomatous reaction may be observed.47 The immunophenotype of the neoplastic lymphocytes is CD3+, CD4+, and CD8−. The differential diagnosis includes idiopathic follicular mucinosis and follicular eczema. Multiple lesions, atypical lymphoid cells, loss of T-cell antigens, and the presence of a clonal T-cell population indicate folliculotropic MF. Folliculotropic MF has a worse prognosis than the classic form of MF.45

leading to circumscribed alopecia without follicular mucinosis.48 In patients presenting with more localized disease and mild lymphoid atypia, the lesions may represent a form of syringotropic T cell dyscrasia rather than overt syringotropic MF (ie, a so-called facultative precursor lesion to MF).

 FIGURE 34-7 Folliculotropic mycosis fungoides with follicular mucinosis with infiltration of follicular epithelium by tumor cells and mucinous degeneration.

Syringotropic MF (Syringolymphoid Hyperplasia with Alopecia) This very rare variant of MF presents with a specific histomorphologic pattern that shows small lymphocytes with

cerebriform nuclei and preferential involvement of the sweat glands and ducts with associated epithelial hyperplasia reminiscent of Sjögren-associated lymphoepithelial lesions48,49 (Fig. 34-8). There may also be involvement of hair follicles,

GRANULOMATOUS MF Clinically, patients show erythematous or hyperpigmented patches and plaques commonly on the trunk. The clinical presentation of skin lesions in GMF is not indicative of the histologically detected granulomatous features.52 Histologically, there is a diffuse infiltrate of small and occasionally mediumsized lymphocytes and sarcoid-like granulomas throughout the entire dermis (Fig. 34-9). Histiocytic giant cells are often present.50,51 Epidermotropism of lymphocytes is absent in almost half of the biopsies, limiting their value as a diagnostic marker in GMF. Remarkably, infiltration of the vessel walls of large veins by small lymphocytes and even by large multinucleated histiocytic giant cells is found in one-third of cases.52 Immunophenotyping reveals in most cases a CD4+ T-helper phenotype, but CD8+ cases have been observed. In the vast majority, a clonal T-cell population can be demonstrated by PCR, which may be a useful adjunctive diagnostic marker in the discrimination of GMF from inflammatory granulomatous disorders such as sarcoidosis.52 However, a very important diagnostic consideration is the interstitial granulomatous drug reaction (see Chapter 12), which may closely resemble granulomatous MF, including in the context of T cell clonality and a reduction in the expression of CD7.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-6 Tumor stage of mycosis fungoides showing a dense infiltrate involving all layers of the dermis. Only focal epidermotropism is seen.

GRANULOMATOUS VARIANTS AND SUBTYPES OF MF Granulomatous reactions are present in about 2% of various CLs, including both cutaneous T- and B-cell lymphomas.50,51 The granulomatous component in the dermal infiltrate can vary from a few giant cells to prominent epithelioid granulomas.52 The granulomatous variant of MF represents the most common CTCL with granulomatous features. Granulomatous MF and granulomatous slack skin (GSS) display overlapping histologic features but differ clinically by the development of bulky skin folds resembling cutis laxa in GSS.51 Due to the unique clinical features, GSS is listed as a separate subtype of MF in the WHO-EORTC calssification.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

or absent in GSS. There is an almost complete loss of elastic fibers, and fragments of the elastic fibers can be found as small inclusions in the cytoplasm of the giant cells (elastophagocytosis). There is overlap with histologic features of granulomatous MF.52 The small lymphoid cells express a CD3+, CD4+, CD8−, CD30− T-helper phenotype.56 The giant cells are of monocyte or macrophage derivation and thus express histiocytic markers such as lysozyme and CD68. Clonal TCR gene rearrangement is commonly found.

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DIFFERENTIAL DIAGNOSIS The differential diagnosis includes cutis laxa, which usually shows slack skin but lacks significant lymphocytic infiltration.  FIGURE 34-8 Syringotropic mycosis fungoides (syringolymphoid hyperplasia) showing lymphocytes within and around sweat gland structures.

 FIGURE 34-9 Granulomatous mycosis fungoides with epithelioid granulomas and numerous small lymphocytes embedded in fibrosis.

GMF exhibits a therapy-resistant slowly progressive course. However, extracutaneous spread or development of a second LPD occurs in a subset of patients. Prognosis in GMF is worse than in classic nongranulomatous MF, with a diseasespecific 5-year-survival rate of 66%.52 A subset of GMF with onset in childhood has been referred to as juvenile granulomatous CTCL.53 These patients appear to be at high risk for the development of a second lymphoid neoplasm. GRANULOMATOUS SLACK SKIN Characteristic clinical manifestations include poikilodermatous patches in the flexural areas (the groins and axillae) that evolve to pendulous, bulky folds of skin

resembling cutis laxa. The age of onset is between the second and fifth decades of life in most instances, but GSS may also begin in childhood.54 The course is indolent and slowly progressive, but some patients are at risk for the development of systemic CD30+ anaplastic large cell lymphomas or Hodgkin lymphoma have been reported. Histologically, most biopsies show a diffuse infiltrate composed of predominantly small lymphocytes and scattered large multinucleated giant cells is present in the dermis50,55 (Fig. 34-10). These giant cells contain up to 30 peripherally located nuclei and display emperipolesis (ie, phagocytosis of lymphoid cells). Also, epidermotropism is usually limited

Pagetoid Reticulosis (PR) This distinct subtype can be regarded as a circumscribed, unilesional, low-grade malignant form of MF. In 1939, Woringer and kolopp reported a solitary plaquelike lesion on the arm of a 6-year-old boy.57 The term PR was introduced later by Braun-Falco and colleagues.58 Only the localized form of PR should be referred to as PR, according to the WHO-EORTC classification.3,4 The disseminated form of PR described in 1931 by ketron and Goodman59 is no longer referred to as PR and corresponds to classic MF, primary cutaneous aggressive CD8+ cytotoxic T-cell lymphoma, or gamma delta-positive CTCL. CLINICAL FEATURES PR presents as a solitary psoriasiform or bowenoid erythematous, scaling, or crusty plaque with acral localization exhibiting slow centrifugal growth over years. In contrast to MF, PR does not disseminate or spread to extracutaneous sites. HISTOPATHOLOGIC FEATURES The epidermis shows marked psoriasiform hyperplasia with para- and hyperkeratosis. Characteristically pronounced epidermotropism of atypical haloed lymphoid cells with convoluted and hyperchromatic nuclei and clear cytoplasm manifest a sponge-like disaggregation of the epidermis60,61 (Fig. 34-11). Mitotic figures are rare. A perivascular or diffuse bandlike infiltrate of small cerebriform lymphocytes is present in the upper dermis. Immunophenotypically, PR displays a heterogeneous spectrum of phenotypes, including a CD3+, CD4+, CD5+, CD8− T-helper phenotype, but there have also been reports of CD8+ and CD30+ cases.61 Clonal TCR gene rearrangement is found in most cases.

DIFFERENTIAL DIAGNOSIS The clinical differential diagnosis includes solitary lesions of psoriasis, Bowen disease, extramammary Paget disease, and lichen simplex chronicus. Histologically, PR has to be differentiated from other epidermotropic neoplasms such as classic MF, lymphomatoid papulosis (type B), and primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma as well as from epithelial neoplasms with a pagetoid pattern and malignant melanoma.

The Parapsoriasis Group

CLINICAL FEATURES Two main forms of PPS can be distinguished. Small-plaque PPS (SPP; digitate dermatosis, chronic superficial dermatitis) is characterized by oval or digitate patches 2 to 6 cm in diameter that are preferentially located on the lateral parts of the trunk and show a reddish or yellowish surface with pseudoatrophic wrinkling and slight pityriasiform scaling. In large-plaque PPS (LPP; PPS en grandes plaques), relatively few large (>10 cm in diameter), irregularly shaped, reddish and fairly welldemarcated lesions with pityriasiform scaling are located on the trunk, extremities, or both. The prognosis for patients with SPP is exceptionally good without any influence on survival. Fatal outcome of SPP has so far not been reported.65

 FIGURE 34-11 Pagetoid reticulosis. Spongelike disaggregation of epidermis by haloed atypical lymphoid cells.

HISTOPATHOLOGIC FEATURES The epidermis shows slight acanthosis with patchy parakeratosis. Scant perivascular infiltrates of small lymphocytes may be seen in the upper dermis, with or without subtle single-cell epidermotropism. In general, a few eosinophils are present, but plasma cells are not observed (Fig. 34-12). Phenotypically, the infiltrate in SPP and LPP is mainly composed of CD4+, CD8−, and CD45RO+ T cells intermingled with a few CD8+ cells. Clonal rearrangement of TCR genes is found occasionally in SPP and LPP.64,66

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-10 Granulomatous slack skin. Dense lymphoid infiltrate in all dermal layers with a prominent scattered multinucleated giant cell exhibiting numerous peripherally located nuclei.

Although described more than 100 years ago,62 there is considerable debate on the terminology and nosologic relation of parapsoriasis (PPS) to MF. A subset of patients with large-plaque PPS (LPP) shows progression from LPP to overt MF.63,64 Thus, some authors, including ourselves, consider LPP as variant of MF with usually very slowly progressive course and low-grade potential for evolution to conventional MF. In contrast to LPP, in our experience small-plaque PPS (SPP) behaves biologically similar to a chronic benign inflammatory disorder. In our opinion, SPP does not represent a precursor of MF.

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lymphomatoid papulosis (type B) and tumor-stage lesions of MF from CD30+ anaplastic large-cell lymphoma as well as from peripheral T-cell lymphoma, not otherwise specified, which may present with identical cytomorphology.

Sézary Syndrome

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

SS is a leukemic and erythrodermic peripheral T-cell NHL with distinct clinical features, circulating tumor cells, and lymphadenopathy72,73 (Table 34-5). It is listed as a separate entity in the WHO-EORTC classification.3,4

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 FIGURE 34-12 Parapsoriasis (small plaque form). Sparse perivascular lymphocytic infiltrate. No significant epidermotropism is seen. Subtle acanthosis and focal parakeratosis is present.

DIFFERENTIAL DIAGNOSIS The major differential diagnosis of SPP and LPP includes early-stage MF and chronic eczema, which usually cannot be distinguished on histologic grounds alone. Additional information, including clinical presentation and course of the disease, are needed for the diagnosis. However, in some cases, only the stable course of the condition without progression allows one to differentiate SPP from MF retrospectively. OTHER VARIANTS OF MF Other variants include bullous, verrucous, or hyperkeratotic; pustular and acanthosis nigricans–like; and hypo- and hyperpigmented and purpuric forms of MF.44,67,69 IMMUNOPHENOTYPIC FEATURES OF MF The characteristic phenotype in classic MF is CD3+, CD4+, CD45RO+, CD8−, CD30−, and βF1+ (TCRβ+). Rare cases display a CD3+, CD4−, CD8+ cytotoxic/ suppressor T-cell phenotype or a CD4−, CD8−, or a CD56+ phenotype. CD8+ MF and CD56+ cases often manifest with hypo- or hyperpigmented patches and plaques but behave biologically identical to classic CD4+ MF.68,69 Poikiloderma is also a common feature of CD56+ variants of MF. Loss of T-cell antigens such as CD2, CD5 or CD7 is commonly found, with CD7 being expressed in one-third of the lesions. In the tumor stage, an aberrant phenotype with loss of several T-cell antigens and occurrence of CD30 expression are common findings.

GENOTYPIC FEATURES OF MF Clonal rearrangement of TCR beta or gamma chain genes can be detected in most (90%) plaque- and tumor-stage MF lesions.16 In cases with extracutaneous involvement, the same clone may be detected in either site. In early-stage MF, however, a clonal T-cell population is only found in half of the biopsies from patch lesions. This finding limits the value of detection of clonal T-cells as a diagnostic marker in early stage MF. Many structural and numerical chromosomal abnormalities on several chromosomes, such as chromosomes 1, 6, 8, 9, 11, 13, 15, and 17, have been identified in MF, with most of them being more common in patients with advanced stage disease.21 Chromosomal loss at 10q and abnormalities in p15, p16, and p53 tumor suppressor genes are commonly found in patients with MF.70 DIFFERENTIAL DIAGNOSIS In the early stages of MF, differentiation from chronic eczema and SPP on histologic grounds alone may be challenging or even impossible. Loss of T-cell antigens is a useful adjunctive diagnostic marker but is not definitive. Clinicopathologic correlation is mandatory in appropriate diagnosis and management of patients.71 Differentiation of plaque-stage MF from SS is based on clinical and hematologic parameters. PR shows characteristic clinical features and a prominent epidermotropic infiltrate of haloed cells. The patient’s history and clinical presentation are crucial to distinguish patch- and plaque-stage MF from

CLINICAL FEATURES SS is characterized by an erythroderma with scaling and edematous swelling of the skin, palmoplantar hyperkeratosis, hair loss, onychodystrophy, and enlargement of lymph nodes and intense pruritus. Infiltration of bone marrow is a rare event. SS affects patients in their 5th to 7th decades of life. The prognosis is worse than in MF, with a 5-year-survival rate of 24%.3 Transformation may occur in the skin with ulcerated tumors or in the lymph nodes.74 In the advanced stages, tumorous infiltration may result in leonine facies. HISTOPATHOLOGIC FEATURES In most cases, a nonspecific perivascular or bandlike infiltrate with or without atypical lymphocytes is observed.40,75,76 Epidermotropism of atypical lymphocytes with formation of

Table 34-5 Sézary Syndrome

Clinical Features Pruritic erythroderma with edematous swelling of the skin Palmo-plantar hyperkeratosis Alopecia and onychodystrophy Lymphadenopathy Histopathologic Features Bandlike infiltrate and edema in the upper dermis Epidermotropism with Pautrier abscesses in only 40% of the biopsies Small lymphocytes with or without convoluted or cerebriform nuclei Immunohistologic Features CD2+, CD3+, CD5+, CD8−, CD30−, CD45RO+ Peripheral blood: >1000 Sézary cells/mm3; CD4/CD8 ratio >10 Differential Diagnosis Red man syndrome/idiopathic erythroderma Generalized (atopic) eczema Drug reactions Mycosis fungoides

A

B

Pautrier microabscesses (ie, collections) is found in only up to 40% of biopsies76 (Fig. 34-13). Lymph nodes may show dermatopathic changes without histologic signs of involvement by tumor cells. Specific involvement is characterized by the effacement of lymph nodes by small cerebriform tumor cells. In transformation of SS to a high-grade lymphoma, dense sheets of large lymphoid cells with pleomorphic nuclei or immunoblasts are found in cutaneous tumors or lymph nodes.74 IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The lymphoid cells express CD2+, CD3+, CD5+, CD45RO+, CD8−, and CD30−. There is clonal rearrangement of TCR genes in most of the cases in skin infiltrates, peripheral blood, and tumor-affected lymph nodes. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Based on the histologic features, SS cannot be distinguished from MF in the patch or plaque stage.77 Similar clinical and histologic changes are seen in the “red man syndrome,”78 or “pre-Sezary syndrome”,79 generalized eczema, and drug reactions.80 CD8+ cases have to be differentiated from actinic reticuloid. SS must be distinguished from erythrodermas with polyclonal lymphoid infiltrates. Detection of clonal rearrangement of TCR genes in the skin and peripheral blood, demonstration of at least 1000/mm3 Sézary cells, and the presence of a strikingly elevated CD4+ T-cell population resulting in a significantly increased CD4/CD8 ratio (>10)

are useful diagnostic criteria for the distinction of SS from other erythrodermas.72,73

Adult T-Cell Lymphoma/Leukemia (ATLL) ATLL is a systemic LPD etiologically associated with human T-cell leukemia virus I or II (HTLV-I/II), which is endemic in Japan, Central Africa, South America, and Caribbean islands. CLINICAL FEATURES Skin involvement occurs in about 50% of patients during the course of the disease81; the most prevalent form is acute ATLL, which includes papules, nodules, tumors or erythroderma, and leukemia, lymphoadenopathy, and hypercalcemia. In the chronic and smoldering forms, patients show patches and plaques resembling MF, but leukemic cells are few in number or absent. HISTOPATHOLOGIC FEATURES The skin lesions usually show a superficial or diffuse infiltrate of medium- to large-sized pleomorphic cells with or without epidermotropism.82 The findings are similar to MF. In chronic or smoldering forms, there are only a few atypical cells in a subtle perivascular infiltrate. IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumor cells express a CD3+, CD4+, CD8−, CD25+ phenotype.81,82 Characteristically, they express CD62L, but cases of MF and related prelymphomatous T-cell dyscrasias typically

show a loss of CD62L. In the endemic variants, integration of retroviral DNA into the host cell genome has been shown. The tumor cells are often FoxP3 positive (CD4+, CD25+). DIFFERENTIAL DIAGNOSIS Clinically and histologically, the most important differential diagnoses are MF and SS, which differ by the lack of HTLV I/II. If tumors are present, the differential diagnoses include transformation of MF and SS as well as ALCL and PTL, NOS.

Primary Cutaneous CD30+ Lymphoproliferative Disorders Primary cutaneous CD30+ LPD represent a spectrum of low-grade malignant CTCL. They are characterized by highly atypical (ie, pleomorphic and anaplastic) tumor cells expressing CD30 (Ki-1) antigen. CD30+ LPD consist of lymphomatoid papulosis (LyP), primary cutaneous (CD30+) anaplastic large cell lymphoma (CD30+ ALCL), and so-called borderline cases.2,3,83 All forms of CD30+ LPD have a tendency for spontaneous regression of tumoral lesions but also recurrences and exhibit a favorable prognosis, with 5-year-survival rates of over 90%.84,85

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-13 (A) Sézary syndrome with epidermotropism of lymphoid cells and formation of Pautrier’s microabscesses. (B) Critical to the diagnosis of Sézary syndrome are the peripheral blood abnormalities. Rendering a diagnosis of Sézary syndrome from a peripheral blood morphologic perspective requires the identification of 1000/mm3 or more Sézary cells in the peripheral blood. This particular peripheral blood smear shows a classic cerebriform lymphocyte exhibiting nuclear hyperchromasia and gyrate nuclear contours.

Lymphomatoid Papulosis (LyP) LyP (Table 34-6) is a lymphoproliferative disease with a benign course but is nonetheless characterized by tumor cells with a histologic appearance suggesting malignancy. 86

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Table 34-6 Lymphomatoid Papulosis

Clinical Features Recurrent, often grouped papulonodular self-regressing eruptions Preferential localization on the trunk and extremities Healing often with hyper- or hypopigmented scars Course over years or decades Histopathologic Features Superficial and deep, wedge-shaped dermal infiltrate Medium-sized or large pleomorphic lymphoid cells with atypical mitoses, that are scattered (type A), epidermotropic (MF-like, type B), or in cohesive sheets (type C) Numerous small lymphocytes, neutrophils and eosinophils admixed Ulceration Immunohistologic Features CD3+, CD4+, CD5+, CD8−, CD30+, TIA-1+, Ki-67+ Differential Diagnosis Primary cutaneous CD30 anaplastic large cell lymphoma Pityrasis lichenoides varioliformis et acuta Bite reaction, infestation Pseudolymphoma

CLINICAL FEATURES LyP is a chronic, recurrent disease with papulonodular lesions that undergo spontaneous regression after several weeks, sometimes leaving behind hypo- or hyperpigmented varioliform scars (Fig.34-14A).86 The lesions are located mainly on the trunk and

A

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extremities. Their number can range from only a few grouped lesions to hundreds of disseminated lesions.87 LyP mainly affects individuals in the third and fourth decades of life, with a slight male preponderance. Despite its malignant histologic appearance, the disease may persist over many years or decades as an indolent process.85 A subset of patients (~10%-20%) develop a second malignant lymphoma such as MF, Hodgkin lymphoma, or nodal or cutaneous CD30+ anaplastic large cell lymphoma.85 Molecular studies indicate a clonal relationship between the tumor cells in LyP and these secondarily developing lymphomas in some, but not all, patients. 88,89 HISTOPATHOLOGIC FEATURES The histologic features vary considerably in LyP and depend on the stage of the disease.90-92 The most common histologic presentation (80% of cases) is that of LyP type A lesions. The fully developed LyP lesion is typified by a wedge-shaped dermal mixed cellular infiltrate (see Fig. 34-14). Cytomor-phologically, the infiltrate is composed of scattered medium- or large-sized pleo-morphic or anaplastic lymphoid cells admixed with numerous neutrophils and eosinophils; mitoses are commonly observed. There is a variable degree of epidermotropism of lymphoid cells. In LyP type C, cohesive sheets of tumor cells with only limited numbers of neutrophils and eosinophils are found. Rarely, an epidermotropic infiltrate of small- to medium-sized tumor cells indistinguishable from MF is present and defines the LyP type B variant. Despite the delineation of these three

histologic types of LyP, one must recognize that there is a considerable overlap and that the composition of the lesions may vary from lesion to lesion in any individual patient.92 IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The proliferating cells in LyP are activated helper T-cells and express CD3+, CD4+, CD5+, CD8−, CD15−, EMA−, and CD30+ (Ki-1) as the immunophenoytpic hallmark93,94 (Fig. 34-15). Interestingly, TIA-1 expression and a high proliferative activity are common features of the tumor cells.95 MUM1 and TRAF-1 are expressed in the vast majority of LyP cases and represent adjunctive differential diagnostic markers because they are expressed only in a minority of pcALCL.96,97 Expression of fascin by tumor cells in LyP may be associated with an increased risk for the development of a second lymphoma.98 Clonal rearrangement of TCR genes can be demonstrated in fresh-frozen tissue but may not be detected in archival specimens, thus limiting its diagnostic value.99 DIFFERENTIAL DIAGNOSIS Clinically, LyP resembles pityriasis lichenoides et varioliformis acuta (PLEVA) (MuchaHabermann disease), but the latter lesions show pronounced epidermal changes with necrotic keratinocytes, exocytosis of CD8+ lymphocytes, and a lack of large anaplastic CD30+ cells. Arthropod bite reactions may occasionally contain smallto medium-sized CD30+ activated lymphocytes. In addition, viral infections (eg, herpesvirus, molluscum contagiosum) and infestations (eg, scabies) may harbor

B

 FIGURE 34-14 Lymphomatoid papulosis. (A) Scattered erythematous papules and nodules on the trunk. (B) Medium- to large-sized pleomorphic lymphoid cells intermingled with reactive inflammatory cells.

cells are disposed in dense cohesive sheets reminiscent of melanoma or an undifferentiated carcinoma90,91 (Figs. 34-16A-D). Clusters of small reactive lymphocytes and eosinophils are found within and around the tumor.104 In neutrophil-rich variants of ALCL, the tumor cells are obscured by an profuse infiltrate of neutrophils.105 Cases with pseudocarcinomatous hyperplasia of the overlying epidermis mimicking keratoacanthoma have been described.106

CD30+ atypical-appearing lymphoid cells and thus may be misinterpreted as LyP.100

Primary Cutaneous Anaplastic Large Cell Lymphoma Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a low-grade malignant CTCL that differs from its systemic counterpart by a different biology and prognosis.85,101 CLINICAL FEATURES Solitary or multiple large nodular tumoral lesions confined to one anatomic region are the most common presentation.102 These tumorous lesions occur on normal-appearing skin without preceding patches or plaques and tend to ulcerate. Mostly patients in their fifth to sixth decades of

A

life are affected, with a male-to-female ratio of 2:1. Nevertheless, pcALCL may also occur in children. Up to 20% to 25% of tumoral lesions have been reported to undergo spontaneous regression.85 ALCLs are one of the most common forms of CTCL arising in transplant recipients.103 HISTOPATHOLOGIC FEATURES The histology shows a nodular dermal infiltrate often extending into the subcutis. The morphologic hallmark are large, pleomorphic, anaplastic, and immunoblastic cells with large, irregularly shaped nuclei and dispersed chromatin; one or multiple nucleoli; and abundant pale or eosinophilic cytoplasms. Multinucleate giant cells with nuclei arranged in annular configurations are characteristic. Tumor

DIFFERENTIAL DIAGNOSIS The clinical differential diagnosis includes LyP (type C), large cell transformation of MF or SS, CD30− large cell PTL, type unspecified. PcALCL must be differentiated from

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-15 Lymphomatoid papulosis.Expression of CD30 antigen (Ki-1) by pleomorphic tumor cells. Note the perinuclear dotlike staining of the Golgi apparatus.

IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The most striking feature is expression of CD30 by the large anaplastic cells (Fig. 34-16 E-G). T-cell-associated antigens (CD43, CD45RO) are expressed with variable loss of pan T-cell antigens (CD2, CD3, CD5, CD7). In contrast to nodal ALCL, primary cutaneous forms may lack EMA and typically express the cutaneous lymphocyte antigen (CLA, HECA-452).101 CLA expression can, however, be seen in nodal ALCLs that disseminate to the skin. They may express perforin, TIA, and perforin. In addition, expression of homeobox gene HOXC5 as well as lack of MUM1 and TRAF-1 expression are found pcALCL in contrast to LyP and systemic (CD30+) ALCL, which may involve the skin secondarily.96,97 Alk (p80) and the (2;5) translocation are usually absent in pcALCL.22 Clonal rearrangement of TCR genes is found in most patients with pcALCL.

B

 FIGURE 34-16 (A) Primary cutaneous anaplastic large-cell lymphoma. Cohesive sheets of large anaplastic lymphoid cells. (B) This patient presented with an ulcerating tumor nodule of a few weeks’ duration. An effacing superficial and deep nodular infiltrate with associated ulceration of the surface is seen.

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C

D

E

F

G  FIGURE 34-16 (C) and (D) The cells that make up the infiltrate are large and pleomorphic, including the presence of classic binucleated (Reed Sternberg like) and multinucleated cells with a horseshoe arrangement of nuclei. (E) The tumor cells express CD30 in cytoplasmic membrane and perinuclear golgi patterns. (F) The tumor cells are extensively epithelial membrane antigen positive. (G) The tumor cells are granzyme positive. Note the granular staining within the tumor cells.

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secondary cutaneous involvement of systemic ALCL and Hodgkin lymphoma by immunophenotyping and staging examinations. Furthermore, phenotyping is essential to differentiate CD30+ ALCL from nonlymphoid undifferentiated neoplasms such as melanoma and various carcinomas.

Cytotoxic Cutaneous Lymphomas

Clinical Features Subcutaneous nodules simulating panniculitis with or without ulceration Preferential localization: trunk, extremities (legs) Histopathologic Features Subcutaneous infiltrate simulating lobular panniculitis Small or medium-sized to large pleomorphic lymphoid cells Rimming of fat cells by proliferating (Ki-67+) lymphoid cells Possible involvement of dermis, especially in γ/δ (TCRδ-1+) cases Immunohistologic Features Various phenotypes: T-cell: CD3+, CD4−/+, CD5+, CD8+/−, CD30−, TIA-1+, Ki-67+ TCR α/β (βF1+) more frequent than TCR γ/δ (TCRδ-1+) NK and NK/T-cell: CD56+ TCR α/β (βF1+): usually rather indolent course. TCR γ/δ (TCRδ-1+) or CD56: usually aggressive course Differential Diagnosis Panniculitis, especially lupus panniculitis Cytophagic histiocytic panniculitis

Subcutaneous Panniculitis-Like T-Cell Lymphoma According to the WHO-EORTC classification and the 2008 WHO classification, SPTCL is defined by its primary subcutaneous localization (Table 34-7) and the alpha/beta TCR+ as well as cytotoxic phenotype.3,4,109,110 Subcutaneous lymphomas with gamma/delta TCR+ phenotype belong to cutaneous gamma/delta T-cell lymphomas. CLINICAL FEATURES SPTCL presents clinically as panniculitis mimicking erythema nodosum, with erythematous, firm subcutaneous nodules favoring the legs.111 The lesions are persistent and may become ulcerated. Systemic signs may be present. In a subset of patients, a hemophagocytic syndrome may accompany SPTCL.110,112 The course is usually slowly progressive. Prognosis of SPTCL is favorable, with 5-year-survival rate of 82%.110 HISTOPATHOLOGIC FEATURES The histopathologic criteria for this type of CTCL include the primary subcutaneous location and a growth pattern of lymphoid infiltrates simulating a lobular panniculitis113,114 (Fig. 34-17). Cytomorphologically, the tumor cells may be small, medium, or large in size and pleomorphic.

Margination (rimming) of lipocytes by tumor cells is a common but nonspecific finding.115 IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumor cells have a cytotoxic T-cell profile (CD2+, CD3+, CD5+, CD4−, CD8+, CD43+, T1A-1+, granzyme B+, perforin+)(see Fig. 34-17A-C). By definition, they are TCR α/β+ (βF1+) (3). There is no association with EpsteinBarr virus (EBV). Clonal rearrangement of α/β of the T-cell receptor is found. DIFFERENTIAL DIAGNOSIS SPTCL must be differentiated from subcutaneous γ/δ+ T-cell lymphoma, which exhibits a poor prognosis.110,116 Among the nonneoplastic disorders, the differential diagnosis includes atypical lymphocytic lobular panniculitis; lupus panniculitis; and other forms of inflammatory panniculitis, especially histiocytic cytophagic panniculitis. The latter is a reactive process associated with a number of systemic diseases and presents with a hemorrhagic diathesis owing to hemophagocytosis in the absence of an LPD (see Chapter 11). Atypical lymphocytic lobular panniculitis is a

distinct form of subcutaneous T-cell dyscrasia characterized by clonal infiltrates of T cells whereby lymphoid atypia is mild, density of infiltration is low, and there is minimal to absent necrosis. This condition may potentially correspond to the waxing and waning phase that may presage subcutaneous panniculitis-like T cell lymphoma.

Extranodal NK/T-Cell Lymphoma, Nasal Type The skin represents the second most common site of involvement by this rare lymphoma. Cutaneous lesions may be the primary or secondary manifestation of the disease. CLINICAL FEATURES Papulonodular lesions with ulceration are the most prevalent clinical manifestations.117 Systemic symptoms, including fever, malaise, and weight loss, are noted commonly. In addition, hemophagocytic syndrome may be observed. Most NK/T-cell lymphomas have an aggressive course. The median survival time is 12 to 15 months.118 HISTOPATHOLOGIC FEATURES The dermal and often subcutaneous infiltrates display an angiocentric and angiodestructive growth pattern with necrosis and ulceration117 (Fig. 34-18). The lymphocytes are of variable size but are mostly medium sized. Lymphocytes have round or oval nuclei. IMMUNOPHENOTYPIC GENOTYPIC FEATURES Pale cytoplasms numerous small lymphocytes, eosinophils, plasma cells, and macrophages may be present. The true NK lymphomas express CD2; cytoplasmic CD3 (CD3 epsilon); CD56; and cytotoxic proteins T1A-1, granzyme B, and perforin. EBV is found in nearly all cases of secondary cutaneous NK lymphomas but rarely in primary cutaneous forms. 118 NK lymphomas exhibit a germline configuration; however, in the NK-like T-cell lymphomas, clonal TCR rearrangement can be detected, defining a critical discriminatory factor separating NK lymphoma from NK-like T-cell lymphoma. In addition, in the NK T-cell lymphomas, there is surface expression of CD3. The polyclonal CD3 used on paraffin-embedded tissue cannot reliably discriminate between CD3 epsilon and surface CD3; hence, both NK and NK-like T-cell lymphomas may show CD3 expression on routine immunohistochemical staining for CD3 on paraffinembedded tissue.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Cytotoxic CLs are a heterogeneous group of disorders linked by the common expression of a cytotoxic phenotype by the tumor cells.107 Cytotoxic proteins such as perforin, granzymes, and granule membrane-associated cytotoxic protein TIA-1 are mainly expressed by cytotoxic T cells, NK/T cells, and NK cells and mediate cell lysis.108 Four main groups of cytotoxic CLs can be distinguished: (1) primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; (2) cutaneous gamma/delta-positive T-cell lymphomas, which both belong to the group of peripheral T-cell lymphomas; (3) extranodal NK/T-cell lymphomas, in which skin involvement often occurs secondarily; and (4) subcutaneous panniculitis-like T-cell lymphoma (SPTCL).

Table 34-7 Subcutaneous Panniculitis-like Lymphoma

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A

920

B

C  FIGURE 34-17 (A) Subcutaneous panniculitis-like T-cell lymphoma. Infiltration of subcutaneous fat tissue by small- to medium-sized pleomorphic cells surrounding adipocytes. (B) There is permeation of the interstitial spaces of the fat by small- to intermediate-sized lymphocytes. In many cases, the cells may appear only mildly atypical. (C) Subcutaneous panniculitis–like T-cell lymphoma is a tumor of cytotoxic CD8 lymphocytes in the majority of cases. Illustrated here is a CD8 preparation showing extensive staining.

 FIGURE 34-18 Extranodal natural killer/T-cell lymphoma, nasal type. Angiocentric and angiodestructive growth of atypical lymphoid cells is seen.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other CD56+ CLs119 and lymphomas with angioinvasive growth. Detection of EBV is useful to distinguish extranodal NK/T-cell lymphoma from other SPTCL and peripheral T-cell lymphomas, unspecified.

Hydroa Vacciniforme-Like Lymphoma

Primary Cutaneous Peripheral T-Cell Lymphoma, Unspecified (PTL) PTL, unspecified represents a phenotypically and prognostically heterogenous group of CTCL. According to the WHOEORTC classification and WHO classification, the designation PTL, unspecified refers to CTCLs that do not fit into any of the other better-defined subtypes of CTCL.3,4 Among PTLs, three (provisional) entities have been identified based on their characteristic clinicopathologic, immunophenotypic, and prognostic features, which are discussed below. For the remaining diseases that do not fit into these three provisional entities the designation PTL, unspecified (sensu stricto) is maintained.

Primary Cutaneous CD4+ Small- to Medium-Sized Pleomorphic T-Cell Lymphoma (SM-PTL) This lymphoma predominantly consists of small- to medium-sized pleomorphic tumor cells that do not express CD30 and differs from other entities within the group of PTL because of its excellent prognosis.5,122 CLINICAL FEATURES SM-PTL manifests skincolored or red-brown nodules without ulceration. The prognosis is favorable, with a 5-year survival of more than 90%.123 HISTOPATHOLOGIC FEATURES Histologically, there is a nodular dense monomorphous

 FIGURE 34-19 Primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma. Nodular dense infiltrate of lymphocytes throughout the entire dermis. Note the Grenz zone and absence of epidermotropism.

lymphocytic infiltrate (Fig. 34-19). Epidermotropism is usually absent or only focally present. The monomorphous infiltrate extends throughout the entire dermis and is composed of smallto medium-sized lymphocytes with pleomorphic moderately chromatindense nuclei and a small cytoplasmic rim. Eosinophils, plasma cells, and histiocytes may be admixed, and granulomatous features may be present.123 Clusters of B cells are commonly noted. IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumor cells have a CD3+, CD4+, CD8−, CD30− T-helper phenotype. There may be loss of T-cell antigens. Clonal rearrangement of TCR genes has been detected in almost all cases reported and may be useful in the distinction of SM-PTL from T-cell PSL. DIFFERENTIAL DIAGNOSIS SM-PTL must be distinguished from MF by the absence of patches and plaques and the lack of epidermotropism. T-cell pseudolymphoma differs from SM-PTL by the lack of clonality and lack of T-cell antigen loss of .38 Recently, a nodular proliferation of CD3+, CD8+, CD4−, TIA-1+ blast-like medium-sized clonal lymphocytes was reported that clinically mimics SM-PTL because of a slowly growing nodule on the ear and an indolent course.124

Primary Cutaneous Aggressive Epidermotropic CD8+ T-Cell Lymphoma (AE-TCL) This rare aggressive form of CD8+ CTCL with rapid course, poor prognosis,

and involvement of mucosal areas and visceral organs was identified by Berti and coworkers.125 CLINICAL FEATURES Patients of all ages are affected. This type of lymphoma often exhibits widespread erosive and occasionally hyperkeratotic patches, plaques, or papules and nodules undergoing ulceration.125 The disease may spread to extracutaneous sites, particularly the visceral organs, oral mucosa, and central nervous system (CNS). The disease has an aggressive course, with a median survival of less than 3 years. HISTOPATHOLOGIC FEATURES There is prominent epidermotropism of smallmedium or medium-large lymphocytes with pleomorphic chromatin-dense nuclei. Apoptotic keratinocytes, epidermal necrosis, and spongiosis with blister formation are commonly found (Fig. 34-20). Angiocentric growth and destruction of adnexal structures may be present.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

This is a rare CD8+ LPD associated with chronic EBV infection. Most affected patients are children or young adults of Asian and Latin American origin, presenting with edema, vesiculopapular lesions, crusts, necrotic areas, and scars predominately on the face and limbs.120,121 Clinical manifestations resemble those of severe hydroa vacciniforme. Histologically, there is necrosis of the epidermis and dense perivascular and periadnexal nodular infiltrates in the dermis containing medium sized lymphocytes with irregular, hyperchromatic nuclei. The infiltrate displays a prominent angiocentric or angiodestructive pattern. The atypical cells express a CD8+ phenotype. EBV is detected in the majority of patients.

IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumors exhibit a CD3+, CD4−, CD8+, CD45RA+, CD45RO−, TIA-1+ phenotype (Fig. 34-21). No association with EBV has been found. A CD2− CD7+ phenotype seems to be associated with a more aggressive course.126 Clonal rearrangement of TCR genes can be demonstrated in most cases. DIFFERENTIAL DIAGNOSIS Clinical features are essential to distinguish AE-TCL from CD8+ variant of MF, which is characterized by long-standing, often hypo- or hyperpigmented patches and plaques

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are negative for TCR α/β (βF1).3 Primary and secondary cutaneous forms appear to have a similar poor prognosis. CLINICAL FEATURES The clinical manifestations include disseminated, often necrotic or ulcerated, plaques or nodules.129 Involvement of the oral mucosa is common, and other extranodal sites may often become involved; the lymph nodes and bone marrow are usually spared. The disease may be accompanied by a hemophagocytic syndrome, especially in patients with subcutaneous form of CGD-TCL. The clinical course of CTCL with a γ/δ+ phenotype is usually aggressive, with a median survival of 15 months.130

 FIGURE 34-20 Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. Prominent lining up of lymphoid cells along junctional zone, epidermotropism, and apoptotic keratinocytes are present. .

IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES Tumor cells exhibit a CD3+ CD56+ phenotype and are often CD4-, CD8- double negative. By definition, they do not express betaF1 but are TCRdelta positive. The latter can be demonstrated on frozen sections only. TCR gamma genes are clonally rearranged. Isochromosome 7q is a common genetic abnormality.

 FIGURE 34-21 Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. Expression of CD8+ by the intraepidermal lymphoid cells.

922

HISTOPATHOLOGIC FEATURES Epidermotropic (pagetoid), dermal (diffuse or nodular) and subcutaneous patterns are distinguished (Fig. 34-22A). Epidermal and dermal involvement, however, may also occur in predominantely subcutaneous CGD-TCL and may be associated with production of large amounts of γ-interferon (132). Tumor cells are medium to large sized with chromatin-dense irregular nuclei (Fig. 34-22B). Angioinvasive infiltrates and necrosis are common.

and the slowly progressive course of classic CD4+ MF.68,69 In addition, the vast majority of cases of MF are CD45 RO positive and only rarely are the neoplastic cells CD45RA positive. Pityriasis rosea may present with similar histologic features, but it is clinically characterized by a “herald patch”. Febrile ulcero-necrotic PLEVA may simulate clinically and histologically AE-TCL but does not express CD45RA. Because clonality has been

demonstrated in pityrasis lichenoides,127 detection of clonality does not serve as a discriminating marker. Moreover, transition from febrile ulceronecrotic PLEVA to CD8+ AE-TCL has been reported.128

Cutaneous γ/δ+ T-Cell Lymphoma (CGD-TCL) CGD-TCL is characterized by clonal Tcells expressing γ/δ TCR (TCRδ+) but

DIFFERENTIAL DIAGNOSIS Subcutaneous CGD-TCL has to be distinguished from its TCRalpha/beta+ counterpart SPTCL, which has an often indolent course with a favorable prognosis. EBV is generally negative in CGD-TCL in contrast to CD3(epsilon)+, CD56+ NK/T-cell lymphoma, nasal type.

Primary Cutaneous Peripheral T-Cell Lymphoma, Unspecified The clinicopathologic features of this CTCL entity are still poorly characterized. Thus far, only a few case series have been reported in the literature.133 These are rare primary CTCLs composed predominantly of medium- to large-sized pleomorphic or immunoblastic T cells. Cases of the d’emblee form of MF reported in the literature belong to this entity.

B

 FIGURE 34-22 Cutaneous gamma/delta T-cell lymphoma. (A) Medium to large lymphoid cells infiltrating the subcutaneous fat. (B) The nuclei are irregular with dense chromatin.

CLINICAL FEATURES This form of CTCL presents usually in adults with solitary, grouped, or disseminated nodules without preceding patches or plaques. 133 The prognosis is poor,

A

with a 5-year-survival rate of less than 20%.133,134 HISTOPATHOLOGIC FEATURES The tumors are characterized by nodular infiltrates

composed of medium-sized to large cells with pleomorphic nuclei and pale cytoplasms and a few associated reactive cells.135 Epidermotropism is not a prominent feature (Fig. 34-23).

B

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

A

C  FIGURE 34-23 Peripheral T cell lymphoma, type unspecified. The patient was a 45-year-old woman who presented with three tender nodules on the back of a few weeks’ duration. The biopsy shows an effacing deep dermal and subcutaneous infiltrate composed of large atypical cells.

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IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES Tumor cells express a T-helper phenotype (CD2, CD3, CD5) but show T-cell antigen loss (eg, CD7). In some cases, however, there may be relative preservation of CD7 but a diminution in the extent of staining for CD2. By definition, the tumor cells lack expression of CD30. Molecular biology reveals a clonal rearrangement of TCR genes (Fig. 34-24).

924

DIFFERENTIAL DIAGNOSIS The differential diagnoses includes transformation of MF and SS, which differ by clinical features, as well as ALCL expressing CD30 by at least 75% of the tumor cells.3 Secondary cutaneous involvement by nodal PTL has to be excluded by staging examinations.

A

Secondary Skin Involvement by Nodal Lymphomas ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA (AITL) Patients typically present with nodal disease and type B symptoms. They may also have hepatosplenomegaly. Skin involvement is seen in 30% to 40% of patients. Skin involvement occurs mostly as a generalized maculopapular eruption with a predilection for the trunk and mimics a viral exanthem or drug eruption. Patients present with fever, weight loss, night sweats, lymphadenopathy, hepatosplenomegaly, and abnormalities in the peripheral blood. The lymph node changes are characteristic. The nodal architecture is effaced, with proliferation of high endothelial venules associated with follicular dendritic cells. The lymphocytic infiltrate is relatively sparse with medium-sized tumor cells with a clear cytoplasm. Histologic findings in the skin vary from a nonspecific pattern typified by scant superficial perivascular infiltrates composed of eosinophils and normal-looking lymphocytes around hyperplastic capillaries to distinctive patterns suggesting AITL. The latter findings include prominent vascular endothelial hyperplasia and the presence of pleomorphic lymphocytes with medium- to large-sized reniform nuclei (Fig. 34-25). Immunohistochemically, the neoplastic lymphocytes express the phenotype of mature T-helper cells (CD3+, CD4+, CD86+) with aberrant loss of T-associated antigens in some cases. 136 In addition there may be a proliferation of CD 21 positive dendritic cells (Fig. 34-26). CD10 serves as a useful marker for tumor cells in AITL.137 EBV may be found in a few cells138

B

C  FIGURE 34-24 Peripheral T-cell lymphoma, type unspecified. Phenotypic studies conducted on the tumor revealed a (A) CD30− (B) CD25+ and (C) CD4+ T-cell lymphoma.

B

 FIGURE 34-25 Angioimmunoblastic lymphadenopathy. (A) The patient presented with skin nodules, constitutional symptoms, anemia, and polyclonal hypergammaglobulinemia. The biopsy showed a striking lymphocytic infiltrate localized to the subcutaneous fat. (B) Higher power magnification reveals a welldifferentiated small lymphocytic infiltrate with an arborizing vascular network and scattered eosinophils.

B

A

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

A

C  FIGURE 34-26 Angioimmunoblastic lymphadenopathy The immunophenotypic profile is compatible with angioimmunoblastic lymphadenopathy. (A) The lymphocytes are CD10 positive. (B) In addition, the extent of vascularity is highlighted by the CD34 stain. (C) There is a prominent dendritic cell network, as demonstrated by the CD21 stain.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Precursor Hematologic Neoplasms

926

PRECURSOR T-LYMPHOBLASTIC LYMPHOMA T-lymphoblastic lymphoma (precursor T-lymphoblastic lymphoma) presenting solely as a cutaneous process is uncommon. Histopathologically, there is a dermal proliferation of cells with a high nuclear-to-cytoplasmic ratio. Cytologic variations include the presence of cells with round, oval, or convoluted nuclei; the size of the nuclei (from small to large); and chromatin appearance (condensed with inconspicuous nucleoli to finely dispersed with prominent nucleoli).139,140 A common finding is the presence of numerous mitotic figures and apoptotic cells imparting the typical “starry sky” appearance of the neoplastic infiltrate.140 The lymphoblasts are TdT+ in most cases. The expression of T-associated antigens and CD99 and CD34 is typical but variable. CD3 is considered to be lineage-specific.7 The diagnosis of primary cutaneous T-lymphoblastic lymphoma requires the exclusion of systemic disease (precursor T-lymphoblastic leukemia/lymphoma) by staging.139

CD4+, CD56+ Hematodermic Neoplasm This lymphoma has originally been referred to as blastic NK-cell lymphoma. Because recent studies have demonstrated that this neoplasm is the neoplastic counterpart of plasmacytoid dendritic cells (PDCs),141 it has been renamed plasmacytoid dendritic cell neoplasia in the 2008 WHO classification. CLINICAL FEATURES The disease usually presents with contusiform, bruiselike disseminated plaques and nodules.142,143 The trunk and head are the most common sites, and mucosal involvement is common. Usually, there is already systemic involvement at the time of diagnosis with circulating malignant cells, lymph node and bone marrow involvement, and CNS infiltrates. The course is aggressive, with rapid dissemination and fatal outcome within 2 years of diagnosis. In some patients, the disease develops in the setting of preexisting myelodysplastic syndrome.144 HISTOPATHOLOGIC FEATURES Histologically, there is a monomorphous infiltrate of blast cells that is bandlike in the upper and mid-dermis with column-like extensions into the deeper dermis and subcutis.143 Neither a grenz zone nor epidermotropism of tumor cells is observed. The tumor cells display nuclei with fine-dispersed

 FIGURE 34-27 CD4+, CD56+ hematodermic neoplasm. Cohesive sheets of medium-sized blastlike cells are seen. Note the prominent extravasation of erythrocytes.

chromatin and a sparse cytoplasm. Extravasated erythrocytes are found within the tumorous infiltrates. IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumor cells express CD4, CD56, CD123, and TCL-1 but are negative for T- and B-cell as well as myeloidmonocytic markers145 (Fig. 34-27). There usually is no clonal rearrangement of TCR detectable. There is no association with EBV. The tumor cells express other plasmacytoid dendritic cell markers such as myxovirus protein(MXA), CD83, and BDCA-2. In addition, there may be expression of CD2 and CD7. DIFFERENTIAL DIAGNOSIS The neoplasm has primarily to be distinguished from specific infiltrates of myeloid/monocytic leukemia, which expresses myeloid–monocytic markers such as CD14 and MPO and is negative for TCL-1 in most cases.145 Some CD56+ variants of monocytic leukemia typically follow an even more aggressive clinical course compared with cases of CD56- monocytic leukemia . The phenotypic profile is very similar to that of hematodermic neoplasm. There may also be CD123 expression, although the extent of CD56 and CD123 expression are typically not as extensive as the prominent staining observed for both markers in patients with hematodermic neoplasm. Phenotyping is useful to differentiate CD4+ CD56+ hematodermic neoplasms from B-cell lymphomas.

Cutaneous B-Cell Lymphoid Hyperplasia and Cutaneous B-Cell Lymphomas Lorenzo Cerroni Helmut Kerl

CUTANEOUS B-CELL LYMPHOID HYPERPLASIA Synonyms: lymphadenosis benigna cutis, lymphocytoma cutis, pseudolymphoma of Spiegler-Fendt In the recent past, many lymphoid proliferations that were classified previously as cutaneous B-cell lymphoid hyperplasia (pseudolymphoma) have been reclassified as low-grade malignant B-cell lymphomas with a favorable clinical behavior. The term cutaneous B-cell lymphoid hyperplasia is still used, but it is not a specific diagnosis.146,147 It is descriptive and refers to a heterogeneous spectrum of diseases that simulate malignant B-cell lymphomas clinically, histopathologically, or both. Whenever possible, a diagnosis of cutaneous lymphoid hyperplasia should be avoided in favor of specific designations using the language of clinical dermatology. The classical example of a cutaneous B-cell lymphoid hyperplasia (Table 34-8)

Table 34-8 Cutaneous B-Cell Lymphoid Hyperplasia

is lymphadenosis benigna cutis (synonyms are lymphocytoma cutis and pseudolymphoma of Spiegler-Fendt). CLINICAL FEATURES Erythematous or redbrown to red-purple solitary nodules with a smooth surface are usually found. Agminated lesions in a region or disseminated papules may be observed rarely. Favored sites of involvement are the face (cheek, nose, earlobe), mammary area, and scrotum.147,148 Children and adults may be affected. The course of cutaneous B-cell lymphoid hyperplasia varies. The lesions may resolve with or without treatment. Various stimuli may induce lesions of cutaneous B-cell lymphoid hyperplasia, including insect bites, persistent nodules of scabies, drugs (antidepressant therapy), vaccinations, injections of antigens for hyposensitization, and tattoos. Cases of cutaneous B-cell lymphoid hyperplasia are often associated with infection by Borrelia burgdorferi (Borreliainduced lymphocytoma).148 In many cases, however, a precise cause is not found. HISTOPATHOLOGIC FEATURES Relatively symmetrical, rather well-circumscribed nodular infiltrates within the dermis and sometimes within the subcutaneous fat can be observed.147,148 As a rule, the infiltrates are more dense in the upper part of the dermis than in the lower part (in Borrelia-associated lymphocytoma cutis arising on the nipple, however, the infiltrate has usually a “bottom-

 FIGURE 34-28 Cutaneous B-cell lymphoid hyperplasia (lymphadenosis benigna cutis). Nodular infiltrates with a follicular pattern. Stained with Giemsa stain.

heavy” arrangement).148 Germinal centers are frequently present (follicular type of pseudolymphoma) (Fig. 34-28). Sometimes a nonfollicular pattern without formation of germinal centers can be observed. An important diagnostic criterion is the mixed character of the infiltrate (Fig. 34-29). Although lymphocytes, especially small ones, are nearly always predominant, eosinophils, plasma cells, histiocytes, and giant cells are often found as well. The epidermis is not involved and is usually separated

from the infiltrates of inflammatory cells by a thin zone composed of normal collagen bundles. Adnexal structures are spared. These histopathologic features frequently represent responses to infectious agents such as B. burgdorferi, but other etiologies may be responsible.148,149 Drug-associated cutaneous lymphoid hyperplasia (most commonly associated with antidepressant therapy) usually reveal a mycosis fungoides-like pattern, but can occasionally also induce

 FIGURE 34-29 Cutaneous B-cell lymphoid hyperplasia. Mixed-cell infiltrate with small lymphocytes, lymphoplasmacytoid cells, eosinophils, and histiocytes.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Clinical Features Preferential locations (Borrelia-induced lymphocytoma): nipple, earlobe, scrotum Solitary (or rarely multiple) nodules Both children and adults affected Histopathologic Features Nodular, "top-heavy", mixed cell infiltrates Small lymphocytes predominate, plasma cells, eosinophils, and histiocytes Reactive lymphoid follicles frequently present Immunohistologic Features CD20+ CD79a+ Polyclonal pattern (κ+, λ+) Bcl-2− (germinal center cells) CD10 −, Bcl-6− (outside lymphoid follicles) Regular pattern of CD21+ follicular dendritic cells CD3+ reactive cells

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histopathologic features similar to lymphadenosis benigna cutis.150 It should be emphasized that a “pseudolymphomatous” appearance does not necessarily mean that a tumor is benign; rarely, malignant nonlymphoid tumors may present with histopathologic features simulating a lymphoproliferative disorder (eg, lymphoepithelial-like carcinoma, pseudolymphomatous angiosarcoma).151

928

IMMUNOLOGY AND RELATED FEATURES Immunohistological investigations reveal the presence of B-cell compartments (CD20+) surrounded by T-cell aggregations. The T-cells (CD3+, CD45RO+) may even predominate. Cases with germinal center formation (CD10+, Bcl6+, Bcl2−) are associated with a regular network of dendritic reticulum cells (CD21+). Analysis of Ig-light chain expression usually discloses a polyclonal proliferation of B cells that express both κ and λ light chains. Very few systematic molecular studies have been performed. Polyclonal Ig-gene rearrangements are observed as a rule. DIFFERENTIAL DIAGNOSIS Certain clinical features may be helpful in the differential diagnosis of benign versus malignant B-cell infiltrates of the skin. Whereas benign B-cell lymphoid hyperplasias often present as a single papule or nodule with a smooth surface on a special location (eg, earlobe, nipple, genital area), lymphomas tend to be associated with clusters of papules, plaques, and tumors that may be ulcerated. B-cell lymphoid hyperplasias occur frequently in children, in contrast to CBCLs. In B-cell lymphoid hyperplasia, there may be a history of a causative event (eg, drug intake, B. burgdorferi infection), but in lymphomas, the cause is usually obscure. The histologic differentiation of cutaneous B-cell lymphoid hyperplasia from malignant CBCLs is one of the most difficult problems in diagnostic dermatopathology (Table 34-9).147,152 As a rule, but not in all cases, cellular infiltrates in cutaneous B-cell lymphoid hyperplasia are relatively symmetrical, rather well-circumscribed, and more dense in the upper part of the dermis than in the lower part (“top heavy”). In contrast, infiltrates in malignant B-cell neoplasms are more massive, asymmetrical, poorly circumscribed, and are frequently more or less equally distributed in the superficial and deep dermis or more dense in the lower part of the dermis and subcutaneous fat (“bottom heavy”). There is a mixed character of the infiltrate in B-cell cutaneous

Table 34-9 Histopathologic Criteria: B-Cell Cutaneous Lymphoid Hyperplasia Versus Malignant B-Cell Lymphoma Cutaneous B-Cell Hyperplasia

Malignant B-Cell Lymphoma

Symmetry Wedge-shaped pattern Involvement of upper part of the dermis usually greater than that of the lower dermis Adnexal structures spared Lymphoid follicles with normal mantle zone Tingible body macrophages present in lymphoid follicles

Asymmetry Lack of wedge-shaped pattern Involvement of the lower part of the dermis equal or greater that that of the upper dermis Adnexal structures often obliterated Lymphoid follicles devoid of mantle zone Tingible body macrophages absent or reduced in lymphoid follicles

lymphoid hyperplasia. In addition to lymphocytes, eosinophils, plasma cells, histiocytes, and giant cells are often present, but similar features can be observed in many low-grade malignant B-cell lymphomas, especially marginal zone lymphoma.153 Nuclear atypia is found more frequently in malignant lymphomas. However in low grade B-cell lymphomas nuclear atypica may be minimal. The histologic features of distinct lymphoid follicles with germinal centers, which have been misinterpreted in the past as characteristic criteria of a benign inflammatory process, are not reliable for the differential diagnosis of lymphoma versus pseudolymphoma. Reactive follicles may also be present in lymphomas. Other findings helpful in the differential diagnosis are the tendency of the cellular infiltrates in cutaneous lymphoid hyperplasia to spare the epithelium of adnexa, in contrast to lymphomas, in which the adnexal epithelium structure is frequently involved by neoplastic infiltrates, and the presence of tingible bodies (lymphocytic nuclear debris engulfed by macrophages) in germinal centers in cutaneous lymphoid hyperplasia but not in neoplastic follicles in lymphomas. Immunohistologic features are very important for the differential diagnosis. Whereas malignant populations of B lymphocytes usually show a monoclonal restriction to either κ or λ immunoglobulin light chain, benign infiltrates exhibit a polyclonal pattern with expression of both light chains. Unfortunately, however, there are several cases of B-cell lymphoproliferative disorders, both benign and malignant, in which the cells do not express immunoglobulins (or expression cannot be demonstrated in routinely fixed, paraffin-embedded specimens). A useful clue for the diagnosis of follicle center lymphoma with a follicular growth pattern is the diminished prolif-

erative activity of malignant follicular cells as outlined by the Ki67/MIB-1 antibody (<50% of cells positive).154 Reactive germinal centers, in contrast, show a high proliferation (almost 100% of cells positive). About 80% of follicle center cell lymphomas and 15% to 30% of high-grade malignant B-cell lymphomas in the lymph nodes are characterized by the t(14;18) translocation, which is associated with overexpression of the bcl-2 protein. By contrast, studies of cutaneous cases have showed that t(14;18) is very rare, and expression of Bcl-2 can be observed only in a small minority of cases. Thus, in the skin, Bcl-2 expression cannot be used as a criterion for the differentiation of follicle center cell lymphoma from B-cell pseudolymphoma with a follicular pattern. CD10 and Bcl-6 expression outside of the follicles may be useful in differentiating follicle center cell lymphomas (CD10+ and/or Bcl-6+ interfollicular clusters can be found in these cases) from cutaneous B-cell lymphoid hyperplasias (no interfollicular clusters of CD10+ or Bcl-6+ cells).154 Low-grade malignant lymphomas of B-cell lineage may show aberrant expression of some T-cell–associated markers most commonly CD43. CD5 is a pan T-cell marker that reacts with the cells of most cases of B-cell chronic lymphocytic leukemia. Normal B lymphocytes are CD43 negative, but several low-grade B-cell lymphomas are CD43 positive. The detection of an aberrant phenotype of the B lymphocytes (CD20+, CD5+, CD43+) is considered a sign of malignancy. Concerning molecular analyses, the detection of a polyclonal pattern of immunoglobulin genes rearrangement using the PCR favors a diagnosis of cutaneous B-cell lymphoid hyperplasia, but a monoclonal rearrangement is usually (but not always) associated with malignancy. However, it must be stressed that CBCLs do not always show a monoclonal pattern by PCR.

It is important to emphasize that there are clear exceptions to each of the abovementioned criteria. The diagnosis must therefore be based on a constellation of clinical, histologic, immunohistologic, and molecular features, including followup information.

CUTANEOUS B-CELL LYMPHOMAS

CLINICAL FEATURES CBCLs occur far more frequently than is generally believed. The clinical manifestations are variable. The lesions may be single, regionally multiple, or generalized in distribution. Large, sometimes ulcerated tumors, nodules, or plaques of varying hues of red, blue, purple, and brown are very common. Erythematous macularpapular eruptions can also be observed. Sub-cutaneous masses are seen occasionally. In contrast to cutaneous T-cell lymphomas, there is usually no scaling or erythroderma. The lesions can be localized anywhere on the skin and may rarely involve the mucous membranes. Preferred locations are the head, back, and extremities. It is increasingly evident that most primary CBCLs have an excellent prognosis. The 5-year survival rate for low-grade CBCLs is over 90%; a more aggressive course is characteristic of diffuse large B-cell lymphomas. HISTOPATHOLOGIC AND CYTOMORPHOLOGICAL FEATURES Morphology remains a crucial feature for defining CBCLs. The optimal technical quality of the sections (fixation, embedding) is a precondition for a correct diagnosis. The specimen must be of sufficient size to reveal the critical information. Whenever possible, punch biopsies should be avoided. The standard methods for the light microscopic diagnosis of CBCLs include hematoxylin-eosin, giemsa, and periodic acid-Schiff (PAS) staining. Giemsa is very useful for the recognition of a follicular pattern, and it reveals precise cytologic

cells and appear to display specific homing patterns (extranodal marginal zone lymphoma, MALT-type lymphoma).

Principal Cell Types of the B-Cell Series LYMPHOBLASTS These are uniformappearing, medium-sized cells with round, oval, or indented nuclei; fine chromatin; inconspicuous nucleoli; and scanty cytoplasm. These cells are found in precursor B-lymphoblastic lymphomas. SMALL LYMPHOCYTES, B-TYPE These are small lymphocytes, usually with round nuclei, dense chromatin, and a small rim of cytoplasm. These cells correspond to those that are found in B-cell chronic lymphocytic leukemia. LYMPHOPLASMACYTOID CELLS Lymphoplasmacytoid cells are smaller than typical mature plasma cells. The nucleus resembles the nucleus of small lymphocytes, and the cytoplasm is abundant and basophilic, as in plasma cells. PLASMA CELLS The typical mature plasma cells are also known as the Marschalkotype plasma cells. They are characterized by a round, frequently eccentrically located, nucleus that exhibits the oftenmentioned “cartwheel” or “clock face” pattern of chromalin distribution. The abundant cytoplasm is strongly basophilic and may show a paranuclear halo. Lymphoplasmacytoid cells and plasma cells are found in marginal zone lymphomas and plasmacytomas. GERMINAL CENTER CELLS Two main types of lymphoid cells can be distinguished: 1. Centroblasts: Large cells with a narrow rim of cytoplasm and oval, vesicular nuclei containing one or more distinctive nucleoli, typically situated near the nuclear membrane.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

CBCLs are distinct clinical and morphological subtypes of extranodal lymphomas.147,155,156 They can be defined as neoplasms of the immune system characterized by a proliferation of B lymphocytes that infiltrate the skin in absence of extracutaneous manifestations. The neoplastic cells sometimes produce monoclonal immunoglobulins, and the demonstration of light-chain restriction is an important diagnostic criterion.

details, especially in large B-cell lymphomas. The PAS method helps in the identification of intracytoplasmic or intranuclear immunoglobulins in B cells. As a rule, CBCLs present with patchy infiltrates, a nodular growth pattern, or diffuse lymphoid aggregates. The infiltrates are predominantly perivascular and periadnexal and show a distribution at all levels of the dermis extending into the subcutaneous fat. The epidermis is usually not involved. A follicular pattern with neoplastic follicles can be observed in CBCL. Superficial bandlike infiltrates and epidermotropism, as in cutaneous T-cell lymphomas, may be found rarely, usually in large cell CBCLs. To understand the different cytomorphologic appearances of the cells and their neoplastic counterparts, it is necessary to be familiar with the main pathways of B-cell differentiation. In the bone marrow, stem cells give rise to B-precursor cells (pre-pre-B cells). They are the earliest detectable stage of B-cell differentiation: rearrangement of the immunoglobulin heavy chain gene has already begun, but immunoglobulins are not yet produced. Pre-B cells, in contrast, reveal intracytoplasmic μ heavy chain; they do not express surface Ig. Morphologically, the B-precursor cells appear as lymphoblasts. The end stage of antigen-independent B-cell differentiation is the mature, naive B lymphocyte. They have rearranged Ig genes. Upon antigen stimulation, naive B lymphocytes transform into proliferating cells with a blastic appearance (early primary response). These subsequently evolve into antibody-secreting plasma cells. In other instances, naive B lymphocytes transform into centroblasts that colonize the dendritic network of dendritic reticulum cells and form germinal centers (late primary response, secondary response). In germinal centers, a high rate of somatic mutations takes place to enhance the affinity of produced antibodies for the specific antigens. Germinal center cells whose somatic mutations have resulted in decreased affinity for the antigen die rapidly and are eliminated from the germinal center by macrophages (“tingible-body” macrophages). Additional B-cell subtypes with characteristic morphologic features are the marginal zone cells and the mantle cells of the inner follicle mantle. Marginal zone cells are closely related to monocytoid B cells. The position of marginal zone cells in the B-cell differentiation pathway is not completely clear, but they have the capacity to mature into plasma

2. Centrocytes: Smaller cells with irregular, sometimes cleaved nuclei, a fine chromatin pattern, and small nucleoli. The cytoplasm can be rarely identified. The neoplastic counterparts of centroblasts and centrocytes are seen mainly in follicle center lymphomas. B-IMMUNOBLASTS B-immunoblasts have large, round to oval, vesicular nuclei with a particularly distinct nuclear membrane and very prominent centrally placed nucleoli. The cytoplasm is broad and basophilic. Some large B-cell

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lymphomas are composed predominantly of B-immunoblasts.

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MARGINAL ZONE B LYMPHOCYTES These are small- to medium-sized cells with moderately abundant pale cytoplasm. The nuclei are round or indented (centrocyte-like cells). Marginal zone cells are found in marginal zone B-cell lymphomas (MZLs). Besides B-lymphocytes, CBCLs contain various other cell types. Macrophages (including T-zone histiocytes) are regularly distributed in any lymphoid infiltrate of the skin. Dendritic reticulum cells are an important component of germinal centers. IMMUNOHISTOLOGICAL FEATURES The application of monoclonal antibodies to routinely fixed paraffin-embedded material with the use of the microwave treatment technique for antigen retrieval enhances the staining quality and provides the basis for a reliable immunohistologic analysis of CBCLs. Table 34-10 displays a selected panel of antibodies suitable for the diagnosis of B-cell lymphoid infiltrates. The most useful B-cell markers are CD20 and CD79a, which detect nearly all lymphoid infiltrates of B-cell lineage. Large cell lymphomas of B-cell type may reveal partial loss of one or more B-cell–associated antigens. Whereas malignant B-cell populations usually show a clonal restriction to either κ or λ light chain, benign infiltrates exhibit a polyclonal expression pattern of both light chains. Unfortunately, however, there are several cases of B-lymphoproliferative disorders, both benign and malignant, in which the cells do not express Ig or the Ig cannot be detected. In low-grade malignant lymphomas of B-cell lineage, aberrant expression of some T-cell associated markers can be observed. CD5 reacts with the cells of B-cell chronic lymphocytic leukemia and of mantle cell lymphoma. Another abnormal pattern of reactivity that may be indicative of a low-grade malignant B-cell lymphoma is the coexpression of CD20 and CD43 (benign infiltrates of B-lymphocytes are CD43 negative). Germinal center cells can be detected by the use of CD10 and Bcl-6 monoclonal antibodies. In follicle center cell lymphomas, CD10 and Bcl-6-positivity can be found also in interfollicular areas (Fig. 34-30 and 34-31). Antibodies directed against the follicular dendritic reticulum cells (CD21, CD35) demonstrate the network of dendritic reticulum cells in reactive and malignant germinal centers (Figs. 34-32 and 33).

Table 34-10 Immunohistology: Antibodies Useful for the Diagnosis of Cutaneous B-Cell Lymphomas CLUSTER/ANTIBODY

SPECIFICITY

CD20 CD79a Ig CD5 CD10 CD43 CD138 MIB-1 CD21 Bcl-2 Bcl-6 MIB-1/Ki67 TdT CD34 CD30 CD68 MUM-1 Cycline D-1

B lymphocytes B lymphocytes B lymphocytes T lymphocytes, B-CLL Germinal center cells, common ALL antigen T lymphocytes, monocytes Plasma cells Proliferating cells Dendritic reticulum cell Bcl-2 protein Germinal center cells Proliferating cells Precursor B lymphocytes Precursor B lymphocytes Activated B and T lymphocytes Histiocytes Multiple myeloma antigen 1 Activation or overexpression of cyclin D1 (mantle cell lymphoma)

The assessment of proliferative activity with MIB-1 antibody may be useful in identifying areas with the greatest likelihood of containing tumor and in detecting the transformation from a low-grade lymphoma to high-grade “blastic” disease. In this context, it must be emphasized that neoplastic follicles in follicular lymphoma are characterized by a lesser degree of proliferation than reactive ones and that a reduced proliferation of cells within follicles is a diagnostic criterion of follicular lymphoma (Fig. 34-34).154,157 CBCLs almost always show a distinct T-cell population, which is usually

numerically predominant in low-grade malignant types. MOLECULAR GENETIC ANALYSIS B-lymphoid malignancies can be studied using specific probes detecting rearrangements of the Ig heavy- or light-chain genes.158 Microdissection of tumor areas may increase the sensitivity and specificity of the molecular analysis.159 However, a negative result does not exclude a diagnosis of malignant lymphoma. Specific translocations and numerical aberrations can be detected by fluorescence in situ hybridization (FISH) methods; however,

 FIGURE 34-30 Primary cutaneous follicle center cell lymphoma with follicular grown pattern (CD10 stain). Note the positive cells outside the neoplastic follicle.

in primary CBCLs, only a minority of cases displays specific features by FISH. CLASSIFICATION Patients with involvement by CBCLs can be divided into the following groups: 1. Primary CBCLs: Cutaneous disease alone with no evidence of extracutaneous manifestations after complete staging procedures have been performed.156,160 2. Secondary CBCLs: Extracutaneous disease and subsequent development of skin lesions

 FIGURE 34-31 Primary cutaneous follicle center cell lymphoma with a follicular growth pattern (Bcl-6 staining). Note the staining of a follicle and of interfollicular cells.

 FIGURE 34-32 Network of dendritic reticulum cells as identified by expression of CD21 in this reactive germinal center.

Clinicopathologic correlation is extremely important in the accurate interpretation of CBCL. Adequate staging procedures should include examination of the entire integument, laboratory investigation, chest radiography, ultrasound examination of superficial lymph nodes and abdomen, computed tomography, and bone marrow biopsy. Primary CBCLs comprise a broad spectrum of lymphomas with characteristic clinical, histopathologic, immunophenotypic, and molecular genetic findings. Thus, it is important that the various subtypes are appropriately classified as separate entities. It is also evident that lymphomas arising in lymph nodes and primary CBCLs, which may show similar or identical morphologic features, are different with respect to pathogenesis and clinical outcome. CBCLs only rarely exhibit the typical cytogenetic and molecular alterations characteristic of nodebased B-cell lymphomas. The classification system proposed in 2005 by the WHO and EORTC156 can be applied satisfactorily for all CBCLs (Table 34-11).160 Secondary CBCLs can be observed in all types of B-cell lymphomas of

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

3. Concurrent CBCLs: Extracutaneous disease at the same time as the skin lesions are diagnosed

Table 34-11 Joint World Health Organization–European Organization for Research and Treatment of Cancer Classification of Cutaneous B-Cell Lymphomas

 FIGURE 34-33 Primary cutaneous follicle center cell lymphoma with follicular growth pattern. Staining with anti-CD21 antibody outlines the irregular network of follicular dendritic cells.

Primary cutaneous marginal zone B-cell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other Intravascular large B-cell lymphoma

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lymphoid organs after dissemination and involvement of the skin. These lymphomas usually reveal the histopathologic features, immunology, and genetic features of the original lymphoma. The prognosis is usually poor. Of special interest for dermatopathologists are specific skin infiltrates in B-cell chronic lymphocytic leukemia and B-lymphoblastic lymphoma.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Follicle Center Lymphoma

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Synonyms: Reticulohistiocytoma of the dorsum (Crosti), large-cell lymphocytoma Follicle center lymphomas (Table 34-12) are defined as neoplasms of B cells composed of germinal center cells showing a follicular or diffuse pattern with a mixture of centrocytes (cleaved follicle center cells) and centroblasts (large noncleaved follicle center cells).161-170 CLINICAL FEATURES Patients present with solitary or grouped reddish papules, plaques, or tumors that may be surrounded by erythematous patches (see Fig. 34-35). Preferential locations are the scalp and forehead or the back (“reticulohistiocytoma of the dorsum,” according to Crosti).164 Recurrences are observed in about 50% of patients. Dissemination to extracutaneous sites is rare, and follow-up data suggest that these patients have a

Table 34-12 Follicle Center Cell Lymphoma

Clinical Features Preferential locations: head, back Solitary or regionally localized patches, papules, plaques, and tumors Favorable prognosis (5-year survival, 95%) Histopathologic Features Nodular or diffuse infiltrates Follicular, mixed, or diffuse pattern of growth Mixture of germinal center cells: centroblasts and centrocytes Predominance of large centrocytes in cases with diffuse pattern of growth Immunohistologic Features CD20+ CD79a+ CD21+ (follicular pattern of growth) CD5− Bcl-2−/+ Bcl-6+ CD10 +/− Differential Diagnosis Cutaneous lymphoid hyperplasia Marginal zone B-cell lymphoma Large B-cell lymphoma, leg-type

 FIGURE 34-34 Primary cutaneous follicle center cell lymphoma with follicular growth pattern. MIB-1 staining reveals decreased proliferative activity of follicular cells.

favorable prognosis after adequate treatment (5-year survival, 95%).160 HISTOPATHOLOGIC FEATURES These lymphomas are characterized by nodular or diffuse infiltrates commonly involving fullthickness dermis and often extending into the subcutaneous fat. Epidermotropism is usually not observed. A follicular pattern with germinal centers is found in a minority of cases (Fig. 34-35). The diffuse growth pattern does not exhibit follicular formation (Fig. 34-36). Sometimes, however, follicular structures are present at the periphery of diffuse infiltrates. The neoplastic cells consist mainly of centrocytes and centroblasts, but

centrocytes usually clearly predominate (Figs. 34-37). In cases with a prominent follicular pattern, the interfollicular areas contain small lymphocytes with a T-cell phenotype and histiocytes, as well as small clusters of follicular (neoplastic) cells. In cases with a diffuse pattern of growth, the cytomorphologic appearance may be that of a large B-cell lymphoma. However, the clinical features and prognosis of these cases are similar to those of other cutaneous follicle center lymphomas, and they should not be classified as large B-cell lymphomas. A variant of cutaneous follicle center lymphoma with predominant spindle

 FIGURE 34-35 Primary cutaneous follicle center lymphoma with follicular growth pattern. Note the markedly reduced mantle zone.

which has been shown to be very common in follicular lymphomas of the lymph nodes, is extremely rare in primary cutaneous follicle center lymphoma.172 Despite the similar morphologic features, the differences in bcl-2 protein expression and incidence of t(14;18) between nodal and cutaneous follicular lymphomas suggest that different mechanisms may be involved in the pathogenesis of these neoplasms.

Marginal Zone B-Cell Lymphoma

 FIGURE 34-37 Primary cutaneous follicle center cell lymphoma. Large centrocytes predominate admixed with a few centroblasts.

cell morphology has been described.171 This variant may simulate other cutaneous spindle cell malignant neoplasms, such as sarcomas and spindle cell melanoma, among others. IMMUNOLOGY AND RELATED FEATURES The tumor cells express monotypic surface Ig and B-cell–associated antigens. They are CD5 and CD43 negative. In practically all cases with a follicular pattern and in the majority of cases with a diffuse pattern, neoplastic B lymphocytes are positive for Bcl-6. Staining for CD10 is positive in a smaller percentage of cases. The finding of CD10-positive or

Bcl-6-positive cells in clusters outside follicular structures is considered a criterion of malignancy (see Figs. 34-30 and 34-31). Bcl-2 and MUM-1 are usually negative; they are positive only in a minority of tumor cells (Fig. 34-38). Staining with markers detecting proliferating cells shows that neoplastic follicles are characterized by a reduced proliferation compared with reactive germinal centers (see Fig. 34-34). Within the follicular areas, an organized network of dendritic reticulum cells is present (see Fig. 34-33). Clonal Ig gene rearrangement can be demonstrated in many cases. The interchromosomal (14;18) translocation,

Synonyms: MALT lymphoma, cutaneous immunocytoma MZL (Table 34-13) is a low-grade malignant lymphoma with morphologic evidence of differentiation into cells of the marginal zone that display tissuespecific homing patterns.173-175 Primary cutaneous MZL is closely related to MALT lymphomas.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-36 Primary cutaneous follicle center cell lymphoma with diffuse growth pattern. Diffuse proliferation composed predominantly of centrocytes. Neoplastic follicles are not present.

DIFFERENTIAL DIAGNOSIS The major differential diagnosis in cases of cutaneous follicle center lymphomas with follicular pattern is cutaneous lymphoid hyperplasia with follicular structures (lymphadenosis benigna cutis). Findings that enable the differentiation are summarized earlier in this chapter. The diffuse variant of follicle center lymphoma should be differentiated from large B-cell lymphomas that are usually Bcl-2 and MUM-1 positive and often show a predominance of immunoblasts. The differential diagnosis includes also MZL and immunocytoma, especially if follicles are present. Both are characterized by reactive polyclonal follicle centers. However, it may be difficult or impossible to differentiate the neoplastic cells (centrocyte-like cells) in MZL from the centrocytes in follicular lymphoma.

CLINICAL FEATURES Recurrent, localized, red to reddish-brown papules, plaques, and tumors located predominantly on the trunk and upper extremities are observed. The prognosis is excellent (5-year survival, 98%).160 In a few cases, an association with B. burgdorferi infection has been well demonstrated.176,177 However, other cases from different parts of the world have been negative, suggesting a regional variability of association of B. burgdorferi with MZLs and other CBCLs.178 HISTOPATHOLOGIC FEATURES MZLs show patchy, nodular (Fig. 34-39A), or diffuse infiltrates involving the dermis and

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Table 34-13 Marginal Zone B-Cell Lymphoma

 FIGURE 34-38 Primary cutaneous follicle center lymphoma with a follicular growth pattern. Staining for Bcl-2 reveals negativity of neoplastic follicles.

superficial subcutaneous fat. The epidermis is not involved. A characteristic pattern can be observed at scanning magnification; nodular infiltrates, sometimes containing reactive germinal centers, are surrounded by a pale-staining population

A

of small- to medium-sized cells with indented nuclei, inconspicuous nucleoli, and abundant pale cytoplasms (variously described as marginal zone cells, centrocyte-like cells, or monocytoid B cells) (Figs. 34-39B and 34-39C). In addition,

Clinical Features Preferential location: upper extremities, trunk Solitary or localized papules, plaques, and tumors Excellent prognosis (5-year survival, 98%) Histopathologic Features Nodular or diffuse infiltrates Nodules of reactive B lymphocytes surrounded by neoplastic marginal zone cells Plasma cells are frequent Reactive lymphoid follicles may be present Some cases show predominance of lymphoplasmacytoid cells (formerly cutaneous immunocytoma) or plasma cells (formerly cutaneous plasmacytoma) Immunohistologic Features cIg+ (60-65%) CD20+ CD79a+ CD5− CD10− Bcl-6− Bcl-2+ Differential Diagnosis Cutaneous lymphoid hyperplasia Follicle center cell lymphoma

B

C

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 FIGURE 34-39 Primary cutaneous marginal zone B-cell lymphoma. (A) Patchy and nodular infiltrates. Reactive follicles can be vaguely recognized. (B) Marginal zone (centrocyte-like) cells with abundant pale cytoplasm. (C) Marginal zone cells are a little larger than lymphocytes and show round to irregular nuclei. A few blast cells can be observed.

A

B

plasma cells (at the margins of the infiltrate), lymphoplasmacytoid cells, small lymphocytes, and occasional large blasts are observed. Eosinophils are also a common finding. In some cases, there may be a granulomatous reaction with epithelioid and giant cells.179 Some cases of MZL present with predominance of lymphoplasmacytoid cells or plasma cells, showing features that were classified in the past as cutaneous immunocytoma or cutaneous plasmacytoma (Figs. 34-40 to 34-42). IMMUNOLOGY AND RELATED FEATURES The centrocyte-like cells reveal a CD20+, CD79a+, CD5−, CD10−, Bcl-6−, and Bcl-2+ phenotype. In the vast majority of cases, a monoclonal distribution of Ig light chains can be observed (especially in the plasma cells). A clonal Ig heavy chain gene rearrangement can be observed in the majority of cases. Genetic studies have shown features similar to other extranodal MALT lymphomas.180-183 DIFFERENTIAL DIAGNOSIS MZL can be confused with cutaneous lymphoid hyperplasia, which is characterized by a polyclonality of B cells. MZL must be distinguished from follicle center lymphoma. As already pointed out, whereas MZL may show follicles that are reactive, and is characterized by an interfollicular proliferation of centrocyte-like cells, in follicle center lymphoma, the neoplastic follicles reveal malignant morphologic and immunophenotypic features (previously discussed). Mantle cell lymphoma, which is not well defined in the skin and has been observed only in exceptional cases, is composed of relatively uniform, smallto medium-sized lymphocytes with

 FIGURE 34-41 Primary cutaneous marginal zone B-cell lymphoma with predominance of lymphoplasmacytoid lymphocytes (formerly immunocytoma). Intranuclear globular periodic acidSchiff–positive inclusion (Dutcher body).

 FIGURE 34-42 Primary cutaneous marginal zone B-cell lymphoma with prominent plasma cell differentiation (formerly cutaneous plasmacytoma). The predominant cell population consists of Marschalko type cells and atypical plasma cells.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-40 (A) and (B) Primary cutaneous marginal zone B-cell lymphoma with predominance of lymphoplasmacytoid lymphocytes (formerly immunocytoma).

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irregular nuclear contours. Because of the cytologic similarities, it may be very difficult to differentiate this lymphoma from MZL. Neoplastic mantle cells express CD5 and cyclin D1 (both negative in cutaneous MZL), and the bcl-1 gene rearrangement can frequently be documented. Cases classified in the past as cutaneous immunocytoma represent variants of cutaneous MZL with a predominance of lymphoplasmacytoid cells and plasma cells.147,156,184 In these cases, the histology often reveals more monotonous infiltrates with large sheets of small lymphoid, lymphoplasmacytoid cells, and plasma cells, which contain cIg. It has also been proposed that cases classified previously as primary cutaneous plasmacytoma (monoclonal proliferations of plasma cells that develop in the skin in the absence of bone marrow involvement) are variants of MZL.156,185 In fact, some patients with lesions classified as cutaneous plasmacytoma have presented with recurrent lesions showing histopathologic features of MZL.

Clinical Features Preferential location: lower leg Solitary or multiple tumors Older females predominate 5-year survival, ~55% (with multiple lession; higher survival with solitary lession) Histopathologic Features Diffuse growth pattern Large cells with round nuclei (features of immunoblasts and centroblasts) High mitotic rate; sometimes “starry-sky” pattern Immunohistologic Features CD20+ CD79a+ CD10 −/+ (mainly CD 10−) Bcl-6 +/− Bcl-2+ MUM-1+ Differential Diagnosis Follicle center lymphoma, diffuse type Granulocytic sarcoma Large cell anaplastic lymphoma Histiocytic tumors Metastases

Large B-Cell Lymphoma, Leg Type This group consists of more aggressive malignant lymphomas that contain a predominant population of large B-cells.147,156 About 80% of cases of primary cutaneous large B-cell lymphoma, leg type, develop on the legs (hence the term) of elderly patients (Table 34-14).147,156,186,187 CLINICAL FEATURES The clinical features are variable. Solitary or multiple reddishbrown or violaceous tumors localized on one (or sometimes both) lower legs are observed. Ulceration can be found. The disease predominantly affects older women (>70 years of age). Relapses and

A

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Table 34-14 Large B-Cell Lymphoma, Leg Type

extracutaneous involvement are common. The prognosis is more unfavorable than that in the other primary CBCLs, and the 5-year survival rate is approximately 55%.156,187 HISTOPATHOLOGIC FEATURES Dense, diffuse infiltrates (Fig. 34-43A) are seen within the dermis and subcutis. Infiltration of the epidermis (epidermotropism) simulating a T-cell lymphoma can be observed rarely. Cytomorphologically, the neoplastic cells resemble either immunoblasts (Fig. 34-43B) or centroblasts.

There are many mitotic figures. A “starry sky” pattern is sometimes present. IMMUNOLOGY AND RELATED FEATURES Surface Ig or cytoplasmic Ig can be demonstrated in some cases. The neoplastic cells are CD20, CD79a (loss of antigen expression can be observed), MUM-1, and Bcl-2 positive.188 In many cases, a proportion of neoplastic cells is positive for Bcl-6.188 Molecular studies have revealed that cutaneous large B-cell lymphoma, leg type, is characterized by the monoclonal proliferation of postgerminal center B lymphocytes.189 DIFFERENTIAL DIAGNOSIS Large B-cell lymphoma, leg type, must be distinguished from large cell anaplastic lymphoma, which consists of CD30-positive large T cells with irregularly shaped nuclei admixed with giant cells resembling Reed-Sternberg (RS) cells. In this context, it must be emphasized that there is a variant of large B-cell lymphoma that is characterized by anaplastic B lymphocytes positive for CD30. This variant should not be included in the group of CD30positive anaplastic large cell lymphoma but should rather be classified among the large B-cell lymphomas.190 Granulocytic sarcoma, histiocytic neoplasms, metastases, and other nonhematopoietic tumors can be excluded not only by morphology but also by applying a panel of monoclonal antibodies.

LARGE B-CELL LYMPHOMAS, OTHER This group of CBCL consists of rare cases that do not fit into the category of primary CBCL, leg type, including cases of diffuse large B-cell lymphoma

B

 FIGURE 34-43 Primary cutaneous large B-cell lymphoma, leg-type. (A) Dense diffuse infiltrate. (B) Immunoblasts predominate.

without Bcl-2 expression, intravascular large B-cell lymphoma, and rare examples of large B-cell lymphomas in the setting of immune suppression.147,156,188

Intravascular Large B-Cell Lymphoma

CLINICAL FEATURES Patients present with indurated, erythematous, or violaceous patches and plaques, preferentially located on the trunk and thighs. The clinical appearance is not typical of lymphoma and may sometimes suggest a diagnosis of panniculitis or of purpura.

Table 34-15 Intravascular Large B-Cell Lymphoma

Clinical Features Preferential location: extremities Infiltrated patches and plaques Sometimes confined to cherry hemangiomas Usually systemic disease with involvement of the central nervous system; primary cutaneous disease possible Poor prognosis Histopathologic Features Aggregates of large B cells within dilated blood vessels in the dermis and superficial subcutis Cytomorphology: immunoblasts, centroblasts-like cells Immunohistologic Features CD20+ CD79a+ Bcl-2+ MUM-1+ CD5 −/+ Differential Diagnosis Intravascular histiocytosis

 FIGURE 34-44 Intravascular large B-cell lymphoma. Note the large lymphocytes within a dilated blood vessel.

Intravascular large B-cell lymphoma has been observed confined to lesions of cherry hemangiomas.192 HISTOPATHOLOGY, IMMUNOLOGY AND RELATED FEATURES Intravascular large B-cell lymphoma is characterized by a proliferation of large lymphocytes filling dilated blood vessels within the dermis and superficial subcutaneous tissues (Fig. 34-44).193 In some cases, atypical cells may also be observed around blood vessels. The malignant cells are large, with scanty cytoplasm and often prominent nucleoli. Neoplastic cells are positive for B-cell– associated markers and in a subset of cases show aberrant CD5 expression. Staining with endothelial cell–related antibodies (eg, CD31, CD34) highlights the characteristic intravascular location of the cells. Molecular analysis shows monoclonal rearrangement of the Ig genes. DIFFERENTIAL DIAGNOSIS Intravascular large B-cell lymphoma should be differentiated from other large B-cell lymphomas. The typical location of neoplastic cells within dilated blood vessels is almost pathognomonic of this rare variant of B-cell lymphoma.

Large B-Cell Lymphomas in Immunocompromised Patients Patients are adults or children who have received allogenic solid organ or bone marrow transplantation and are

under immunosuppressive treatment (Table 34-16). CLINICAL FEATURES The cutaneous lesions are variable, including erythematous plaques, nodules, and tumors that are sometimes ulcerated. Cutaneous lesions may be solitary, localised to a single anatomical region, or generalized. Concomitant involvement of other organs can be observed and is usually associated

Table 34-16 Large B-Cell Lymphomas in Immunocompromised Patients

Clinical Features Patients under immunosuppressive treatment Erythematous plaques, nodules, and tumours, sometimes ulcerated Histopathologic Features Polymorphic posttransplant lymphoproliferative disorder: monoclonal infiltrates composed of plasma cells, immunoblasts, and intermediate-sized lymphoid cells Monomorphic posttransplant lymphoproliferative disorder: picture of diffuse large B-cell lymphoma, Burkitt lymphoma, plasma cell myeloma, or extramedullary plasmacytoma Immunohistologic Features CD20+ CD79a+ Monoclonal IgL Differential Diagnosis Marginal zone B-cell lymphoma Other types of large B-cell lymphoma

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Intravascular large B-cell lymphoma is a malignant proliferation of large B-lymphocytes within blood vessels (Table 34-15).191 This disease was formerly classified as a vascular neoplasm (malignant angioendotheliomatosis). Most cases show a B-cell phenotype, but a T-cell variant has also been reported. In rare patients, the skin may be the only affected site, but more often, there is systemic dissemination with common involvement of the CNS. It has been reported that the prognosis for patients with intravascular large B-cell lymphoma limited to the skin is better than for patients with generalized disease, but only a very limited number of cases have been observed.

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the skin, that is, staging investigations are negative. This variant is observed especially in young patients on the head (scalp) and neck region and is characterized by solitary or localized reddishbrown to bluish tumors.146,194,195 Patients with localized skin disease appear to have a relatively good prognosis, but treatment strategies should be the same applied for those with systemic variants of the disease.

 FIGURE 34-45 Cutaneous B-cell lymphoma in immunosuppressed patient (iatrogenixc immunosuppression). Note the large cells admixed with atypical plasmacytoid cells and plasma cells.

with systemic symptoms, including elevated serum levels of lactate dehydrogenase. Precise staging investigations should be always performed to evaluate the extent of involvement before planning the treatment. HISTOPATHOLOGY, IMMUNOLOGY, AND RELATED FEATURES The histopathologic features vary according to the subtype of posttransplant lymphoproliferative disorder (Fig. 34-45). Early lesions show polyclonal (rarely monoclonal) proliferations of mature plasma cells with rare immunoblasts. Polymorphic posttransplant lymphoproliferative disorder is characterized by the presence of a monoclonal infiltrate of B lymphocytes comprising the whole spectrum of maturation and including plasma cells, immunoblasts, and intermediate-sized lymphoid cells. In monomorphic posttransplant lymphoproliferative disorder, the histopathologic picture is that of a malignant lymphoma (diffuse large B-cell lymphoma, Burkitt lymphoma, plasma cell myeloma, or extramedullary plasmacytoma). Cases involving the skin present mostly with the features of diffuse large B-cell lymphoma.

B-Lymphoblastic Lymphoma

938

B-lymphoblastic lymphomas are neoplasms of precursor-B cells (pre-pre-B lymphoblasts, pre-B lymphoblasts, and “mature” B lymphoblasts) (Table 34-17).

CLINICAL FEATURES Patients usually have acute lymphoblastic leukemia with bone marrow and peripheral blood involvement and secondary skin manifestations. However, in some cases, these lymphomas may arise “primary” in

Table 34-17 B-Lymphoblastic Lymphoma

Clinical Features Preferential location: head (scalp) Usually solitary tumors Sometimes primary cutaneous involvement Histopathologic Features Dense, diffuse, monotonous infiltrates Medium-sized lymphoblasts with scanty cytoplasm, round or convoluted nuclei with fine chromatin and inconspicuous nucleoli High mitotic rate Immunohistologic Features CD79a+ CD20+ TdT+ CD10+ cMu+ CD34+ Differential Diagnosis Myelomonocytic leukemia Mantle cell lymphoma Merkel cell carcinoma Metastatic neuroendocrine carcinoma

HISTOPATHOLOGIC FEATURES Dense, diffuse monomorphous infiltrates are found within the dermis and the subcutaneous fat. Cytomorphologically, the lymphoblasts are medium-sized cells with round, oval, or convoluted nuclei; fine chromatin; inconspicuous nucleoli; and scant cytoplasm. Mitoses are frequent, and a “starry sky” pattern may be seen (Fig. 34-46). In some cases, neoplastic cells display a characteristic “mosaiclike” pattern. IMMUNOLOGY AND RELATED FEATURES The cutaneous lymphoblastic lymphomas usually express CD79a, CD19, CD20, TdT, CD10 (CALLA), CD34, and cytoplasmic μ heavy chain without surface immunoglobulin. Expression of the various markers is related to the stage of differentiation of the cells, and B-cell markers may be negative in some cases. Molecular studies show monoclonal rearrangement of the Ig genes in most cases. In rare instances, a concomitant monoclonal rearrangement of T-cell receptor gene can be observed, thus giving rise to potential pitfalls in the molecular features of the tumor.195 DIFFERENTIAL DIAGNOSIS One must consider in the differential diagnosis myelomonocytic leukemia that shows a proliferation of immature granulocytic and monocytic cells arranged in a figurate pattern. Mantle cell lymphoma may be confused with lymphoblastic lymphoma. However, the cytomorphology in mantle cell lymphoma with cleaved or irregularly shaped nuclei and the immunophenotype of the neoplastic mantle cells (sIg+, CD5+, CD10−) are distinct from lymphoblastic lymphoma. The differential diagnosis may also include cutaneous Merkel cell tumor and metastatic neuroendocrine carcinoma, which are characterized by the coexpression of cytokeratin filaments, neurofilament proteins, and various other neuroendocrine markers (eg, chromogranin-A).

Cutaneous Hodgkin lymphoma is usually manifested as advanced (stage IV) disease and carries a bad prognosis. In some patients, nodal Hodgkin lymphoma may be associated with second cutaneous lymphoproliferative diseases. MF, lymphomatoid papulosis, anaplastic large cell lymphoma, and granulomatous slack skin sometimes occur in the course of Hodgkin lymphoma or may presage the development of Hodgkin lymphoma.

Cutaneous Hodgkin Lymphoma Lorenzo Cerroni Helmut Kerl

Hodgkin lymphoma is regarded as a distinct malignant lymphoma (Table 34-18) characterized by the presence of neoplastic Reed-Sternberg (RS) cells in association with different patterns of reactive cells. The exact nature of RS cells has been elucidated, and it is now clear that more than 90% of cases of Hodgkin lymphoma represent variants of B-cell lymphomas (origin from a germinal center B lymphocyte).196,197 A viral etiology is possible because the EBV genome has been detected frequently. CLINICAL FEATURES Cutaneous involvement in patients with Hodgkin lymphoma may be “nonspecific” (zoster, prurigo, ichthyosis acquisita), or the skin may be affected by specific infiltrates with Hodgkin and RS cells.198,199 Specific cutaneous manifestations are uncommon, occurring in only about 1% of patients with systemic Hodgkin lymphoma.200 The incidence of specific cutaneous involvement, however, seems to be even lower since the introduction of more effective treatment modalities. The skin lesions are usually confined to the drainage area of affected lymph nodes (retrograde lymphatic spread).

In rare cases, direct extension from underlying lymph nodes or hematogenous spread may be observed. Primary cutaneous Hodgkin lymphoma also exists, as demonstrated in the literature.201,202 Clinically, the lesions appear as localized erythematous papules and plaques or reddish-brown to bluish, often ulcerated tumors. The trunk seems to be the most common site of involvement, but all other sites of the body may also be affected.

Table 34-18 Hodgkin Lymphoma

Clinical Features Solitary or multiple papules, plaques, or tumors Skin involvement most often results from retrograde lymphatic spread from involved lymph nodes Unfavorable prognosis Histopathologic Features All main subgroups can be observed in the skin Nodular or diffuse infiltrates Hodgkin cells, Reed-Sternberg cells (in about half of cases) Reactive component: lymphocytes, plasma cells, neutrophils, eosinophils, histiocytes Immunohistologic Features CD30+ CD15 +/− CD45− Differential Diagnosis Lymphomatoid papulosis Anaplastic large cell lymphoma

IMMUNOLOGY In classic Hodgkin lymphoma, the RS cells show constant positivity for CD30 and negativity for CD45 (LCA); CD15 is expressed frequently but may also be negative.202-204 In contradistinction, the lymphocyte-predominant form of Hodgkin lymphoma is phenotypically distinct whereby the cells are CD15 negative, leukocyte common antigen positive, and CD20 positive. Because these tumors are of B-cell derivation, B-cell clonality can be seen in both the classic and lymphocyte predominant forms of Hodgkin lymphoma. The accompanying reactive infiltrate is composed mostly of T-lymphocytes. DIFFERENTIAL DIAGNOSIS Lymphomatoid papulosis morphologically resembles Hodgkin lymphoma. Clinically, lymphomatoid papulosis differs by its benign course with generalized recurrent papular or papulonecrotic, self-healing eruptions. Histologically, lymphomatoid papulosis shows wedge-shaped epidermotropic infiltrates with large atypical (RS-like) cells. In contrast to Hodgkin lymphoma, the phenotype of these cells is usually CD3+, CD4+, CD30+, and CD15−, and as with anaplastic large cell lymphoma, the cells express cytotoxic proteins, including granzyme, TIA and perforin.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-46 Cutaneous pre-B lymphoblastic lymphoma. Monomorphous population of lymphoblasts. Prominent starry-sky pattern.

HISTOPATHOLOGIC FEATURES All subtypes of Hodgkin lymphoma may be observed in the skin (Fig. 34-47). Nodular or diffuse infiltrates may be seen within the dermis extending into the subcutaneous fat. Areas of fibrosis, sclerosis, or both may be found. The epidermis is usually spared. Hodgkin cells are a constant finding, but typical RS cells are present only in about 50% of cases (Fig. 34-48). The background of the infiltrate contains lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils. It is well known that Hodgkin and RS cells are not a unique feature of Hodgkin lymphoma. These cells have been found in a variety of other conditions (lymphomatoid papulosis, anaplastic large cell lymphoma).

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In the differential diagnosis of cutaneous Hodgkin lymphoma, special attention should be given to exclude anaplastic large cell (CD30+) T-cell lymphoma. In Hodgkin lymphoma, Hodgkin and RS cells are found in small numbers together with an appropriate polymorphous background of inflammatory cells. Anaplastic large cell lymphoma is characterized by cohesive sheets of large blastic cells, occasionally with features of RS cells. The large blastic cells are CD30+ and CD15−, and frequently reveal an aberrant T-cell phenotype. The cells express cytotoxic proteins, granzyme, perforin, and T-cell intracellular antigen. It should be mentioned that in a few cases, a common cell of origin has been demonstrated for lesions of Hodgkin lymphoma, lymphomatoid papulosis, and anaplastic large T-cell lymphoma occurring in the same patient.205

 FIGURE 34-47 Cutaneous Hodgkin lymphoma (classical Hodgkin lymphoma, nodular sclerosis).

A

B

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 FIGURE 34-48 Cutaneous Hodgkin lymphoma. (A) Reed-Sternberg cells set in a background of lymphocytes, histiocytes, and eosinophils. (B) Hodgkin cell.

Cutaneous Leukemic Infiltrates Stanislaw A. Buechner W.P. Daniel Su

Hematopoietic malignancies may have their initial manifestations in the skin, they may present with concurrent cutaneous and hematologic involvement, or they may exhibit cutaneous disease some period of time after the initial hematologic diagnosis. There is a spectrum of lesions of which the commonest are observed in the context of overtly malignant infiltrates. However,they also include paraneoplastic lesions and infections secondary to a relative state of immunodeficiency.206,207 In some cases, the cutaneous lesions may be the initial manifestation of the underlying hematologic malignancy, whether it is in the context of aleukemic leukemia cutis or a sterile paraneoplastic neutrophilic dermatosis such as Sweet syndrome.208-210 A definitive diagnosis can be made in most instances based on combined light microscopic and immunophenotypic studies. However, it should be emphasized that in many cases, the presentation in the skin is in the context of an established diagnosis of leukemia whereby exhaustive flow cytometric and cytogenetic studies have already been conducted on liquid phase material. This allows the dermatopathologist to perform an array of stains that are

Table 34-19 French-American-British Classification of Leukemias

more directed based on the preexisting immu-nophenotypic and genotypic profiles. The purpose of this chapter is to briefly review the primary myeloid, T-cell and B-cell leukemic infiltrates that involve the skin. This chapter does not focus significantly on nonneoplastic skin lesions that could potentially be seen in the spectrum of these conditions. A more detailed analysis of these various leukemias can be obtained by consulting the various hematopathology textbooks currently available.

CLINICAL FEATURES Leukemia cutis lesions have been reported to occur in up to 10% of patients with AML subtypes M0 to M3.10 Clinically, the skin lesions are erythematous or violaceous, slightly elevated papules or nodules (Fig. 34-49 and Table 34-20).204,206,209,210 The eruption of lesions is usually widespread, but in general, the most frequent areas of involvement are the trunk and extremities.9 Hemorrhagic lesions may occur, and nodules may

ulcerate, especially if they enlarge progressively. Painful hemorrhagic infiltrated plaques and nodules involving both the palm and fingers have also been observed.216 Bullous hemorrhagic lesions and painful genital ulcers have been reported as an initial presentation of AML.206,217 Oral involvement occurs in about 4% of patients and may be the initial presentation of the disorder.218 HISTOPATHOLOGICAL FEATURES Biopsy specimens from specific skin lesions of AML show a dense leukemic infiltrate in the upper and deep dermis that usually extends to the subcutaneous tissue (Fig. 34-49B). It is generally separated from the epidermis by a narrow grenz zone, although the dermal-epidermal interface may be obliterated. The infiltrates typically surround the dermal blood vessels, hair follicles, and sweat glands.219-221 Transmural infiltration of dermal blood vessels and intravascular collections of atypical myeloid cells may be found. In some instances, the vessel is not only permeated by leukemic cells but may show evidence of vascular

CLASSIFICATION OF LEUKEMIAS The French-American-British (FAB) classification of leukemias is based on the morphologic appearance of bone marrow and blood leukemic blasts, supplemented by cytochemical and immunohistochemical stains.211-213 The FAB classification of leukemias in which leukemic skin infiltrates occur is shown in Table 34-19.

A

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Acute Leukemias M0 Acute myeloid leukemia with minimal evidence of myeloid differentiation M1 Acute myeloid leukemia without maturation M2 Acute myeloid leukemia with maturation M3 Acute promyelocytic leukemia M4 Acute myelomonocytic leukemia M5 Acute monocytic leukemia M6 Acute erythroleukemia M7 Acute megakaryoblastic leukemia Acute lymphoblastic leukemia Chronic Leukemias Chronic myeloid leukemia Chronic lymphocytic leukemia T-cell prolymphocytic leukemia Adult T-cell leukemia/lymphoma Hairy cell leukemia Chronic myelomonocytic leukemia

essential requirement for diagnosis. The AML types differ with respect to cell line and degree of differentiation. In AML with minimal evidence of myeloid differentiation (M0) or without maturation (M1), the predominant cell is undifferentiated by light microscopy, is peroxidase negative, and expresses CD34 and CD33 but lacks CD15. In AML with maturation (M2), myeloblasts with granules and promyelocytes account for more than 50% of nucleated cells. Acute promyelocytic leukemia (APL, M3) is recognized by a predominance of promyelocytes.215

Acute Myeloid Leukemia Acute granulocytic (myeloid) leukemia (AML) (M0-M3) accounts approximately for 40% to 50% of all acute leukemias, with the incidence of the different FAB types reported as 18% for M1, 28% for M2, and 8% for M3.214 Demonstration of the accumulation of blasts resulting from the block in differentiation characteristic of AML is the

B  FIGURE 34-49 (A) Leukemia cutis involving face. (B) Acute myelocytic leukemia (AML, M2). Diffuse dermal infiltrate of leukemic cells.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 34-20 Leukemic Skin Infiltrates of Myeloid Leukemias

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Clinical Features Erythematous papules and nodules Usually widespread, mainly on the trunk Sometimes solitary nodule Ulceration may occur Gingival involvement, especially in AMoL Aleukemic leukemia cutis may occur Histopathologic Features Nodular or diffuse infiltrates of atypical myeloid cells Subcutaneous tissue mostly involved Grenz zone mostly present Medium to large mononuclear cells with large nuclei (myeloblasts and myelocytes, AML) Medium-sized or large mononuclear cells with indented or kidney-shaped nuclei (AMMoL,AMoL) Thin rows of neoplastic cells between collagen bundles (“Indian file”) Concentric layering of neoplastic cells around blood vessels Mitotic figures frequent Immunohistochemistry Predominant reactivity for lysozyme, myeloperoxidase, CD68, CD74, CD43, CD45 Differential Diagnosis Metastatic carcinoma Malignant melanoma Merkel cell carcinoma B-lymphoblastic lymphoma Sweet syndrome Cutaneous extramedullary hematopoiesis

compromise as evidenced by red blood cell extravasation in concert with mural and/or luminal fibrin deposition. Typically, the leukemic myeloid cells spread between the collagen bundles and permeate the interstitial spaces of the fat lobule.207,219 (see Table 34-20). The infiltrate of AML is composed predominantly of medium-sized or large atypical myeloblasts and myelocytes with round or oval basophilic nuclei and prominent nucleoli.220 Immature atypical myeloid cells with bizarre nuclei are frequently present.219 Also, there may be admixtures of polymorphonuclear leukocytes, although the numbers are small. AML M0 is characterized by a monomorphous infiltrate of mediumsized blasts with folded vesicular nuclei.222 Mitotic figures are a consistent finding in the infiltrate of AML.220 A prominent giant cell reaction occurring singly among the neoplastic cells or

 FIGURE 34-50 Acute myelocytic leukemia (AML, M2). Dense infiltrate of neoplastic cells showing positive staining for myeloperoxidase.

forming granulomas in the leukemic infiltrate of AML FAB subtype M1 has been reported.223 HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS Staining for lysozyme and myeloperoxidase usually shows positivity in specific infiltrates of AML subtypes (Fig. 34-50).219,224-226 However, staining for chloroacetate esterase is variable and may be negative in some M1 to M3 subtypes of AML.220 In addition, neoplastic cells are usually positive for CD68.226 Expression of CD56 has been reported in specific skin infiltrates of some patients with AML.220,227 CD56 expression in AML has been associated with an increased incidence of leukemia cutis and a poor prognosis.228,229

Monocytic Leukemia Acute monocytic leukemia (AMoL, FAB M5) accounts for approximately 10% of all cases of acute nonlymphocytic leukemia.230 Extramedullary disease is more common in AMoL than in other subtypes of leukemia and is associated with a worse prognosis. Leukemic skin infiltrates are present in 10% to 30% of patients with AMoL.206,210 CLINICAL FEATURES The neoplastic skin lesions in AMoL are violaceous to red-brown papules, nodules, and

plaques. 220,231,232 The eruption occurs all over the body and may involve the face and scalp. Leukemic gingival hyperplasia is a characteristic feature of AMoL, occurring in up to 60% of patients.218 Rarely, leukemic skin infiltrates may be observed before evidence of leukemic involvement is found in the bone marrow.233-236 This condition, known as aleukemic leukemia cutis, has a poor prognosis in adults. Aleukemic skin lesions present as solitary or multiple red or violaceous papules or cutaneous and subcutaneous nodules.235 Congenital monocytic leukemia is a rare form. Among 175 cases of congenital leukemia, 14 of the 41 patients with leukemic skin infiltrates had AMoL.237 Skin lesions present as red-brown to purple papules and nodules and may have a “blueberry muffin” appearance.238 HISTOPATHOLOGIC FEATURES A dense perivascular or a more diffuse and confluent infiltrate is found predominantly in the dermis but may often involve the lower part of the dermis and extend into the subcutis (Figs. 34-51 and 34-52).219,220,239 The epidermis is uninvolved. Usually, there is a concentric layering of neoplastic cells around blood vessels and adnexal structures. Infiltration and disruption of the cutaneous adnexa by leukemic infiltrates are present in some biopsy specimens. In most cases, thin rows of atypical cells migrating between collagen bundles, called an Indian file array, can be identified

esterase may be present in AMoL; however, in some patients, negative staining or only a weak reactivity is seen. Myeloperoxidase is less useful, and some cases show little or no positivity. The atypical cells are negative for CD20, CD3, CD34, and CD117. CD56 expression may be observed.228 In addition, the cells are characteristically CD4 positive.

Myelomonocytic Leukemia Myelomonocytic leukemia (AMMoL, FAB M4) represents about 25% of all cases of acute nonlymphocytic leukemia.230 In AMMoL, both granulocytic and monocytic precursors are present in varying proportions, and each cell line accounts for at least 20% of nucleated bone marrow cells. Leukemic mucocutaneous lesions are found in 13% to 27% of patients.207,218

 FIGURE 34-52 Acute monocytic leukemia (AMoL, M5) showing a dense infiltrate in the subcutaneous tissue.

at the periphery of the infiltrate (Fig. 34-53 and Table 34-20). Cytologically, the infiltrate is composed of a monomorphous population of medium-sized, round to oval neoplastic cells with large folded or kidney-shaped basophilic nuclei and a basophilic cytoplasmic seam (Fig. 34-54).219,220 Large, atypical mononuclear cells with hyperchromatic, irregular nuclei are frequently present in the infiltrate. Atypical mitotic figures vary

in number but may be frequent. A few granulocytes and extravasated erythrocytes are intermingled with the tumor cells. There may be prominent interstitial mucin deposition. HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS The leukemic infiltrate in most cases of AMoL show strong reactivity for CD68 and lysozyme (Fig. 34-55A).225,226,240 Chloroacetate

CLINICAL FEATURES Most patients have multiple red or purple asymptomatic papules, nodules, or plaques on the head, trunk, or extremities.207,218,220 The gums are involved in about 18% of patients.218 Specific infiltrations into scars of previous sites of catheter placement, trauma, burns, and herpes simplex may occur.207 In rare cases, the clinical features of the lesions may be atypical, with the initial appearance being reported as a bullous,241 conjunctival lesion242 or as a vesiculopapular rash mimicking chickenpox.243 CD56 positivity in patients with AMMoL presenting with fast-growing tumors appears to be associated with a highly aggressive clinical course and a poor prognosis. Less commonly, the leukemic skin infiltrates

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-51 Acute monocytic leukemia (AMoL, M5). Nodular to diffuse infiltrate of atypical cells in the dermis. There is a sparing of the papillary dermis.

DIFFERENTIAL DIAGNOSIS A tumor showing both CD4 and CD56 positivity may be confused with CD4+, CD56+ hematodermic neoplasm (Fig. 34-55B to 3455E). Figure 34-55B illustrates a striking interstitial and angiocentric infiltrate composed of a monomorphic infiltrate of small- to intermediate-sized mononuclear cells with a finely dispersed chromatin and inconspicuous nucleoli. The cytoplasms are minimal. There is a paucity of other inflammatory elements. The tumor cells that define this neoplasm have a highly characteristic phenotypic profile that includes CD4 (Fig. 3455C), CD56 (Fig. 34-55D), and CD123 positivity (Fig. 34-55E). Nevertheless, some cases of AMoL may be CD123 positive. Perhaps the most useful differentiating stains are CD68 and lysozyme, which are negative in CD4+, CD56+ hematodermic neoplasms.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

(Fig. 34-57). In addition, infiltration and destruction of vessels and skin appendages are characteristic of AMMoL. Rarely, a granulomatous pattern of the leukemic infiltrate may occur (see Table 34-20).244 HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS Most leukemic cells in the infiltrate show strong immunoreactivity for CD68 and lysozyme (Fig. 34-58).220,226,240 Staining for chloroacetate esterase is variable, and positive as well as negative reactions may occur.220 Most cases also show a strong positive reaction for myeloperoxidase, although negative staining may be observed in some cases. A variable expression for CD4, CD56, and CD117 has been observed.226

 FIGURE 34-53 Acute monocytic leukemia (AMoL, M5). Leukemic cells with large round to oval or folded basophilic nuclei infiltrate between the collagen bundles.

Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cells accounting for 15% of adult leukemias. The median age at presentation is between 50 and 60 years. The majority of patients present in the chronic phase with relatively stable disease. Unpredictably, the disease eventually transforms into accelerated and blastic phases, becoming more resistant to treatment. CML was one of the first diseases in which a specific chromosomal abnormality was identified, a Philadelphia (Ph’) chromosome resulting from the t(9;22)(q34;q11) chromosomal translocation.245,246 Juvenile CML, a rare malignancy in childhood, is characterized by a rapidly progressive course.  FIGURE 34-54 Acute monocytic leukemia (AMoL, M5). Dense nodular infiltrate of atypical mononuclear cells in the deep dermis.

may be evident before leukemia is detected in the peripheral blood and bone marrow.244

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DIFFERENTIAL DIAGNOSIS As with acute monocytic leukemia, the differential diagnosis also encompasses CD4+, CD56+ hematodermic neoplasm. As a point of reiteration, these lesions (ie, CD4+, CD56+ hematodermic neoplasm) do not show immunoreactivity for CD68, lysozyme, and myeloperoxidase.

HISTOPATHOLOGIC FEATURES A dense infiltrate of atypical mononuclear cells is seen throughout the dermis and in the subcutaneous fat (Fig. 34-56). A distinct grenz zone overlies the infiltrate and separates it from the epidermis.219,220

Occasionally, focal involvement of the epidermis may be seen.240 There are medium- and large-sized atypical cells with large basophilic nuclei, single nucleoli, and slightly eosinophilic cytoplasms.219,220 Scattered eosinophils and lymphocytes are present throughout the lesion. Mitotic figures may be seen. The tumor cells are arranged in strands and cords, spreading between collagen bundles

CLINICAL FEATURES Specific (ie, neoplastic) skin lesions in CML are uncommon, with a reported incidence of 2% to 8%. The lesions are erythematous papules, plaques, or nodules (Table 34-21). They occur anywhere on the skin and may be generalized in distribution. Occasionally, only a single lesion is present.247 Circinate erythematous annular plaques and nodules have been described in a few patients with juvenile CML.248 HISTOPATHOLOGIC FEATURES A dense nodular to diffuse infiltrate is present.

B

C

D

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

A

E  FIGURE 34-55 (A) Acute monocytic leukemia (AMoL, M5). The neoplastic cells strongly express CD68. (B) Hematodermic neoplasm. There is a striking interstitial and angiocentric infiltrate composed of a monomorphic infiltrate of small- to intermediate-sized mononuclear cells with a finely dispersed chromatin and inconspicuous nucleoli. The cytoplasms are minimal. There is a paucity of other inflammatory elements. (C) The tumor cells which define this neoplasm have a highly characteristic phenotypic profile which includes CD4 positivity. (D) Characteristically the tumor cell express CD56 and (E) CD123.

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HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS In CML, leukemic cells strongly stain for CD43, CD45, CD68, lysozyme, and myeloperoxidase.220 In addition, the presence of CD56 expression in specific skin infiltrates of CML has been reported.227

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Granulocytic Sarcoma Granulocytic sarcoma is an extramedullary tumor mass composed of immature cells of the myeloid series that may occur specifically as a manifestation of AML, in the course of myelodysplastic syndrome, or as an isolated tumor in patients without evident hematologic disorders.249 The disease has been reported to occur in 2% to 8% of patients with acute nonlymphoblastic leukemia.250,251

 FIGURE 34-56 Acute myelomonocytic leukemia (AMMoL, M4). Diffuse infiltrate of atypical cells in the dermis.

 FIGURE 34-57 Acute myelomonocytic leukemia (AMMoL, M4). Rows of atypical cells migrating between collagen bundles.

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The infiltrate is most often concentrated in the dermis but may also involve the subcutaneous fat. In CML, the infiltrate is more pleomorphic and dominated by granulocytes in various stages of differentiation, including atypical myelocytes,

metamyelocytes, eosinophilic metamyelocytes, and neutrophils.219,220 The neutrophils characteristically exhibit dysplastic features characterized by hyperlobation, nuclear lobe asymmetry, and hypogranularity.

CLINICAL FEATURES Clinically, the patients present with single or multiple erythematous or violaceous nodules.224,252 When cut, the nodules may also have a diagnostic yellow-green coloration caused by the high concentration of myeloperoxidase, which changes color on exposure to air. The trunk, head, and extremities are the most commonly affected sites. Occasionally, the oral mucosa and conjunctiva are also involved.224,253 In patients with underlying myelodysplastic syndrome (MDS), the development of granulocytic sarcoma portends an aggressive clinical course with blast transformation. Granulocytic sarcoma rarely occurs in the setting of MDS, and factors that have been associated with its development include CD56 expression, trisomy 8, and an 8;21 translocation. In one comprehensive review of MDSassociated granulocytic sarcoma, 32 of the 46 cases occured in the absence of AML. Of the 32 patients, 47% developed AML 38 weeks after the initial diagnosis of the granulocytic sarcoma; the other patients did not develop AML. HISTOPATHOLOGIC FEATURES In granulocytic sarcoma, a diffuse, confluent infiltrate consisting of a mixture of immature myeloid cells is present throughout the dermis and in the subcutaneous tissue (Fig. 34-59).224,250 The atypical hematopoietic cells may show marked variation in size and nuclear configuration. An inflammatory infiltrate of eosinophils, neutrophils, and small lymphocytes may be present. HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS In most cases of granulocytic sarcoma, the tumor cells show

Myelodysplastic Syndrome MDS consists of a heterogeneous group of stem cell disorders that includes refractory anemia, refractory anemia with ring sideroblasts, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation, and chronic myelomonocytic leukemia (CMMoL).254,255

strong reactivity for myeloperoxidase and lysozyme. 224 There is a variable expression for CD45, CD43, CD68, and CD15.224,249 A percentage of these cases may be CD56 positive. DIFFERENTIAL DIAGNOSIS In terms of distinguishing granulocytic sarcoma from CD4+, CD56+ hematodermic neoplasms, most cases of the latter express plasmacytoid dendritic cell markers such as MXA, CD83, and CD123, and TCL1 oncogene

is negative. Conversely, lysozyme and CD68 are positive in granulocytic sarcoma and negative in CD4+, CD56+ hematodermic neoplasm. One caveat is that CD123 can be expressed at lower levels by monocyte precursors, so expression of CD123 does not rule out a diagnosis of myelomonocytic leukemia.

HISTOPATHOLOGIC FEATURES In MDS, the predominant microscopic finding is a dense infiltrate of medium- to large-sized cells with indented hyperchromatic nuclei in the dermis and subcutaneous fat. The infiltrate tends to surround and invade dermal blood vessels, hair follicles, and sweat glands. Vasculitis with leukemic infiltration may be seen in cutaneous

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-58 Acute myelomonocytic leukemia (AMMoL, M4). Atypical myeloid cells show strong reactivity for lysozyme.

CLINICAL FEATURES Specific skin lesions are uncommon in MDS, and only a few cases have been reported.8,256,257 The appearance of specific lesions is a poor prognostic indicator and is usually associated with transformation into the blastic phase. The specific skin lesions in MDS are described as multiple red to violaceous papules and nodules.257 Hemorrhagic lesions may be present on the hands and feet. Unusual specific cutaneous lesions are ecchymoses, necrotic plaques or ulcers, and prurigo-like lesions.258 Specific cutaneous involvement is rare in CMMoL.259 An erythematous, infiltrated plaque as a first sign of CMMoL has been reported.260

Table 34-21 Leukemic Skin Infiltrates of Chronic Myeloid Leukemia

Clinical Features Age 50-60 years Rare juvenile form Erythematous papules, plaques or nodules Almost any location Histopathologic Features Dense nodular to diffuse infiltrate Subcutaneous tissue frequently involved Pleomorphic infiltrate Atypical myelocytes, metamyelocytes and neutrophils Immunohistochemistry Predominant reactivity for lysozyme, myeloperoxidase, CD43, CD45, CD68

 FIGURE 34-59 Granulocytic sarcoma.

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lesions and is generally an indicator of a poor prognosis.261,262

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS On paraffin-embedded sections, neoplastic cells express CD43 and CD68 and usually show positivity for lysozyme and myeloperoxidase. A weaker variable expression for CD34,CD117, CD123, and CD4 may be observed.226

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DIFFERENTIAL DIAGNOSIS OF LEUKEMIC MYELOID INFILTRATES The diagnosis of leukemic myeloid skin infiltrates may be extremely difficult with routine histologic examination. The histologic differential diagnosis includes cutaneous B-cell lymphoma, cutaneous lesions of Hodgkin disease, malignant histiocytosis, lymphomatoid papulosis, metastatic undifferentiated carcinomas, Merkel cell carcinoma, and various benign dermatoses (eg, granuloma faciale, erythema elevatum diutinum, mastocytosis, secondary syphilis, acute febrile neutrophilic dermatosis [Sweet syndrome], and neutrophilic eccrine hidradenitis).263-265 The histologic differentiation may be problematic, and a clinicopathologic correlation is important in establishing a diagnosis. Leukocyte common antigen (CD45) helps to exclude poorly differentiated carcinomas. Positive staining for lysozyme, myeloperoxidase, chloroacetate esterase, and CD68 favors the diagnosis of a specific skin infiltrate of myeloid leukemia.220,226 Cutaneous lesions of Hodgkin lymphoma express CD30, CD15, CD25, and HLA-DR and are negative for CD45R. Blastic NK-cell lymphoma should show immunoreactivity for CD4, CD56, and CD123 but is negative for myeloid markers. The tumor cells of B-cell lymphoma express B-cell associated antigens. Lymphomatoid papulosis is of T-cell origin with a CD3+, CD4+, CD8−, and CD30+ phenotype. The presence of immature myeloid cells and dysplastic-appearing neutrophils are indicative of malignancy and should be differentiated from benign neutrophilic infiltrates. Erythema elevatum diutinum is ruled out by the presence of leukocytoclastic vasculitis. Neutrophils, pyknotic neutrophil nuclei, and neutrophil fragments are hallmarks of acute febrile neutrophilic dermatosis.266 Sweet syndrome is typically characterized by a benign neutrophilic infiltrate, but in a biopsy taken from a patient with AML, the dermal infiltrate may contain leukemic cells especially in regards to those cells lying in close apposition to blood vessels.267 It should be kept in mind that vasculitis

composed of leukemic cells may accompany the leukemic skin infiltrates and is generally associated with an aggressive clinical course.262

Chronic Lymphocytic Leukemia, B-Cell Type Chronic lymphocytic leukemia (B-CLL) is a B-cell neoplasm and the most frequent form of leukemia in Western countries, accounting for nearly 25% of all leukemias with an estimated annual age-adjusted incidence of three to five per 100,000 persons. The median age at diagnosis is approximately 70 years, and the disease affects men twice as frequently as women.268,269 CLINICAL FEATURES Specific skin lesions occur in approximately 8% of patients with CLL. The reported incidence of cutaneous lesions ranges from 4% to 45% if one takes into account nonspecific findings including purpura, ecchymoses, and maculopapular eruptions.10,270 The lesions are solitary, or more often multiple, red or violaceous macules, papules or nodules (Table 34-22). 270,271 Large

Table 34-22 Leukemic Skin Infiltrates of Chronic Lymphocytic Leukemia

Clinical Features Most common form of leukemia in adults Older than 60 years old Men and women affected equally Red or violaceous macules, papules, and nodules Often ulcerated, large nodules Located on face, scalp, trunk, and extremities Sometimes at site of herpes zoster and herpes simplex scars Histopathologic Features Patchy perivascular and periadnexal lymphoid infiltrate Nodular or diffuse infiltrate Bandlike infiltrate in the upper and middle dermis May involve subcutaneous tissue Immunophenotype CD5+, CD19+, CD20+, CD23+ Monoclonal expression of either κ or γ chain Molecular Biology Clonal rearrangement of Ig heavy (IgH) Differential Diagnosis Immunocytoma Cutaneous B-cell lymphoma Cutaneous B cell pseudolymphoma Lymphocytic infiltration Jessner-Kanof Mycosis fungoides

nodules may become necrotic and ulcerated. The lesions tend to occur on limited areas of the body, mainly the trunk, extremities, face, and scalp, but often spread and become generalized.9,272 Specific cutaneous infiltrates arising at the site of herpes zoster and herpes simplex scars are common.273,274 These lesions may be a temporary phenomenon and frequently regress without treatment.275 In patients with CLL, infection with B. burgdorferi may also trigger the development of specific cutaneous infiltrates at sites typical for lymphadenosis benigna cutis such as the nipple, scrotum, and earlobe.276 In addition, a predilection for specific infiltrates to arise at the site of squamous cell carcinoma, basal cell carcinoma, and actinic keratosis has been observed.277 The clinical lesions may have striking variations in their morphologic features and distribution. Atypical manifestations may present as chronic paronychia,278 subungual nodules, plaques on the volar surface of the hands and fingers,279 finger clubbing with periosteal bone destruction,280 and papulovesicular eruptions.281 Involvement of the mucous membranes is rare. The prognosis of patients with specific skin lesions is probably not affected by skin involvement.272 HISTOPATHOLOGIC FEATURES Three main patterns of skin infiltrates can be distinguished in CLL: a superficial and deep perivascular and periadnexal infiltrate, a nodular-diffuse infiltrate and a bandlike infiltrate (Fig. 34-60 and Table 34-22). 272 Extensive involvement of the subcutaneous tissue is usually seen, particularly in large nodular lesions. A grenz zone of normal dermis is seen between the uninvolved epidermis and the dermal infiltrate, although the infiltrate occasionally extends close to the dermal-epidermal junction, with isolated epidermotropic lymphoid cells.219,272 Occasionally, a subepidermal bullous separation, accompanied by edema of the superficial dermis, may be present. Less commonly, leukemic infiltrates may invade the walls of blood vessels. Cyclic lymphocytic vasculitis associated with CLL has been reported.282 A granulomatous reaction composed of epithelioid and giant cells may occur, especially in skin infiltrates at sites of previous herpes infections.273 At higher magnification, the infiltrate is monomorphous and composed mainly of small- to medium- sized lymphocytes with a round nucleus and dense nuclear chromatin.219,272 Eosinophils, neutrophils, and plasma cells also may be present in the infiltrate (Fig. 34-61).

CD20, CD23, and CD5 positivity.269,272 The detection of a monoclonal restriction to either κ or λ immunoglobulin light chain is an important feature of malignant cells in B-CLL. The neoplastic cells express monoclonal sIgM or sIgM and sIgD. Demonstration of light-chain restriction may be difficult in formalin-fixed tissue and frozen sections are usually required for optimal analysis. MOLECULAR BIOLOGY Clonal rearrangement of Ig heavy (IgH) is demonstrable in most cases.272

 FIGURE 34-60 Chronic lymphocytic leukemia (B-CLL) showing a nodular-diffuse pattern of infiltrate in the dermis.

The entity T-cell chronic lymphocytic leukemia has been reclassified as T-cell prolymphocytic leukemia (T-PLL) according to the WHO classification.283 T-PLL is a rare and aggressive neoplasm of T cells, usually with a mature immunophenotype. It accounts for approximately 2% of all forms of small lymphocytic leukemias in adults older than age 30 years.284,285 CLINICAL FEATURES T-PLL is characterized by the presence of lymphocytosis, lymphadenopathy, splenomegaly, and skin involvement.283-286 The median age at presentation is 63 years (range, 33-91 years). The skin is frequently involved, with a reported incidence between 25% and 30%.287 Patients with T-PLL present with edema, petechial or purpuric rash, and macular and papular lesions. Other manifestations include diffuse infiltrative erythema, nodules, and erythroderma. The lesions are usually found on the face and trunk and may show a symmetrical and linear distribution.286,288 Facial involvement with or without associated swelling is a characteristic finding.286,287

 FIGURE 34-61 Chronic lymphocytic leukemia (B-CLL). There is a periadnexal infiltrate of small- to medium-sized lymphoid cells. Note the presence of eosinophils.

IMMUNOHISTOCHEMICAL FINDINGS B-CLL cells are characterized by a CD19+, CD20+, CD43+, CD23+, and CD5+ immunophenotype (Fig. 34-62A). In Fig. 34-62B to 34-62E, one sees a well-differentiated

small lymphocytic infiltrate that was found peripheral to an infiltrating squamous cell carcinoma. The lymphocytes showed a typical chronic lymphocytic leukemia phenotypic profile comprising

HISTOPATHOLOGIC FEATURES A bandlike infiltrate involving the superficial dermis or a perivascular or periadnexal infiltrate in the dermis are the most prevalent findings in skin biopsies of T-PLL patients.286-288 Focal epidermotropism is usually present. In some cases, the infiltrate extends to the subcutaneous tissue. Prominent red cell extravasation is a frequent finding. Fig. 34-63A shows a predominantly angiocentric lymphocytic infiltrate surrounding and permeating vessels. The cells are intermediate in size with finely dispersed chromatin, somewhat eccentrically disposed nuclei, and eosinophilic rims of cytoplasm. There is attendant red cell extravasation (Fig. 34-63B). The infiltrate usually consists of small- and medium-sized

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A

B

C

D

E  FIGURE 34-62 (A) Chronic lymphocytic leukemia (B-CLL). Perivascular pattern of infiltrate of CD20+ cells. (B) Chronic B-CLL. In this collage, one sees a well-differentiated small lymphocytic infiltrate that was found peripheral to an infiltrating squamous cell carcinoma. The lymphocytes showed a typical chronic lymphocytic leukemia phenotypic profile composed of (C) CD20 positivity, (D) CD23 positivity, and (E) CD5 positivity.

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lymphoid cells with a finely dispersed heterochromatin and a single nucleous. However, tumor cells may show a significant degree of nuclear pleomorphism, and large tumor cells with irregularly shaped nuclei or atypical lymphoid

cells with cerebriform or Sézary cell-like nuclei can be observed.286,288 IMMUNOHISTOCHEMICAL FINDINGS In the majority of cases, the tumor cells express CD4, CD3, CD7, CD52, and TCL-1

(T-cell leukemia 1 proto-oncogene antibody). Whereas CD4 and CD8 are coexpressed in 25% of cases, the CD4−/CD8+ phenotype is rare. Twenty percent of cases of T-PLL are CD3-.285,286,289 Clonal rearrangement of the T-cell receptor

B

 FIGURE 34-63 (A) T-cell prolymphocytic leukemia (T-PLL). The biopsy shows a predominantly angiocentric lymphocytic infiltrate surrounding and permeating vessels. The cells are intermediate in size with finely dispersed chromatin, somewhat eccentrically disposed nuclei, and eosinophilic rims of cytoplasm. (B) The neoplastic cells in T-PLL express CD7. This is an important finding because most cutaneous T-cell malignancies show a loss of CD7 expression.

(TCR) can be demonstrated in all cases. The expression of CD7 is a very important finding because most T-cell dyscrasias are associated with a loss in the expression of CD7.

Hairy Cell Leukemia Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disease characterized by splenomegaly, pancytopenia and circulating leukemic cells that infiltrate the bone marrow, liver, and spleen but rarely the lymph nodes.290 HCL accounts for about 2% to 3% of all leukemias in adults in the Western world. The cells of typical HCL have characteristic prominent cytoplasmic projections and are strongly positive for tartrate-resistant acid phosphatase.

surrounds dermal blood vessels and skin appendages. Less commonly, the infiltrate extends deeply throughout the entire dermis and into subcutaneous tissue.294 The HCL cells are small to medium in size and have an abundant pale cytoplasm and hyperchromatic rounded or indented nuclei. In the bone marrow biopsy specimen shown in Fig. 34-64, the cells have a well differentiated monotypic appearance with clear cytoplasms and sharp cytoplasmic borders. The cells are juxtaposed to one another

without any overlap, imparting an orderly mosaic-like arrangement to the infiltrate. Typically, the nuclei are separated from each other by clear cytoplasmic spaces.Cytoplasmic hairy projections cannot be seen in fixed tissue sections. Usually, there are a small number of neutrophils, eosinophils, and histiocytes. Mitoses are absent.291,295 HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS Most infiltrating hairy cells stain strongly with tartrate-resistant

CLINICAL FEATURES Leukemic skin infiltrates are rarely observed in patients with HCL, and their presence should be proven by skin biopsy.291 Specific skin lesions were seen in 48 (8%) of the 600 cases reported in the literature, but only eight cases were proven by skin biopsy.291 In another series of 113 patients, only one patient had skin infiltration by leukemic cells.292 The lesions usually are erythematous maculopapular eruptions.291 Deep infiltrated nodules of HCL may be present. HCL is also frequently associated with vasculitis.264,292,293 HISTOPATHOLOGIC FEATURES A dense, diffuse or patchy infiltrate of uniform mononuclear cells is present predominantly in the upper dermis. The epidermis is not involved. The infiltrate usually

 FIGURE 34-64 Hairy cell leukemia. In this peripheral blood sample, one can see discernible hairylike, fine cytoplasmic projections.

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acid phosphatase. Hairy cells typically express the B-cell-associated antigens CD19, CD20, CD22, and CD79a. They are usually positive for CD11c, CD25, and CD103 and negative for CD5, CD10, and CD23.290

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Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disorder of CD4+ T cells caused by the human T-cell leukemia virus type I (HTLVI).296-299 Leukemic cells usually have large, highly convoluted nuclei, called flower cells, and characteristically display the mature T-cell phenotype.299,300 ATLL is endemic in the southwestern district of Japan, the Caribbean, South America, and central Africa.298,301 The lifetime risk of developing ATLL among HTLV-I–infected persons is 2.5%.297 ATLL occurs only in adults. The age at onset ranges from 24 to 85 years (average, 58 years).297 CLINICAL FEATURES The classification of ATLL is based on clinical manifestations and laboratory findings and includes four types: the acute, chronic, smoldering, and lymphoma types.296,297,299 Acute ATLL is the best characterized form of the disease and is characterized by a high-grade leukemia, generalized lymphadenopathy, hepatosplenomegaly, skin lesions, leukemic involvement of the bone marrow, and rapid clinical progression. Smoldering ATLL, in particular, presents with predominantly cutaneous manifestations and a protracted clinical course before progressing to an acute, aggressive terminal phase. In addition to the clinical features, the diagnosis of ATLL is based on the immunophenotype of atypical lymphocytes, the presence of circulating antibodies against HTLV-I, and monoclonal integration of the HTLV-I provirus in the tumor cell DNA.296,297,299 In up to 50% of ATLL cases, there is a cutaneous infiltration of malignant T cells. Cutaneous manifestations of ATLL can be quite variable.302 Nodules, tumors, and red papules are the most frequent manifestation. ATLL also presents as generalized erythroderma.303,304 Manifestation as solitary nodule has been reported.305 Patients with papules and nodules have a poorer prognosis than those with erythematous lesions. A median survival time of 14 months for patients with monoclonal proviral DNA integration in cutaneous lesions was reported.306 Spontaneous regression of cutaneous lesions may occur in patients with ATLL.307

HISTOPATHOLOGIC FEATURES There is a dense lymphoid infiltrate that is often concentrated around blood vessels and appendages. The infiltrate may diffusely involve the full thickness of the dermis and the subcutaneous fat. Exocytosis of atypical lymphoid cells into the epidermis, with or without intraepidermal clusters of cells forming Pautrier microabscesses, is seen frequently.308 However, a nonepidermotropic pattern of infiltration may occur. The cells have medium- to largesized pleomorphic nuclei. Mitotic figures are common. Dermal edema may be prominent. Occasionally, eosinophils and a few plasma cells are present in the infiltrate. The perivascular infiltration is frequently associated with evidence of vasculitis, with destructive changes of blood vessels and extravasation of erythrocytes.303 Rarely, epithelioid granulomas or dermal aggregates of lymphocytes and macrophages resembling granulomas are observed in the cutaneous skin lesions of ATLL.309,310 IMMUNOHISTOCHEMICAL FINDINGS Immunophenotyping with monoclonal antibodies shows that the principal phenotype of the neoplastic cells in the skin of patients with ATLL is the helper T cell that predominantly expresses CD4, CD25, CD62 and CD45RO and usually not CD7, CD8, and CD19.300,303,308 MOLECULAR BIOLOGY Clonal rearrangement of TCR genes is found in the majority of ATLL cases. DIFFERENTIAL DIAGNOSIS OF LEUKEMIC T- AND B-CELL LYMPHOID INFILTRATES Differential diagnosis of the T- and B-cell leukemic lymphoid infiltrates may present difficulties because a myriad of clinical and pathological entities are characterized by an extensive lymphocytic infiltrate. In this regard, one could consider many different histomorphologic possibilities, although they all have distinguishing light microscopic and phenotypic features and they include infiltrates of lupus erythematosus, pityriasis lichenoides, lymphomatoid papulosis, cutaneous lymphoid hyperplasia, actinic reticuloid, angioimmunoblastic lymphadenopathy, and cutaneous lymphomas. The presence of marked epidermotropism usually favors the diagnosis of cutaneous T-cell lymphoma over CLL. Reactive lymphoid hyperplasia exhibits a dominant angiocentric disposition and is characterized by a predominance of T cells. In addition, deposition of mucin may be seen in the reticular dermis. Pityriasis lichenoides is

a form of prelymphomatoid cutaneous lymphoid dyscrasia characterized by an almost pure T-cell lymphocytic infiltrate in an angiocentric and epidermotropic array. The extent of epitheliotropism may be striking. Lymphomatoid papulosis demonstrates an angiocentric infiltrate composed of large atypical mononuclear cells with an admixture of neutrophils and eosinophils. The large aberrant cell populace shows a distinctive phenotypic profile, namely, one exhibiting CD3, CD4, CD30, and granzyme positivity along with other activation markers such as HLA-DR and CD25. In contrast, the leukemic cells in HCL are morphologically uniform and typically stain with a B-cell marker.192 At low-power magnification, leukemic infiltrates of CLL may be difficult to differentiate from cutaneous B-cell pseudolymphomas, but the presence of a nodular dermal infiltrate with reactive follicles together with the demonstration of a polyclonal B-cell proliferation usually helps to exclude a malignant process. Insect bite–like reactions may clinically resemble specific skin lesions of CLL. However, the characteristic histopathologic findings of an insect bite–like reaction are a T cell–dominant lymphocytic infiltrate accompanied by eosinophils.311 The differentiation of ATLL from other cutaneous T-cell lymphomas, such as mycosis fungoides and Sézary syndrome, may be difficult. Knowledge of the clinical features of ATLL and clinical shrewdness can usually solve these diagnostic dilemmas. The lack of damage to blood vessels and the demonstration of HTLV-I proviral integration in the clonal population of malignant T cells can help to differentiate ATLL from cutaneous T-cell lymphoma when the clinical presentation overlaps. T-PPL with a cutaneous infiltrate of Sézary-like cells can usually be distinguished from Sézary syndrome by the clinical, cytogenetic, and molecular features.

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5. Willemze, R, Kerl H, Sterry W, et al: EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. 1997; 90:354. 6. Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Haematopoietic and Lmyphoid Tissues. Lyon: IARC Press; 2001. 7. UICC: TNM Classification of Malignant Tumors, 6th ed. New York: Wiley-Liss; 2002. 8. Olsen, E, Vonderheid E, Pimpinelli N, et al: Revisions to the staging and classification of mycosis fungoides and Sezary 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. 9. Kim YH, Willemze R, Pimpinelli N, et al: TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary 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;110:479. 10. Dummer R, Schwarz T: Cytokines as regulatory proteins in lymphoproliferative skin infiltrates. Dermatol Clin. 1994; 12:283. 11. Lessin SR, Vowels BR, Rook AH: Th2 cytokine profile in cutaneous T-cell lymphoma. J Invest Dermatol. 1995;105: 855. 12. Burg G, Zwingers T, Staegemeir E, et al: Interrater and intrarater variabilities in the evaluation of cutaneous lymphoproliferative T-cell infiltrates. EORTCCutaneous Lymphoma Project Group. Dermatol Clin. 1994;12:311. 13. Kempf, W, Haeffner AC, Mueller B, et al: Experts and gold standards in dermatopathology: qualitative and quantitative analysis of the self-assessment slide seminar at the 17th colloquium of the International Society of Dermatopathology. Am J Dermatopathol. 1998;20: 478. 14. Santucci M, Burg G, Feller AC: Interrater and intrarater reliability of histologic criteria in early cutaneous T-cell lymphoma. An EORTC Cutaneous Lymphoma Project Group study. Dermatol Clin. 1994; 12:323. 15. Holm N, Flaig MJ, Yazdi AS, et al: The value of molecular analysis by PCR in the diagnosis of cutaneous lymphocytic infiltrates. J Cutan Pathol. 2002; 29:447. 16. Wood, GS, Uluer AZ: Polymerase chain reaction/denaturing gradient gel electrophoresis (PCR/DGGE): sensitivity, band pattern analysis, and methodologic optimization. Am J Dermatopathol. 1999;21:547. 17. Bruggemann M, White H, Gaulard P, et al: Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936. Leukemia. 2007;21:215.

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CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 956

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and immunohistochemical review. J Cutan Pathol. 2008;35:180. Kaddu S, Beham-Schmid C, Zenahlik P, et al: CD56+ blastic transformation of chronic myeloid leukemia involving the skin. J Cutan Pathol. 1999;26:497. Kuwabara H, Nagai M, Yamaoka G, et al: Specific skin manifestations in CD56 positive acute myeloid leukemia. J Cutan Pathol. 1999;26:1. Assaf C, Gellrich S, Whittaker S, et al: CD56-positive haematological neoplasms of the skin: a multicentre study of the Cutaneous Lymphoma Project Group of the European Organisation for Research and Treatment of Cancer. J Clin Pathol. 2007;60:981. Lukens JN: Classification and differentiation of the acute leukemias, in Lee GR, Bithell TC, Foerster J, et al (eds) Wintrobe's Clinical Hematology. Philadelphia: Lea & Febiger; 1993:1873. Buechner S, Su WPD, Vardiman J: Cutaneous involvement by myeloid leukaemia, in LeBoit PE, Burg G,Weedon D, SarasinA. World Health Organization Classification of Tumours. Pathology & Genetics. Skin Tumours. Lyon, France: IARC Press; 2006:211. Buechner S, Su WPD Acute (myelo-) Monocytic leukemia (AMoL, AMMoL), in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005:393. Ohno S, Yokoo T, Ohta M, et al: Aleukemic leukemia cutis. J Am Acad Dermatol. 1990;22:374. Daoud MS, Snow JL, Gibson LE, et al: Aleukemic monocytic leukemia cutis. Mayo Clin Proc. 1996;71:166. Török L, Lueff S Garay G, et al: Monocytic aleukemic leukemia cutis. J Eur Acad Dermatol Venereol. 1999;13:54. Benez A, Metzger S, Metzler G, et al: Aleukemic leukemia cutis presenting as benign-appearing exanthema. Acta Derm Venereol. 2001;81:45. Resnik KS, Brod BB: Leukemia cutis in congenital leukemia. Analysis and review of the world literature with report of an additional case. Arch Dermatol. 1993;129: 1301. Gottesfeld E, Silverman RA, Coccia PF, et al: Transient blueberry muffin appearance of a newborn with congenital monoblastic leukemia. J Am Acad Dermatol. 1989;21:347. Sepp N, Radaszkiewicz T, Meijer CJLM, et al: Specific skin manifestations in acute leukemia with monocytic differentiation. A morphologic and immunohistochemical study of 11 cases. Cancer. 1993;71:124. Kaiserling E, Horny HP, Geerts ML, et al: Skin involvement in myelogenous leukemia: morphologic and immunophenotypic heterogeneity of skin infiltrates. Mod Pathol. 1994;7:771. Eubanks SW, Patterson JW: Subacute myelomonocytic leukemia—an unusual skin manifestation. J Am Acad Dermatol. 1983;9:581. Lee DA, Su WPD: Acute myelomonocytic leukemia cutis presenting as a conjunctival lesion. Int J Dermatol. 1985;24:369. Hoen B, Neidhardt AC, Aghassian C, et al: Acute myelomonocytic leukemia revealed by a chickenpox-like rash. J Eur Acad Dermatol Venereol. 1996;6:76.

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lymphomas and large B cell lymphomas of the leg descend from germinal center cells. A single cell polymerase chain reaction analysis. J Invest Dermatol. 2001;117:1512. Magro CM, Nash JW, Werling RW, et al: Primary cutaneous CD30+ large cell B-cell lymphoma: a series of 10 cases. Appl Immunhistochem Molec Morphol. 2006;14:7. Sheibani K, Battifora H, Winberg CD, et al: Further evidence that "malignant angioendotheliomatosis" is an angiotropic large-cell lymphoma. N Engl J Med. 1986;314:943. Cerroni L: Hemangiomas with a bad surprise. Dermatology. 2004;209:79. Perniciaro C, Winkelmann RK, Daoud MS, et al: Malignant angioendotheliomatosis is an angiotropic lymphoma. Immunohistochemical, ultrastructural, and molecular genetic studies. Am J Dermatopathol. 1995;17:242. Sander CA, Medeiros LJ, Abruzzo LV, et al: Lymphoblastic lymphoma presenting in cutaneous sites: a clinicopathologic analysis of six cases. J Am Acad Dermatol 1991;25:1023. Chimenti S, Fink-Puches R, Peris K, et al: Cutaneous involvement in lymphoblastic lymphoma. J Cutan Pathol. 1999;26:379. Hummel M, Ziemann K, Lammert H, et al: Hodgkin’s disease with monoclonal and polyclonal populations of Reed-Sternberg cells. N Engl J Med. 1995;333:901. Küppers R, Bräuninger A, Müschen M, et al: Evidence that Hodgkin and ReedSternberg cells in Hodgkin disease do not represent cell fusions. Blood. 2001;97:818. Cerroni L, Gatter K, Kerl H: Cutaneous Hodgkin lymphoma, in An Illustrated Guide of Skin Lymphomas, 2nd ed. Oxford: Blackwell Publishing; 2004:141-143. Rubenstein M, Duvic M: Cutaneous manifestations of Hodgkin's disease. Int J Dermatol. 2006;45:251. Smith JL, Butler JJ: Skin involvement in Hodgkin’s disease. Cancer. 1980;45:354. White RM, Patterson JW: Cutaneous involvement in Hodgkin’s disease. Cancer. 1985;55:1136. Sioutos N, Kerl H, Murphy SB, et al: Primary cutaneous Hodgkin’s disease: unique clinical, morphologic, and immunophenotypic findings. Am J Dermatopathol. 1994;16:2. Cerroni L, Beham-Schmid C, Kerl H: Cutaneous Hodgkin’s disease: an immunohistochemical analysis. J Cutan Pathol. 1995;22:229. Moretti S, Pimpinelli N, Di Lollo S, et al: In situ immunologic characterization of cutaneous involvement in Hodgkin’s disease. Cancer. 1989;63:661. Davis TH, Morton CC, Miller-et al: Hodgkin’s disease, lymphomatoid papulosis, and cutaneous T-cell lymphoma derived from a common T-cell clone. N Engl J Med. 1992;326:1115. Buechner, SA, Su WPD: Leukemia cutis, in Arndt KA, Robinson JK, Leboit PE, Wintroub BU (eds). Cutaneous Medicine and Surgery. Philadelphia: WB Saunders; 1996:1670. Su WPD: Clinical, histopathologic, and immunohistochemical correlations in leukemia cutis. Sem Dermatol. 1994;13: 223.

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244. Tomasini C, Quaglino P, Novelli M, et al: “Aleukemic” granulomatous leukemia cutis. Am J Dermatopathol. 1998;20:417. 245. Kalidas M, Kantarjian H, Talpaz M: Chronic myelogenous leukemia. JAMA. 2001;286:895. 246. Holyoake T: Recent advances in the melecular and cellular biology of chronic myeloid leukaemia: lessons to be learned from the laboratory. Br J Haematol. 2001;113:11. 247. Buechner S, Su WPD: Chronic myeloid leukemia (CML), in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005:383. 248. Heskel NS, White CR, Fryberger S, et al: Aleukemic leukemia cutis: juvenile chronic granulocytic leukemia presenting with figurate cutaneous lesions. J Am Acad Dermatol. 1983;9:423. 249. Breccia M, Mandelli F, Petti MC, et al: Clinico-pathological characteristics of myeloid sarcoma at diagnosis and during follow-up: report of 12 cases from a single institution. Leuk Res. 2004;28:1165. 250. Sun NCJ, Ellis R: Granulocytic sarcoma of the skin. Arch Dermatol. 1980;116:800. 251. Yamauchi K, Yasuda M: Comparison in treatments of nonleukemic granulocytic sarcoma. Cancer. 2002;94:1739. 252. Buechner S, Su WPD: Granulocytic sarcoma (Chloroma), in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005:403. 253. Hon C, Shek T, Liang R: Conjunctival chloroma (granulocytic sarcoma). Lancet. 2002;359:2247. 254. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189. 255. Wood BL: Myeloid malignancies: myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia. Clin Lab Med. 2007;27:551. 256. Avivi I, Rosenbaum H, Levy Y, et al: Myelodysplastic syndrome and associated skin lesions: a review of the literature. Leuk Res. 1999;23:323. 257. Morand J, Lightburn E, Richard M, et al: Skin manifestations associated with myelodysplastic syndromes. Rv Med Interne. 2001;22:845. 258. Aractingi S, Bachmeyer C, Miclea JM, et al: Unusual specific cutaneous lesions in myelodysplastic syndromes. J Am Acad Dermatol. 1995;33:187. 259. O'Connell DM, Fagan WA, Skinner SM, et al: Cutaneous involvement in chronic myelomonocytic leukemia. Int J Dermatol. 1994;33:628. 260. Braga D, Manganoni A, Boccaletti V, et al: Specific skin infiltration as first sign of chronic myelomonocytic leukemia with an unusual phenotype. J Am Acad Dermatol. 1996;35:804. 261. O'Donnell, B, Williams H, Carr R: Myelodysplastic syndrome presenting as cutaneous vasculitis. Clin Exp Dermatol. 1995;20:439. 262. Paydas, S, Zorludemir S: Leukaemia cutis and leukaemic vasculitis. Br J Dermatol. 2000;143:773. 263. Wong TY, Suster S, Bouffard D, et al: Histologic spectrum of cutaneous involvement in patients with myelogenous leukemia including the neutrophilic dermatoses. Int J Dermatol. 1995;34:323.

264. Kurzrock R, Cohen PR: Mucocutaneous paraneoplastic manifestations of hematologic malignancies. Am J Med. 1995; 99:207. 265. Hensley C, Caughman S: Neutrophilic dermatoses associated with hematologic disorders. Clin Dermatol. 2000; 18:355. 266. Jordaan HF: Acute febrile neutrophilic dermatosis. A histopathological study of 37 patients and a review of the literature. Am J Dermatopathol. 1989;11:99. 267. Morgan K, Callen J: Sweet's syndrome in acute myelogenous leukemia presenting as periorbital cellulitis with an infiltrate of leukemic cells. J Am Acad Dermatol. 2001;45:590. 268. Wierda WG, Kipps T: Chronic lymphocytic leukemia. Curr Opin Hematol. 1999;6:253. 269. Yee KOBS: Chronic lymphocytic leukemia: Diagnosis and treatment. Mayo Clin Proc. 2006;81:1105. 270. Robak E, Robak T: Skin lesions in chronic lymphocytic leukemia. Leuk Lymphoma. 2007;48:855. 271. Buechner S, Su WPD: Chronic lymphocytic leukemia, B-cell type (B-CLL), in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005:375. 272. Cerroni L, Zenahlik P, Hofler G, et al: Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia: a clinicopathologic and prognostic study of 42 patients. Am J Surg Pathol. 1996;20:1000. 273. Cerroni L, Zenahlik P, Kerl H: Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia arising at the site of herpes zoster and herpes simplex scars. Cancer. 1995;76:26. 274. Ziemer M, Bornkessel A, Hahnfeld S, et al: 'Specific' cutaneous infiltrate of B-cell chronic lymphocytic leukemia at the site of a florid herpes simplex infection. J Cutan Pathol. 2005;32:581. 275. Wakelin S, Young E, Kelly S, et al: Transient leukemia cutis in chronic lymphocytic leukemia. Clin Exp Dermatol. 1997;22:37. 276. Cerroni L, Höfler G, Bäck B, et al: Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia (B-CLL) at sites typical for Borrelia burgdorferi infection. J Cutan Pathol. 2002;29:142. 277. Smoller B, Warnke R: Cutaneous infiltrate of chronic lymphocytic leukemia and relationship to primary cutaneous epithelial neoplasms. J Cutan Pathol. 1998;25:160. 278. High DA, Luscombe HA, Kauh YC: Leukemia cutis masquerading as chronic paronychia. Int J Dermatol. 1985;24:595. 279. Simon CA, Su WPD, Li CY: Subungual leukemia cutis. Int J Dermatol. 1990;29: 636. 280. Calvert RJ, Smith E: Metastatic acropachy in lymphatic leukemia. Blood. 1955;10:545. 281. Desvignes V, Bosq J, Guillaume JC, et al: Eruption papulo-vésiculeuse du visage au cours des leucémies lymphoides chronique. Ann Dermatol Venereol. 1990; 117:880. 282. Cabuk M, Inanir I, Turkdogan P, et al: Cyclic lymphocytic vasculitis associated with chronic lymphocytic leukemia. Leuk Lymphoma. 2004;45:811. 283. Jaffe,ES, Harris NL, Stein H, Vardiman JW: World Health Organization Classification of

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Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. Dearden C: T-cell prolymphocytic leukemia. Med Oncol. 2006;23:17. Matutes E: T-cell prolymphocytic leukemia. Cancer Control. 1998;5:19. Magro CM, Morrison CD, Heerema N, et al: T-cell prolymphocytic leukemia: an aggressive T cell malignancy with frequent cutaneous tropism. J Am Acad Dermatol. 2006;55:467. Mallett R, Matutes E, Catovsky D, et al: Cutaneous infiltration in T-cell prolymphocytic leukaemia. Br J Dermatol. 1995; 132:263. Valbuena,JR, Herling M, Admirand JH, et al: T-cell prolymphocytic leukemia involving extramedullary sites. Am J Clin Pathol. 2005;123:456. Matutes E, Brito-Babapulle V, Swansbury J, et al: Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia. Blood. 1991;78:3269. Swords R, Giles F: Hairy cell leukemia. Med Oncol. 2007;24:7. Arai E, Ikeda S, Itoh S, et al: Specific skin lesions as the presenting symptom of hairy cell leukemia. Am J Clin Pathol. 1988;90:459. Finan MC, Su WPD, Li CY: Cutaneous findings in hairy cell leukemia. J Am Acad Dermatol. 1984;11:788. Carsuzaa F, Pierre C, Jaubert D, et al: Cutaneous findings in hairy cell leukemia. Review of 84 cases. Nouv Rev Fr Hematol. 1993;35:541. Buechner S, Su, WPD Hairy-cell leukemia (HCL), in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005:387. Lawrence DM, Sun NCJ, Mena R, et al: Cutaneous lesions in hairy-cell leukemia.Case report and review of the literature. Arch Dermatol. 1983;119: 322. Hall WW: Human T cell lymphotropic virus type I and cutaneous T cell leukemia/ lymphoma. J Exp Med. 1994; 180: 1581. Yamaguchi K: Human T-lymphotropic virus type I in Japan. Lancet. 1994; 343:213. Davey FR, Hutchison RE: Pathology and immunology of adult T-cell leukemia/ lymphoma. Curr Opin Oncol. 1991;3:13. Matutes E: Adult T-cell leukaemia/ lymphoma. J Clin Pathol. 2007;60:1373. Dahmoush L, Hijazi Y, Barnes E, et al: Adult T-cell leukemia/lymphoma. Cancer. 2002;96:110. Uchiyama T, Yodoi J, Sagawa K, et al: Adult T-cell leukemia: clinical and hematological features of 16 cases. Blood. 1977;50:481. Tokura Y, Jaffe ES, SanderCA: Cutaneous adult T-cell leukeaemia/lymphoma, in LeBoit PE, Burg G ,Weedon D, Sarasin A (eds). World Health Organization Classification of Tumours. Pathology & Genetics. Skin Tumours, edited by Lyon, France: IARC Press; 2006:189. Nagatani T, Miyazawa M, Matsuzaki T, et al: Adult T-cell leukemia/lymphoma (ATL)—clinical, histopathological, immunological and immunohistochemical characteristics. Exp Dermatol. 1992;1:248. Setoyama M, Katahira Y, Kanzaki T: Clinicopathologic analysis of 124 cases

of adult T-cell leukemia/lymphoma with cutaneous manifestations:the smouldering type with skin manifestations has a poorer prognosis than previously thought. J Dermatol. 1999;26:785. 305. Shimizu S, Yasui C, Koizumi K, et al: Cutaneous-type adult T-cell leukemia/ lymphoma presenting as a solitary large skin nodule: a review of the literature. J Am Acad Dermatol. 2007;57(suppl):S115. 306. Yamaguchi T, Ohshima K, Karube K, et al: Clinicopathological features of cutaneous lesions of adult T-cell leukaemia/ lymphoma. Br J Dermatol. 2005;152:76.

307. Kawabata H, Setoyama M, Fukushige T, et al: Spontaneous regression of cutaneous lesions in adult T-cell leukaemia/lymphoma. Br J Dermatol. 2001;144:434. 308. Kempf W, KazakovDV, Burg G: Adult T-cell leukemia/lymphoma, in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005: 215. 309. DiCaudo D, Perniciaro C, Worrell J, et al: Clinical and histologic spectrum of human T-cell lymphotropic virus type-1 associated lymphoma involving the skin. J Am Acad Dermatol. 1996;34:69.

310. Setoyama M, Katahira Y, Kanzaki T, et al: Adult T-cell leukemia/lymphoma associated with noninfectious epithelioid granuloma in the skin: a clinicopathologic study. Am J Dermatopathol. 1997;19:591. 311. Ulmer A, Metzler G, Schanz S, et al: Dapsone in the management of “insect bite-like reaction” in a patient with chronic lymphocytic leukaemia. Br J Dermatol. 2007;156:172.

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CHAPTER 35 Cutaneous Metastases

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Michael S. Rabkin

960

A metastasis is a neoplasm that has spread from its original site such that it is no longer in continuity with, and often not in close proximity to, the primary lesion. Neoplasms may invade the skin by contiguous spread or may spread into the skin by direct extension into surgical scars and needle biopsy tracts, but the usual pathway of regional or distant metastases is believed to involve lymphatic or blood vessels.1-3 The frequency of cutaneous metastases in patients with cancer ranges from 0.6% to 9% in various studies.4-10 In a study of 4020 patients with metastatic carcinoma and melanoma, 420 patients (10.4%) had cutaneous metastases, and cutaneous metastases were the first sign of extranodal metastatic disease in 306 patients (7.6%).10 In another study of 7316 cancer patients, 5% had skin involvement. Skin involvement was the first sign of cancer in 59 patients (0.8%).9 Twenty-two of the latter patients had direct extension of the primary cancer into the skin, 20 had local (satellite) metastases, and 17 had distant metastases. Thus, although skin

metastases are in general relatively uncommon, they may be the initial presentation of an internal malignancy. Cutaneous metastases reflect the biologic behavior and population-based incidence of their associated primary tumors. The greatest incidence of cutaneous metastases is therefore in the fifth, sixth, and seventh decades of life, and the incidence and distribution of cutaneous metastases are correlated with gender. The incidence of primary tumors in women and men with skin metastases from studies by Brownstein and Helwig on 724 patients is listed in the left-hand columns of Table 35-1.4,5 These authors found that the most common primary tumors in women were breast at 69%, followed by large intestine, melanoma, lung and other internal sites. In men, the lung and large intestine were the most common sources (Table 35-1). Skin metastases were the presenting sign of malignancy in men in 37% of cases and in women in 6% of cases, presumably because primary breast cancer in women is often diagnosed at an earlier stage than primary lung and colorectal cancer are diagnosed in men. In a later study by Lookingbill et al.10 of cutaneous metastases in a population of patients with metastatic carcinoma and melanoma (right-hand columns of Table 35-1), the most frequent tumors to metastasize to the skin in 300 women were the breast and melanoma. In 127 men, the most frequent cutaneous metastases were melanoma, the lung, the large intestine, and the oral cavity. The relative proportion

Table 35-1 Sites of Origin of Skin Metastases PRIMARY SITE

WOMEN (%)

MEN (%)

Breast Large intestine Melanoma Lung Ovary Sarcoma Uterine cervix Pancreas Oral cavity Bladder Kidney Stomach Esophagus Salivary gland Prostate Unknown primary site

69/70.7 9/1.3 5/12 4/2 4/3.3 2/0 2/0.7 2/0.3 1/2.3 1/1.3 0/0 0/0.7 0/0 0/0

2/2.4 19/11 13/32.3 24/11.8

0/3

SOURCES: Data from Brownstein and Helwig5 and Lookingbill et al.10

3/0 2/0.8 12/8.7 2/2.4 6/4.7 6/0.8 3/2.4 2/0 1/0 0/8.7

of cutaneous metastases may change with population-based trends in the incidence of the associated primary tumor. For example, the incidence of cutaneous metastases from lung carcinoma in women is higher in more recent series, reflecting the rising incidence of primary lung carcinoma in women.11,12

CLINICAL AND MORPHOLOGIC FEATURES Cutaneous metastases can take a variety of forms and occur in a variety of locations, but these forms and locations are not entirely specific either for the type of tumor or the site of the primary malignancy. Metastatic tumors frequently are fleshcolored nodules or plaques; multiple lesions are more common than solitary lesions, and sometimes multiple lesions are distributed in a zosteriform pattern.10,13-21 Lookingbill et al.10 reported ulceration in 10% of cutaneous breast carcinoma metastases and clinical pigmentation in 36% of cutaneous melanoma metastases. Metastases of renal cell carcinomas and choriocarcinomas are frequently red-purple and hemorrhagic.22-27 In one series from a cancer center, 45% of cutaneous metastases were not initially suspected of being metastases owing to unusual clinical presentations, including inflammatory lesions or rash in 15%, and several metastatic sarcomas and small cell carcinomas would have been misinterpreted as primary skin tumors by experienced pathologists in the absence of adequate clinical history.12 A recent report described clinically incognito cutaneous metastases discovered as an incidental histologic finding in skin specimens.28 Breast carcinoma is associated with eight types of cutaneous metastases if one includes Paget disease.29 These patterns are not unique to breast carcinoma. Inflammatory carcinoma is a red patch that may resemble cellulitis or a figurate or gyrate erythema. Inflammatory carcinoma results from congestion of capillaries and the dilatation and obstruction of lymphatics by tumor cells.30-35 En cuirasse (encasement in armor) metastases demonstrate diffuse morpheiform induration of the skin resulting from dermal sclerosis in association with tumor cells.36-38 Telangiectatic metastases are composed of clustered, violaceous papulovesicles that may demonstrate pigmentation so prominent as to resemble metastatic melanoma. Telangiectatic metastases

tumors in the cervix, urinary tract, prostate, and rectum.4,5,71-74 Local metastases may also develop at the site of scars from previous surgical incisions, usually within 1 year of the procedure; in needle biopsy tracts; or in unrelated surgical or traumatic scars.6,75-80 Scar metastases at the excision site or as the first sign of metastatic disease have been seen with breast, ovarian, colorectal, liver, oral, laryngeal, lung, renal, and endometrial carcinomas and melanoma.6,10 Metastatic tumors may also be seen in persistent abscesses and fistulas after surgery.9,81,82 Distant metastases have been reported in up to 39% of patients with cutaneous metastases.10 Metastases to distant cutaneous sites have been most frequently associated with melanoma and primary carcinomas of the lung and breast. Tumors associated with vascular invasion are more frequently associated with distant metastases.4,83,84 Such tumors include melanoma, renal cell carcinoma, thyroid follicular carcinoma, and choriocarcinoma. Scalp metastases are disproportionately common in renal cell and thyroid carcinomas. Metastatic tumors were the third most common malignant cutaneous tumors of the scalp (12.8%) in a recent series from Taiwan.85 Most of these metastases resulted from primary tumors in the lung. Metastases to extremities are uncommon; usually occur late; and are seen most often with melanoma and less often with breast, lung, kidney, and large intestine carcinomas.4,10 The time of onset of a cutaneous metastasis is variable and reflects the characteristics of the underlying malignancy. However, when a cutaneous metastasis does occur, it usually portends a poor prognosis.4 In one series, half of 200 patients with cutaneous metastases died within the first 6 months after the diagnosis.86 Metastases to the skin can be delayed from 6 to 32 years after diagnosis of the primary lesion with some tumors, notably malignant melanoma and breast, renal cell, thyroid, colon, larynx, ovary, and bladder carcinomas.4,71,87 Epithelioid cell sarcoma is a sarcoma that occurs on the extremities of young adults and is characterized by a long clinical course of local recurrences and distant metastases.88,89

GENERAL APPROACH TO CUTANEOUS METASTASES Metastatic carcinomas can be classified broadly as adenocarcinoma, squamous carcinoma, undifferentiated carcinoma, or miscellaneous carcinomas. The site of

origin is often unclear from the histologic appearance of the metastasis. Metastatic tumors also include melanomas, sarcomas, and cutaneous involvement by hematopoietic malignancies.6,9 Clinical and histologic features and special studies such as immunoperoxidase staining often help identify the primary site of a cutaneous metastasis, but in some instances, a primary tumor is not identified despite a thorough investigation. As detailed elsewhere in this chapter, the age and gender of the patient and the location, distribution, and clinical appearance of the metastasis are of statistical value in identifying a primary tumor. A history of a known primary tumor can, of course, be of great value. It may be helpful to specifically query the clinician on this possibility if a history of malignancy is not supplied on the request slip because a metastasis may not have entered into the clinical differential because of a nonspecific or atypical clinical appearance, a remote history of malignancy (some malignancies may metastasize decades after treatment of the primary lesion),6 or localization of the metastasis far from the primary tumor. Caution in interpretation is necessary in this area because patients may develop more than one primary malignancy, and a cutaneous metastasis may be the presenting sign of a previously occult primary lesion. Histologic and immunohistochemical comparison of the metastasis with the putative primary lesion (if available) may be of value, with the proviso that a metastasis may be more or less differentiated than and otherwise differ from its associated primary lesion. A series of technical advances has made it possible to apply immunohistochemical methods of antigen detection to routinely fixed and embedded tissues. Convenient application to routine and archival specimens, straightforward correlation with conventional histopathology, identification of a broad range of possible target antigens, and in some instances relatively high specificity have led immunohistochemical staining to largely supplant many histochemical stains and ultrastructural examination as a supplement to morphologic judgments based on gross and hematoxylin and eosin morphology.90,91 Molecular methods such as in situ hybridization, polymerase chain reaction, and gene arrays hold great future promise but as of this writing are not in widespread use in surgical pathology laboratories. As with other techniques, the limitations of immunohistochemical studies must be recognized and the studies interpreted

CHAPTER 35 ■ CUTANEOUS METASTASES

demonstrate tumor cells in blood vessels as well as lymphatics. The obstructed lymphatics are more superficial than the obstructed lymphatics in inflammatory carcinoma.36,39,40 Metastatic lesions from the breast may be pigmented and mimic pigmented basal cell carcinoma or malignant melanoma.41-45 Metastatic tumors of the inframammary crease may present as exophytic nodules suggestive of a primary squamous or basal cell carcinoma or may simulate intertriginous dermatitis.46 Alopecia neoplastica is a form of scarring alopecia that results from a neoplastic process such as metastatic breast carcinoma. Alopecia neoplastica is characterized by alopecia, a smooth surface, and erythema in some instances. Alopecia neoplastica may be the initial presentation of a tumor, primary or metastatic, and must be distinguished from other forms of scarring alopecia47-50 (see Chapter 10). Involvement of the eyelids by metastases has been reported as asymptomatic papules that in eight of 13 cases demonstrated histiocytoid cells resembling xanthoma, histiocytoma, or granular cell tumor cells.51 In 1874, Paget first noted the association of breast carcinoma and “long persistent eczema” of the nipple and areola, now known as Paget disease of the breast.52 A process clinically and histologically similar to Paget disease may involve the skin of areas outside the breast. Although extramammary Paget disease may be a primary adnexal carcinoma, this process sometimes represents epidermal extension of primary visceral carcinomas. Extramammary Paget disease may involve the vulva, male genital area, perianal area, and rarely the axilla, external ear, and eyelid.53-63 Metastases are seen most often in the vicinity of the primary tumor.10 Squamous cell carcinomas of the head and neck tend to metastasize to regional actinically damaged skin, and it may be impossible to distinguish such metastases from primary cutaneous squamous cell carcinomas.5 Breast and lung cancers frequently metastasize to the chest wall.10 Abdominal tumors, such as those arising in the gastrointestinal (GI) tract, ovary, or bladder, most often metastasize to the abdominal wall.10 Umbilical metastases are called Sister Mary Joseph nodules after the nursing superintendent credited with first noting their significance, and they usually result from intraabdominal malignancies, including tumors from the stomach, colon, pancreas, and male and female genitourinary tract.64-70 Lower abdominal and groin metastases may originate from primary

961

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in context. Very few antigens have proven to be totally specific for a given tissue or tumor. Initial studies suggesting high specificity are often followed by larger series that demonstrate a considerably wider and more variable antigen distribution. Malignant tumors may not express detectable amounts of certain antigens characteristically expressed by their related cells of origin (eg, failure of some large cell lymphomas to express CD45RB [leukocyte common antigen [LCA]), and tumors may express antigens not usually seen in their cells of origin eg,(vimentin expression in many spindle cell carcinomas)92 and cytokeratin (CK) expression in epithelioid angiosarcomas.93 Because of these considerations, in most cases when immunohistochemical data are desired, a panel of multiple markers should be applied to confirm or refute the diagnosis or narrow the differential diagnosis. This panel should be chosen in light of a probable diagnosis or reasonable differential diagnosis constructed on the basis of clinical and histopathologic features, and the panel should include markers chosen to both confirm and refute specific diagnoses. When evaluating a neoplasm that is undifferentiated on routine examination, an initial panel of antibodies may be designed to classify the lesion into one of a number of broad categories, and secondary and sometimes tertiary panels are then applied to confirm the initial judgment or to further subclassify the process.90,94 The pathologist’s general approach to a metastatic tumor when the origin is not obvious is to first determine the cell line of differentiation (carcinoma, lymphoma, melanoma, sarcoma, or germ cell) and then to more narrowly classify the process by expression of various classes of antigens such as intermediate filament proteins (CKs, vimentin, neurofilament proteins, glial fibrillary acidic protein); supplemental antigens such as carcinoembryonic antigen (CEA) or epithelial membrane antigen (EMA); and cell-specific products, structures, or receptors such as neuroendocrine granule constituents, prostate-specific antigen (PSA), or thyroid transcription factor 1 (TTF-1). Because most cutaneous metastases are carcinomas,9 the expression of CK subsets as recognized by broad-spectrum antibodies such as MNF116, broad-spectrum antibody cocktails such as AE1/AE3, or more specific antibodies such as CAM5.2 and antibodies to CK7 and CK20 is often of diagnostic utility.90,91 Simple epithelial keratins, as may be detected by antibodies such as CAM5.2, are expressed in almost all

simple (nonstratified), stratified, and ductal epithelial tissues, and these CKs are expressed by almost all mesotheliomas and carcinomas except squamous cell carcinomas.90,91 Complex keratins of high-molecular-weight such as CK5/6 are expressed in stratified epithelia; myoepithelial cells; duct-derived epithelium; and transitional, ovarian, and mesothelial tissues and their associated malignancies.90,91 CK expression, as detected with AE1/AE3, 34BE12/CK903, or MNF116, is a useful screening test for epithelial tumors, including many carcinomas.90-92 Antibodies to CK5/6 stain many spindle cell squamous cell carcinomas as well as conventional squamous cell carcinomas, epithelial mesotheliomas, many transitional cell carcinomas and undifferentiated large cell carcinomas, and some adenocarcinomas. Some tumors that stain with antibodies to CK5/6 do not stain well with screening antibodies such as AE1/AE3.92,96-98 As covered in more detail under the discussions of individual tumors, differential expression of CK7 and CK20 is often useful in combination with other antigens in identifying likely primary sites of metastatic carcinomas, including some adenocarcinomas, small cell carcinomas, transitional carcinomas, and squamous cell carcinomas.98,99 CK20 is also very useful in the evaluation of possible Merkel cell carcinomas.100-103 CKs are well documented to occur in some mesenchymal and neuroectodermal tumors, including epithelioid sarcomas, epithelioid angiosarcomas, leiomyosarcomas, and melanomas.92,93 As with the characteristics of vimentin (discussed later), this fact emphasizes the importance of a panel approach and of correlation of immunohistochemical findings with the clinical setting and histopathology. Vimentin is primarily associated with mesenchymal tissues, but it is also expressed in benign and malignant melanocytes (of neuroectodermal origin)104 and in many malignancies not of mesenchymal origin. Many carcinomas, including renal cell carcinoma, endometrial adenocarcinoma, thyroid follicular carcinoma, and many spindle cell carcinomas, express vimentin, which limits the diagnostic utility of vimentin expression as a marker of mesenchymal differentiation.90,91 Desmin and h-caldesmon are specific markers for myogenic differentiation and hence for benign and malignant tumors of smooth and skeletal muscle, myofibromatoses, and some neoplasms of “divergent” phenotypes such as primitive neuroectodermal tumors and desmoplastic small cell tumors.105 Neurofilament proteins may be useful in the detection

of neuroblastoma variants and of neuroendocrine carcinomas, including Merkel cell carcinomas.100,106,107 Glial fibrillary acidic protein (GFAP) is not usually relevant to the evaluation of cutaneous metastases. Many cutaneous metastases represent metastatic malignant melanoma.10 Markers useful in the evaluation of possible metastatic malignant melanoma include sensitive but less specific antigens such as vimentin and S-100 protein and more specific monoclonal antibodies such as the gp100/PMel 17–related monoclonal antibodies HMB-45 and MART1/Melan-A, tyrosinase-related antibodies, and microphthalmia transcription factor protein.104 These markers are discussed in more detail in the chapters on melanocytic lesions (see Chapter 27). In general, the more specific melanocyte markers tend to label a substantially smaller proportion of spindle cell or desmoplastic lesions than do the less specific melanoma markers.104,108 The oncofetal protein carcinoembryonic antigen (CEA) and EMA are markers that can be useful for the detection of glandular differentiation in primary and metastatic cutaneous neoplasms. The polyclonal antibodies to CEA (p-CEA) that many literature studies are based on often cross-react with tissue-nonspecific cross-reacting antigen and biliary glycoprotein I.94,109 Some monoclonal antibodies to CEA (m-CEA), such as CEAD14, have a narrower range of reactivity then p-CEA, which may be of diagnostic utility. For example, primary adenocarcinomas of the lung and colorectal carcinomas stain for both p-CEA and CEAD-14, but most ductal carcinomas of the breast react with p-CEA but not CEAD-14.94,109,110 Evaluation of CEA staining in a metastasis can help narrow the search for a primary site. Antibodies to EMA were originally raised against human milk fat globule proteins. EMA is expressed in many benign and malignant lesions exhibiting glandular differentiation, including many metastatic adenocarcinomas, and occasional epithelial malignancies stain for EMA but not for CKs.111,112 As with many markers, EMA is not totally specific. EMA is expressed by many epithelial malignancies that do not demonstrate morphologic glandular differentiation, including many squamous cell carcinomas, small cell carcinomas, and mesotheliomas. EMA is also expressed by a number of mesenchymal lesions, including perineural cells and their associated neoplasms, many leiomyosarcomas, and many large cell anaplastic lymphomas.111,112

gender-specific prevalence of primary breast cancer.10 CLINICAL FEATURES Cutaneous metastases of breast cancer frequently occur on the trunk, but they are seen with lower frequency on other parts of the body such as the upper extremities and scalp10 In addition to the previously described clinical presentations that are most specifically associated with metastatic breast carcinoma, less specific non-inflamed cutaneous nodules may be seen. Although infiltrating ductal carcinoma is the most common form of primary and metastatic breast cancer, breast cancer can have many other patterns, including lobular, tubular, cribriform, mucinous, and medullary variants.167 HISTOPATHOLOGIC FEATURES The histopathology of breast carcinoma metastatic to the skin may closely resemble the corresponding histologic pattern of the primary tumor. Some clinical patterns of cutaneous metastasis reflect additional histopathologic features that may develop in the metastasis. In inflammatory carcinoma, tumor cells fill dermal lymphatics, and in some cases, lymphatics in the subcutaneous fat (Fig. 35-1).30,35 Telangiectatic carcinoma has tumor cells in more superficially located lymphatics and blood vessels congested with erythrocytes.36,39 In nodular metastases, some stromal fibrosis may be present,

but tumor cells predominate.6 In contrast, cancer en cuirasse is characterized by a smaller proportion of tumor cells set in a prominent fibrous stroma and alopecia neoplastica by dermal fibrosis, an infiltrate of tumor cells, and loss of hair follicles.6,36,37,47-49 Tumor cells of primary and metastatic infiltrating ductal carcinoma are variably pleomorphic. The tumor cells infiltrate their stroma in sheets or cords that sometimes demonstrate glandular structures, signet ring cells, or both (Figs. 35-1 and 35-2).167 Tumor cells of infiltrating lobular carcinoma are small round to ovoid cells with scant cytoplasms, eccentric nuclei with little pleomorphism, and few mitoses. Intracytoplasmic lumina are more frequent in lobular carcinoma than in infiltrating ductal carcinoma and are best seen with histochemical special stains such as the PAS–Alcian blue stain or with immunohistochemical stains such as antibodies to EMA. The single-file pattern of infiltration that is associated most often with lobular carcinoma consists of cords of cells arranged in one-cell width files in a fibrotic stroma; this pattern of infiltration is not associated exclusively with lobular carcinoma (Fig. 35-3).38,167,168 Mucinous carcinoma (also referred to as colloid or mucoid carcinoma) consists of islands of uniform, small epithelial cells with hyperchromatic nuclei and a cribriform or papillary pattern floating in lakes of mucin (Fig. 35-4). It can be difficult or

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Some relatively specific markers that may be useful in the evaluation of cutaneous metastases include thyroglobulin and TTF-1 for thyroid carcinomas (TTF-1 also stains many carcinomas of the lung)100,101, 103,113-120; mammaglobin and gross cystic disease fluid protein (GCDFP15) for breast cancer (these antibodies also stain many primary cutaneous sweat gland tumors)95,119,121-126; chromogranin, synaptophysin, and specific peptide hormones such as bombesin and glucagon for neuroendocrine tumors such as small cell (oat cell) neuroendocrine carcinoma of the lung and Merkel cell carcinoma107,127-132; calretinin, podoplanin, and D2-40 for epithelioid mesothelioma133-139; CDX2 and villin for GI tumors95,119,122,140149 ; renal cell carcinoma marker (RCCMA), CD10, and PAX-2 for renal cell carcinoma150-153; PSA and prostate-specific membrane antigen (PSMA) for prostate cancer95,142,154-158; placenta-like alkaline phosphatase (PLAP) and human chorionic gonadotropin (hCG) for germ cell neoplasms26,159; CD45RB (LCA)160 PAX5,161 and CD30162 for malignant lymphomas; MyoD1 and myogenin for skeletal muscle105,163; Wilms tumor protein (WT1) for Wilms tumor and desmoplastic small round cell tumor (also positive in malignant mesotheliomas and some Müllerian tumors)117,164-166; and CD99 for Ewing sarcomas and peripheral neuroectodermal tumors (PNETs).102,106,164 (CD99 also stains many lymphoblastic lymphomas, including tumors that exhibit little or no reactivity for LCA.) Some of these markers are discussed below in conjunction with their associated malignancies. Many of these antigens are probably more specific for particular lines of cellular differentiation than is the case for most of the antigens such as CKs, EMA, and CEA described in the preceding paragraphs. However, it should be kept in mind that the known distribution of tumor antigens tends to broaden over time as they are subjected to widespread use and further study, that most antigens are not absolutely restricted to a specific tissue or tumor, and that the expression of many relatively specific antigens tends to be lost in highgrade malignancies.90,91

SITES OF ORIGIN OF METASTATIC TUMORS

Breast Carcinoma Metastases from breast carcinoma account for 71% of cutaneous metastases in women and 2.4% of cutaneous metastases in men, with this difference owing primarily to the difference in

 FIGURE 35-1 Metastatic inflammatory breast carcinoma. Nests of tumor cells fill and expand lymphatics. Tumor cells also infiltrate between dermal collagen bundles.

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 FIGURE 35-2 Metastatic infiltrating ductal breast carcinoma, low power. Infiltration of tumor cells in a single file between dermal collagen bundles results in a resemblance to granuloma annulare.

impossible to distinguish primary cutaneous mucinous carcinoma from mucinous carcinoma metastatic from the breast or GI tract on the basis of histology, but immunohistochemistry can be

very useful in this regard.169-173 Other patterns of primary breast cancer, such as alveolar, solid, tubular, tubulolobular, cribriform, and medullary, are seldom seen in cutaneous metastases.

 FIGURE 35-3 Metastatic infiltrating ductal breast carcinoma, high power. Cytological atypia and intracytoplasmic duct formation are better seen at high power.

DIFFERENTIAL DIAGNOSIS The various patterns of breast carcinoma each have their own list of conditions from which a cutaneous metastasis must be distinguished. A history of primary breast carcinoma is helpful, but patients may have more than one malignancy, so care must be taken not to overlook alternative cutaneous primary or metastatic tumors. Fibrotic nodules with diffuse infiltration by sheets and cords of uniformly atypical cells may suggest dermatofibroma, sarcoma, and small cell or desmoplastic melanoma. A primary ductal eccrine adenocarcinoma may be considered when solid cords, tubules, and lumina formation are noted (see Chapter 29). When single-file rows or cords of deeply basophilic cells predominate, one may need to consider primary Merkel cell or metastatic neuroendoctine carcinoma, hematolymphoid malignancies, sclerosing or morpheaform basal cell carcinoma, and malignant sweat gland tumors.174-176 When there is gland formation with mucin, one should consider malignant sweat gland tumors as well as adenocarcinomas metastatic from locations other than breast such as GI tract, lung, salivary gland, or lacrimal gland.5,174 When islands of tumor cells are surrounded by abundant mucin, one should consider primary mucinous carcinoma of eccrine glands as well as metastases from the breast, lung, or large intestine.169-172,177,178 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Breast cancer and Paget disease of the breast commonly express low-molecular-weight CKs, including CAM5.2 and CK7. Many primary and metastatic breast tumors also express high-molecular-weight CKs such as CK5/6. CK20 expression is uncommon. Breast tumors often express pankeratin markers (eg, AE1/AE3), EMA, gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin/MGB1, p-CEA but not usually m-CEA, and estrogen and progesterone receptors.54,58-183 The presence of mammaglobin, GCDFP-15, and progesterone or estrogen receptors and the absence of CK20, m-CEA, and TTF-1 differentiate most metastatic breast cancers from adenocarcinomas metastatic from other common primary sites, especially if ovarian cancer can be excluded clinically (ie, ovarian cancer can exhibit tremendous phenotypic overlap with breast cancer). Mammaglobin and GCDFP-15 have recently been reported to occur in some primary adenocarcinomas of the lung, but these tumors can be separated from

patients with lung cancer develop cutaneous metastases, such metastases are noted before the lung primary tumor was first recognized in 52% to 60% of patients.4,10,21,207 The chest, back, and abdomen are the most frequent sites of cutaneous metastasis of lung cancer, followed by the scalp and neck.5

 FIGURE 35-4 Metastatic mucinous breast carcinoma. Nests of relatively bland tumor cells float in pools of mucin.

breast cancer because they express TTF-1,182,184 Paget disease and epidermotropic metastases of breast cancer may contain melanin and mimic melanoma clinically and histopathologically,41,42,44,45 and approximately 50% of breast carcinomas are positive for S-100 protein,185 which can pose diagnostic pitfalls. Epidermotropic metastases have also been reported from primary sites other than breast, including the prostate, colon, and skin.186-189 A panel of markers, including CKs, CEA, EMA, and more specific melanoma markers such as HMB-45 and MART-1, will allow the exclusion of melanoma, but it should be recognized that epidermotropism may be seen in metastatic as well as primary melanoma.17,108,190,191 There is considerable morphologic and immunohistochemical homology between some carcinomas of the breast, skin, and salivary glands.175,192 Malignant adnexal neoplasms with eccrine or apocrine differentiation may express CAM5.2, CK7, CK5/6, and other high and low-molecular-weight CKs, EMA, CEA, mammaglobin, GCDFP-15, S-100 protein, and estrogen and progesterone receptors,108,121,174,192-197 contributing to the often considerable difficulty of distinguishing between primary or metastatic sweat gland carcinomas and metastatic breast cancer. Cutaneous adenocarcinomas can be taken as primary in cases in which an in situ component can be

demonstrated. Many, but not all, primary sweat gland carcinomas contain an in situ component that may be highlighted by basal cell and myoepithelial markers such as p63, CK 5/6, and calponin.169,174,177 A number of recent articles have suggested that a p63-positive, CK 5/6-positive, and CK20-negative immunophenotype strongly favors a primary adnexal tumor over a metastasis from a noncutaneous primary tumor.96,169,173,198-201 Immunoreactivity for D2-40 and other podoplanin-related antibodies also seems to be much more common in primary skin tumors than in metastases.202,203 However, it must be emphasized that none of these markers are totally sensitive or specific and that clinical information is often necessary to distinguish with confidence between primary adnexal carcinomas and cutaneous metastases.98,136,202,204-206

LUNG CARCINOMA In older case series, cutaneous metastases from lung carcinoma represent 12% to 24% of cutaneous metastases in men and 2% to 4% in women. More recent series have shown an increase in cutaneous metastases from lung cancer in women, reflecting the increasing incidence of primary lung cancer in women.11,12 Although only 1.5% of

HISTOPATHOLOGIC FEATURES The carcinomas of the lung most commonly observed as cutaneous metastases are adenocarcinoma (30%), squamous cell carcinoma (30%), large cell undifferentiated carcinoma, and small cell neuroendocrine (oat cell) carcinoma. Metastases of bronchioalveolar and mucoepidermoid carcinomas, carcinoid tumors, and pulmonary sarcomas are much less commonly seen.5,6,85,207,208 Metastatic squamous cell carcinomas from the lung are usually moderately to poorly differentiated. The tumor cells are dispersed in sheets and islands of epithelial cells with varying degrees of keratinization and intercellular bridges, often with only a small number of whorls of squamous cells (pearls). More atypical features of the keratinizing cells may include large, bizarre cells, spindle cells, and clear cells with abundant mitotic figures. Central necrosis may occur in larger foci of tumor. Metastatic pulmonary adenocarcinomas are usually moderately differentiated tumors that may include small tubular and glandular structures and scattered, individual tumor cells containing intracytoplasmic mucin (Fig. 35-5). The tumor cells tend to have pleomorphic, hyperchromatic nuclei with numerous mitotic figures. Large cell undifferentiated tumors consist of sheets of large pleomorphic tumor cells with abundant cytoplasms, prominent nucleoli, and numerous mitoses. The giant cell variant has monster cells with bizarre nuclei and cells that frequently contain leukocytes. The clear cell variant is composed of sheets and islands of clear cells without other forms of differentiation. Small cell neuroendocrine carcinomas are composed of islands, trabeculae, and sometimes

CHAPTER 35 ■ CUTANEOUS METASTASES

CLINICAL FEATURES The most common presentation of cutaneous metastatic lung cancer is a localized cluster of discrete, firm, nontender, flesh-colored nodules of recent onset and rapid growth to a certain size followed by a stationary period.6 Some cutaneous metastases from the lung have a vascular appearance clinically, suggesting hemangioma, pyogenic granuloma, or Kaposi sarcoma.

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A

B

 FIGURE 35-5 Metastatic adenocarcinoma of the lung, low power. (A) Irregular glands infiltrate a fibrotic stroma. The process is centered in the reticular dermis. (B) Metastatic adenocarcinoma of the lung, high power. An irregular architecture, fibrotic stroma, and atypical cytology are seen.

rosettes of mildly pleomorphic cells that are somewhat larger than lymphocytes, with scant cytoplasms and hyperchromatic nuclei. There are frequent mitoses, and crush artifact is a common characteristic of these cells.209 DIFFERENTIAL DIAGNOSIS Cutaneous metastases consistent with metastatic lung carcinoma must be correlated with the clinical history of the patient and distinguished from other tumors with a similar histopathologic pattern. Squamous cell carcinomas metastasizing to the skin usually arise from the lung, oral cavity, or esophagus and less often from the uterine cervix, penis, or a distant skin site. Cutaneous metastases classically do not demonstrate the association with the overlying epidermis commonly seen in primary cutaneous squamous cell carcinomas, but squamous cell carcinomas metastasic to the skin have been reported to show direct continuity with the epidermis, epidermotropism, and even a Bowenoid histologic appearance.188,189,210-212 Squamous cell carcinoma of the esophagus and (rarely) esophageal adenocarcinoma may present as cutaneous metastases. Squamous cell carcinomas metastatic from the oral cavity are often better differentiated than those metastatic from the lung, usually appear in the region of the head and neck, and usually develop after the primary tumor has been recognized.6 Cutaneous metastases of squamous cell carcinoma from other sites usually occur after recognition of the primary tumor. Most adenocarcinomas metastatic to the skin originate from the large intestine, lung, or breast. Those from the large intestine are often better differentiated than those from the lung. Metastatic

colonic adenocarcinomas often show well-formed mucinous glandular epithelium or even large pools of mucin with a small amount of epithelium and hence resemble mucinous carcinoma of the skin and metastatic mucinous carcinoma from the breast. Mucinous carcinoma of colonic origin is much more likely then other mucinous carcinomas to show zones of so-called “dirty” necrosis (eosinophilic necrotic foci containing nuclear debris).177 The signet ring cells commonly associated with adenocarcinoma of the stomach are seen only occasionally in metastases from the lung. Cutaneous metastatic lesions of undifferentiated type are usually from the breast or lung and less often from the stomach, liver, or urinary bladder. Large cell undifferentiated lung cancer and its giant cell, clear cell, and large cell neuroendocrine variants need to be differentiated from sarcomas such as rhabdomyosarcoma and malignant fibrous histiocytoma, renal cell carcinoma, sebaceous carcinoma, neuroendocrine tumors from other sites, and melanoma.5,6,209 The differential diagnosis of small cell neuroendocrine carcinoma includes a variety of small round cell tumors, including cutaneous adnexal carcinomas, primary or metastatic melanoma, primary or other metastatic neuroendocrine tumors such as Merkel cell carcinoma primary to the skin and neuroendocrine carcinomas metastatic from another organs, malignant lymphoma, a Ewing sarcoma family tumor, and rhabdomyosarcoma.100,101,105,128,164,209,213-217 SPECIAL STAINS AND IMMUNOHISTO-CHEMISTRY Immunohistochemistry is not currently useful in determining the site of

origin of most squamous cell carcinomas. Squamous cell carcinomas of the lung usually stain for CKs in a similar pattern to squamous cell carcinomas of other organs. Most of these tumors are AE1/AE3 and CK5/6 positive and CK7 and CK20 negative, most stain for EMA, and about half stain with polyclonal antibodies to carcinoembryonic antigen (p-CEA).94,96,128,201 Squamous cell carcinomas of the lung express TTF-1 less commonly then do adenocarcinomas of the lung.218 Squamous carcinomas of the lung frequently show spindle cell features. Neoplastic spindle cells in squamous carcinomas primary to the lung and many other locations often coexpress keratin and vimentin, and these carcinomas may express predominantly vimentin.91,128 Expression of p63 may provide evidence that a vimentin-positive, keratin-negative primary or metastatic spindle cell malignancy is a carcinoma rather than a sarcoma.96,198,201,218-221 Primary pulmonary adenocarcinomas usually express CKs (commonly AE1/AE3 and CK7 positive and CK5/6 and CK20 negative), EMA, m-CEA, p-CEA, p63, and TTF-1 but not GCDFP-15 or mammaglobin.94,119,120,122,126,128,182,209,218 TTF-1 is the most specific antibody for pulmonary adenocarcinoma (TTF-1 is also positive in many other lung cancers and in most thyroid cancers), but TTF-1 staining is negative in 25% to 40% of pulmonary adenocarcinomas. Positive staining for TTF-1, m-CEA, and CK7 and negative staining for mammaglobin, GCDFP-15, and CK20 are consistent with a lung primary in a metastatic adenocarcinoma. Large cell undifferentiated carcinomas from the lung are usually positive for AE1/AE3, CK5/6, and p63 and

gallbladder and bile duct have been noted at the time that the initial tumor was recognized and as late as 40 years after resection of the primary tumor. Cutaneous metastases from the stomach and pancreas usually occur before the discovery of the primary tumor. The usual sites of metastases from GI carcinomas are the abdominal wall, the perineum, and the umbilicus (Sister Mary Joseph nodule). In one series, 10% of metastases to the abdominal wall occurred in the umbilicus, and 28% of those tumors were of gastric origin.226 Esophageal carcinomas occasionally metastasize to the skin. These are usually squamous cell carcinomas that metastasize to the upper trunk and neck as single or multiple nodules, but distant metastases and metastases of esophageal adenocarcinomas have also been reported.10,227,228 CLINICAL FEATURES Cutaneous metastases from the colon and rectum may present as flesh-colored sessile or pedunculated nodules, inflammatory carcinoma, grouped vascular nodules, or occasionally a nodular and inflamed perianal lesion suggestive of hidradenitis suppurativa.9,32,Eleven of 18 patients in one study had only local metastases, and most of these occurred in an abdominal incision site.10 Colorectal carcinoma may also metastasize to a colostomy site.9 Gastric, pancreatic, and gallbladder carcinomas that metastasize to the skin usually present as nodules, sclerodermoid plaques, or Sister Mary Joseph nodules.6,10,64,67,69,70,226,229-231 At least one case of gastric carcinoma that metastasized

to the scalp was associated with alopecia (alopecia neoplastica).6 HISTOPATHOLOGIC FEATURES Cutaneous metastases of colorectal carcinomas are predominantly well-differentiated, mucinsecreting adenocarcinomas that may have a pattern of mucinous carcinoma in some cases (see Fig. 35-4). Poorly differentiated metastases are less common, but on rare occasions, metastatic colorectal carcinomas may be so anaplastic that it is difficult to discern that they are of epithelial origin.5,6 Cutaneous metastases from the stomach are frequently anaplastic, infiltrating carcinomas in a loose or fibrotic stroma with varying numbers of signet ring cells containing intracytoplasmic mucin (Fig. 35-6). Well-formed acini and mucinous carcinoma are occasionally observed. Esophageal carcinomas that metastasize to the skin are usually squamous cell carcinomas.10 DIFFERENTIAL DIAGNOSIS Most cutaneous metastases from the GI tract are adenocarcinomas, and those from the large intestine are often well-differentiated mucin-secreting tumors.5,6,11 Although metastatic mucinous carcinomas from the GI tract usually originate from the large intestine, these tumors may be histologically indistinguishable from primary mucinous carcinoma of the skin and metastases from other organs such as the breast, lung, or less often other sources such as salivary gland, lacrimal gland, pancreas, esophagus, or ovary. Cutaneous metastases of visceral mucinous

CHAPTER 35 ■ CUTANEOUS METASTASES

negative for CK20, S-100 protein, and LCA. They are variable with regard to CK7, EMA, p63, and CEA and may coexpress vimentin.128,209 Large cell undifferentiated carcinomas must be differentiated from sarcomas such as rhabdomyosarcoma, which is positive for myoid markers such as desmin, MyoD1, and myogenin; lymphoma, which is usually positive for LCA; and melanoma, which is positive for S-100 protein and often for MART-1 and HMB-45. Small cell neuroendocrine carcinomas from the lung usually stain with AE1/AE3 and with antibodies to low molecular CKs in a punctate pattern. These tumors often stain for synaptophysin and sometimes for chromogranin A and CK7.128 CK20 and neurofilament protein staining in a punctuate perinuclear pattern is much more common in Merkel cell carcinomas than in neuroendocrine carcinomas of the lung, and CK7 staining is less common in Merkel cell carcinomas than in lung carcinomas.99,100,222 Positive staining for CK7 and TTF-1 and negative staining for CK20 and neurofilament protein favors metastatic small cell carcinoma of lung origin over Merkel cell carcinoma.99-101,117,120,222,223 Small cell carcinomas from areas other than the lung and skin such as the gut, uterine cervix, and salivary glands may also express TTF-1 and less commonly CK20.101 Although positive staining with antibodies to CD 56 is often used to help identify natural killer (NK) cell lymphomas, many neuroendocrine carcinomas, including primary neuroendocrine carcinomas of the lung and Merkel cell carcinomas, stain strongly with antibodies to CD 56.100,224 Many Merkel cell carcinomas also stain with antibodies to terminal deoxynucleotidyl transferase (TdT), a DNA polymerase that is usually considered to be sensitive and specific antibody for blastic hematologic malignancies. It is not clear at this time whether neuroendocrine malignancies of other organ systems express TdT.225

GASTROINTESTINAL CARCINOMA Carcinomas of the colon and rectum are among the most common primary tumors, and colorectal carcinomas are among the most frequent visceral tumors to metastasize to the skin in both men and women, accounting for 11% to 19% of cutaneous metastases in men and 1.3% to 9% in women. 4-6,9-11,64,67,70 Carcinoma of the large intestine is usually discovered before the cutaneous metastasis. Cutaneous metastases from

 FIGURE 35-6 Sister Mary Joseph nodule resulting from metastasis of an adenocarcinoma of gastrointestinal primary. Variable-sized glands lined by cytologically atypical cells infiltrate a fibrotic stroma.

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carcinomas usually occur in the setting of long-standing, disseminated disease. Mucinous carcinoma of colonic origin is much more likely than other mucinous carcinomas to show zones of so-called “dirty” necrosis.177 Immunohistochemical demonstration of an in situ component can be of great value in proving that a mucinous carcinoma in the skin is primary.169-173 Less well-differentiated adenocarcinomas are more likely to come from sites in the GI tract other than the large intestine such as the stomach, pancreas, or gallbladder, or from other areas such as lung, breast, prostate, endometrium, ovaries, and endocervix. Gastric carcinomas are most often anaplastic, with varying degrees of cellularity and signet ring cells set in a loose stroma. Especially in women, cutaneous metastases with this signet ring pattern are more likely to come from the breast and may rarely originate in other organs. SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY GI adenocarcinomas commonly are reactive with AE1/AE3 and with antibodies to CK20 and express p-CEA, m-CEA, and EMA but not mammaglobin, GCDFP-15, or estrogen and progesterone receptors.99,232-235 Colorectal carcinomas are usually CK20 positive and CK7 negative. Pancreatic, mucinous ovarian, and transitional cell carcinomas often strongly coexpress CK20 and CK7, as do some Merkel cell carcinomas. Many primary and metastatic GI carcinomas express homeobox transcription factor CDX2 and brush border protein villin.95,119,122,140-149 The latter markers are not usually expressed by primary tumors of the breast, lung, skin, prostate, or urothelium, but they may be expressed by adenocarcinomas of the ovary, endometrium, kidney, and bladder. Gastric adenocarcinomas commonly express p-CEA, m-CEA, AE1/AE3, and low-molecular-weight CKs such as CAM5.2, but gastric carcinomas are highly variable in their CK7 and CK20 staining patterns. Positive staining (when present) for CDX2, m-CEA, and CK20 and lack of reactivity with mammaglobin, GCDFP-15, or estrogen or progesterone receptors can help distinguish metastatic gastric adenocarcinomas, including signet ring carcinomas, from metastatic breast cancer. Hepatocellular carcinomas usually stain with CAM5.2 and HepPar1, and low-grade lesions often show a canalicular staining pattern with p-CEA. Hepatocellular carcinomas often do not stain with antibodies to CK 7, CK 20, or m-CEA, and many of these tumors stain weakly or not at all with AE1/AE3.232,234,235

Cholangiocarcinomas (carcinomas of the intrahepatic bile ducts) and extrahepatic pancreatobiliary adenocarcinomas are usually positive for AE1/AE3, CK7, CAM5.2, p-CEA, m-CEA, and CDX2, and many cholangiocarcinomas are CK20 negative.

ORAL CAVITY AND SINONASAL CARCINOMAS In one study, 11.1% of cutaneous metastases in men and 2.3% in women originated from the oral cavity and nasal sinuses. Oral cavity and nasal sinuses carcinomas that metastasize to the skin are usually squamous cell carcinomas that present after the diagnosis of the primary tumor, and cutaneous metastases are usually localized to the head and neck.5 CLINICAL FEATURES Cutaneous metastases derived from neoplasms of the oral and sinonasal cavities are frequently single or multiple nodules with or without ulceration. The cutaneous metastases occurred at the site of surgery in 10 of 18 patients in one series.10 Direct extension of tumor and implantation in surgical scars are often considerations in this setting. HISTOPATHOLOGIC FEATURES Most cutaneous metastases of oral cavity and sinonasal carcinomas are moderately to well-differentiated squamous cell carcinomas presenting in the deeper dermis and subcutaneous fat without connection to the overlying epidermis. Tumor cells sometimes involve perineural spaces and lymphatic vessels.5 Nasopharyngeal squamous cell carcinomas include keratinizing, nonkeratinizing, and undifferentiated variants. The undifferentiated variant may have prominent non-neoplastic lymphoid and plasma cell components that may obscure the epithelial nature of the tumor.236Basaloid squamous cell carcinomas may occur in a variety of upper and lower aerodigestive tract sites and frequently follow an aggressive clinical course. Basaloid squamous cell carcinomas are composed of collections of basaloid cells with pleomorphic, hyperchromatic nuclei that may demonstrate peripheral nuclear palisading. They often demonstrate single cell and comedo necrosis, focal squamous differentiation, and associated conventional squamous cell carcinoma and may have a pseudoglandular appearance.236, 237 DIFFERENTIAL DIAGNOSIS Squamous cell carcinomas that metastasize to the skin usually originate in the oral cavity,

esophagus, or lung, with the lung being the most common site of origin.4-6 The primary tumor less frequently originates in other sites such as the uterine cervix or penis or a distant cutaneous site. Cutaneous metastases of squamous cell carcinomas and basaloid squamous cell carcinomas may show continuity with the overlying epidermis and epidermotropism mimicking Bowen disease.188,210,212 Conversely, an epidermal connection is often not apparent in ulcerated primary cutaneous squamous cell carcinomas, especially in small biopsies. Therefore, in some cases, it may not be possible to histologically or immunohistochemically distinguish between a cutaneous metastasis and a primary squamous cell carcinoma. 188,210,212 Basaloid squamous cell carcinomas must be distinguished from adenoid cystic carcinoma, small cell neuroendocrine carcinoma, and adenosquamous or mucoepidermoid carcinoma.213,236,237 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Similar to squamous cell carcinomas derived from other sites, primary and metastatic oral cavity and sinonasal carcinomas usually stain AE1/ AE3, CK5/6, EMA, and p63 and may coexpress or predominately express vimentin in spindle cell areas.213,236,237 Basaloid squamous cell carcinomas usually demonstrate focal squamous differentiation, stain with AE1/AE3 and antibodies to CK5/6 and p63, and may stain for low-molecularweight CKs such as CAM5.2, CK7, and EMA, but not glandular or neuroendocrine markers.

URINARY TRACT TUMORS A total of 4.6% of cutaneous metastases have been reported to originate from the kidney and 8.2% from the urinary bladder.10 Metastases from either organ are seen more frequently in men than in women. Metastases from the urinary bladder usually occur after recognition of the primary tumor. Cutaneous metastases from renal cell carcinoma may be the first sign of the malignancy, but alternatively may occur 10 or more years after resection of the primary tumor.6,10,71 CLINICAL FEATURES Cutaneous metastases from renal cell and transitional cell carcinomas may occur as local metastases, often in surgical scars, or as distant metastases. Metastases from renal cell carcinoma (hypernephroma) are seen most commonly on the head and neck, particularly the scalp, and cutaneous

metastatic transitional cell carcinoma presents most often on the trunk and extremities.10,14,16,22,71,238,239 Renal cell carcinoma may metastasize as solitary or widespread dermal nodules. The nodules can be flesh colored, but they are more commonly violaceous with prominent vascularity resembling Kaposi sarcoma or pyogenic granuloma. Transitional cell carcinoma metastases usually present as one or more fleshcolored dermal nodules. Less common presentations of metastases include zosteriform lesions, warty papules, and inflammatory plaques.

A

DIFFERENTIAL DIAGNOSIS Renal cell carcinoma must be differentiated from other clear cell carcinomas that occasionally metastasize to the skin. These include primary tumors of the lung, liver, ovary, endometrium, cervix, and vagina.12,243 Primary tumors of the skin that may resemble renal cell carcinoma include clear cell hidradenoma (eccrine acrospiroma) and sebaceous tumors.244,245 In contrast to renal cell carcinoma, clear cell hidradenoma is usually multilobular and has prominent ductal structures but is not associated with prominent vascularity, hemorrhage, or hemosiderin deposition. Sebaceous tumors are not as vascular as renal tumors and have fine, vacuolated cytoplasms. Transitional cell carcinomas from the urinary tract that metastasize to the skin usually are moderately to poorly differentiated and may be difficult to differentiate from similar epithelial tumors from other sites and primary or metastatic cutaneous squamous cell carcinoma. Papillary metastases are more suggestive of a primary tumor derived from the urinary tract but must be differentiated from transitional cell carcinomas from other sites such as the ovary and nasal pharynx.12,240,242 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Most urothelial carcinomas, including many metastases, express p63 and high-molecular-weight CKs such as CK5/6 and 34BE12.98,219,246 Most urothelial carcinomas also stain positively for

both CK7 and CK20. This pattern is also seen in many pancreatic and some mucinous ovarian carcinomas but is uncommon in other settings.99,246 Uroplakins are a family of transmembrane proteins present only in urothelia. Expression of uroplakins may be specific for urothelial carcinomas, but as with many other tissue-specific markers, uroplakin expression is reduced or absent in many highgrade and metastatic lesions.246-248 Renal cell carcinomas usually stain with broad-spectrum anti-CK antibodies such as AE1/AE3 and with antibodies to low-molecular-weight CKs (CAM 5.2), EMA, and vimentin but not for CK5/6, p63, CK7, CK20, CEA, or S-100 protein.96,240,246 Vimentin expression is much less common in hidradenomas than in renal cell carcinomas. Hidradenomas may focally express CK7 and CEA, as may clear cell carcinomas from other locations such as the lung.245,249,250 Sebaceous carcinomas stain with antibodies to broad-spectrum CKs, low-molecular-weight CKs including CAM 5.2 and CK7, and EMA but not usually with specific or monoclonal antibodies to CEA.192,244,251,252 Most primary hidradenomas and sebaceous neoplasms stain with antibodies to p63, CK5/6, and D240/podoplanin, and most metastatic renal carcinomas do not stain with these antibodies.173,198-200,202,203,220 Many metastatic renal carcinomas express CD10, but this antigen is also expressed by many primary cutaneous tumors, especially sebaceous tumors.181,253,254 Renal cell carcinoma marker (RCC-Ma) appears to be more specific but is also less sensitive than CD10 as a marker for metastatic renal carcinoma to the skin.150

CHAPTER 35 ■ CUTANEOUS METASTASES

HISTOPATHOLOGIC FEATURES The most common renal cell carcinomas are clear cell adenocarcinomas.240 Metastatic nodules in the dermis are composed of large polyhedral cells with clear to finely granular cytoplasm and a central nucleus with little pleomorphism (Fig. 35-7). The cells are arranged in sheets and cords with some gland formation and often a papillary component. The tumor cells are embedded in a delicate, highly vascular stroma containing extravasated erythrocytes and hemosiderin.240,241 Transitional cell carcinoma metastatic to the skin usually consists of well-demarcated sheets and strands of large oval cells with small amounts of faintly basophilic to clear cytoplasm, some nuclear pleomorphism, and varying numbers of mitoses.12,240,242 These tumors may demonstrate focal squamous differentiation and papillary configurations with varying thicknesses of atypical epithelial cells covering a fine fibrovascular core. The metastatic tumor cells may be located in the dermis in between collagen bundles or sometimes

associated with a desmoplastic stroma, in the subcutaneous fat, or in the lumina of vessels.

B

 FIGURE 35-7 Metastatic clear cell adenocarcinoma from the kidney. (A) Well-demarcated nodule of tumor in the reticular dermis with clear cell and prominent extravasation of erythocytes. (B) Sheets and cords of clear cells embedded in a delicate vascular stroma with some extravasated erythocytes and hemosiderin deposition.

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GENITAL TRACT TUMORS

970

In women, the genital tract tumors that most commonly metastasize to the skin are of ovarian (4%), endometrial (4%), and cervical (2%) origin.4,10 A cutaneous metastasis from the ovary may be the initial manifestation of disease, but metastases from the latter tumors usually occur after recognition of the primary tumor. The trunk and pelvic areas are the primary sites of cutaneous metastases for each of these tumors, and ovarian metastases may involve the umbilicus.70,255 Choriocarcinomas frequently present as a consequence of a metastasis, and metastases to the skin are not uncommon.25-27 In men, the primary site of genital tract tumors is the prostate. Cutaneous metastases from prostate cancer are rare relative to the incidence of primary prostate carcinoma. Metastases are seen most commonly in the pelvic area; however, unusual umbilical, epidermotropic, and telangiectatic lesions have also been reported.25,26,186,187,256-260 CLINICAL FEATURES Cutaneous metastases from the ovary, endometrium, and cervix usually manifest as one or more skin-colored nodules that arise in normal skin, incisional scars, or the umbilicus. Ovarian metastases with erysipelas-like features have been reported. Prostate carcinomas in the skin usually consist of flesh-colored or violaceous nodules. Metastases resembling a pyoderma or having a zosteriform pattern, possibly from growth along nerve sheaths, have also been described. HISTOPATHOLOGIC FEATURES The usual histologic pattern of metastatic carcinoma of the ovary is a moderately to well-differentiated adenocarcinoma, often with a papillary configuration and psammoma bodies (small, laminated, calcified spherules). Less commonly, ovarian metastases may be mucinous. Endometrial carcinoma often presents as adenocarcinoma with solid and glandular patterns. Cutaneous metastases from the cervix are usually poorly differentiated squamous cell carcinomas.5,72,261-265 Choriocarcinomas are usually gestational tumors composed of cytotrophoblasts, which are large, cuboidal cells with vesicular nuclei and pale cytoplasms, and syncytiotrophoblasts, which are large cells with irregular nuclei and basophilic cytoplasms. Clusters of cytotrophoblasts are surrounded by sheets and cords of syncytiotrophoblasts in a plexiform pattern resembling chorionic villi.266 Prostatic

metastases to the skin are usually poorly differentiated adenocarcinomas composed of clusters and cords of cells with little glandular formation that infiltrate dermal collagen bundles.186,257,260 DIFFERENTIAL DIAGNOSIS Metastatic papillary adenocarcinoma from the ovary resembles papillary tumors from other sites such as the colon, thyroid gland, stomach, and lung. Psammoma bodies may be observed in both ovarian carcinoma and papillary carcinoma of the thyroid gland.243,261,267 Mucinous ovarian carcinomas vary considerably in their microscopic appearance and may be difficult to distinguish from endocervical, colorectal, and breast carcinomas.261 Metastatic endometrial carcinoma usually does exhibit histologic features allowing distinction from adenocarcinomas from other organs. Similarly, metastatic cervical carcinoma cannot be readily discriminated from squamous cell carcinoma from other organs.72,263-265 Choriocarcinomas may arise from sites other than the uterus such as the testes, ovaries, and mediastinum.25,26,268,269 Prostate carcinoma in the skin commonly has an infiltrative single-file pattern that also may be observed in other cutaneous metastates such as breast, stomach, pancreas, and oat cell carcinomas.186,243,257,260 Unusual variants, including inflammatory carcinoma and several cases with pronounced epidermotropism, have been reported.187,270,271 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Many ovarian carcinomas focally demonstrate a papillary architecture that suggests papillary thyroid carcinoma. Serous ovarian adenocarcinomas often stain with CK7 and estrogen and progesterone receptors but usually not with CK20, CEA, or GCDFP-15, which facilitates distinction from colorectal adenocarcinomas (which are usually CK7 and ER negative and CK20 and CEA positive) and breast carcinoma (which is GCDFP-15 positive).94,119,232,272,273 Many mucinous ovarian tumors have an intestinal phenotype and express antigens such as CK20, CDX2, and villin.140,146,147,261,272 Significant expression of CK7 and CA125 with weaker and less diffuse staining for CK20 favors a mucinous ovarian carcinoma over a true intestinal carcinoma, but exceptions exist. 95,166,273 CA125 is also negative in most breast cancers. Endometrial adenocarcinomas resemble serous ovarian adenocarcinomas with respect to immunophenotype except that CEA staining and coexpression of CKs and

vimentin are common. Thyroid papillary carcinomas usually stain for a broad range of low- and high-molecular weight CKs, including CK7, but also for relatively specific markers such as thyroglobulin and TTF-1.127 Choriocarcinomas express human chorionic gonadotropin (hCG), PLAP, and with a recently described marker Mel-CAM/CD 146.159,246,272,274,275 PSA, and PSMA are sensitive and specific for metastatic prostate carcinoma.154,155

THYROID TUMORS The various forms of thyroid carcinoma occasionally metastasize to the skin, especially the scalp. Of particular note, papillary thyroid carcinoma metastases have been described after intervals as long as 20 to 30 years.5,83,87,276 CLINICAL FEATURES Thyroid carcinoma metastases may be flesh-colored or redviolet cutaneous nodules, often involving the scalp and abdomen. Thyroid follicular carcinoma metastases may be pulsatile or manifest bruits.83,84,87,115,276-279 HISTOPATHOLOGIC FEATURES Papillary carcinoma of the thyroid gland has an infiltrative pattern that consists of tubulopapillary structures with occasional psammoma bodies and dark, eosinophilicstaining colloid.127,267 The “orphan Annie” nuclei of papillary carcinoma of the thyroid are large, ovoid, ground glass–appearing, and grooved nuclei with small nucleoli. Follicular thyroid carcinoma has trabeculae and follicles with intraluminal colloid. Medullary carcinoma of the thyroid is a neuroendocrine carcinoma that is most commonly composed of sheets of polygonal or plump, spindled cells in a fibrovascular stroma that often contains lymphocytes and amyloid. DIFFERENTIAL DIAGNOSIS The differential diagnosis of papillary tumors with metastases to the skin includes papillary carcinomas of the thyroid and ovary, which may have psammoma bodies, as well as papillary carcinoma from the GI tract, kidney, and lungs and papillary transitional cell carcinomas.83,243 Differentiated follicular carcinoma of the thyroid has a unique appearance because of the colloid in the follicles. The small cell variant of medullary carcinoma of the thyroid must be differentiated from other small cell carcinomas and from malignant lymphoma. SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY TTF-1 stains the nuclei of all types of thyroid carcinomas as well as

NEUROENDOCRINE TUMORS Neuroblastoma is the most common carcinoma seen at birth, is usually of adrenal origin, and is associated with cutaneous metastases in 32% of neonatal patients and 3% of patients of all ages.280,281 In older patients, carcinoid tumors (low-grade neuroendocrine neoplasms) from sites such as the bronchi and small intestines, including the appendix, occasionally metastasize to the skin and may be the first manifestation of the tumor.130,131,243,282-284 Merkel cell carcinoma frequently recurs locally and metastasizes to distant sites, including the skin.132 CLINICAL FEATURES Neuroblastoma metastases are randomly scattered, firm, nontender, mobile, blue subcutaneous nodules that blanch after being stroked.285,286 Carcinoid tumors appear as single or multiple dermal or subcutaneous nodules that may be painful, and the patient may manifest the carcinoid syndrome.130,282-284 Metastases from Merkel cell carcinoma are usually firm, red-pink, nonulcerated nodules 0.4 to 0.8 cm in diameter.132,287,288 HISTOPATHOLOGIC FEATURES Neuroblastoma exhibits clusters of small basophilic cells that have numerous mitoses and form rosettes in a fine, fibrillar, eosinophilic stroma.289 Carcinoid tumor metastases to the dermis and subcutaneous fat are composed of islands, nests, and cords of uniform cells with round nuclei and clear or eosinophilic cytoplasms that occasionally contain eosinophilic granules.282-284 Merkel cell carcinoma is characterized by anastomosing cords, bands, sheets, and clusters of uniform, round basophilic cells with vesicular nuclei, scant cytoplasm, and numerous mitoses.132,287,290-295 Necrosis

and apoptosis may be seen throughout the tumor. Keratin pearls and focal squamous, sweat gland, and sarcomatous differentiation may be seen, and combined carcinomas, including Merkel cell carcinoma in association with squamous cell, basal cell, and sweat gland carcinoma, have been reported. DIFFERENTIAL DIAGNOSIS Neuroblastoma and Merkel cell carcinoma must be differentiated from other small, round, blue cell tumors such as small (oat) cell neuroendocrine carcinoma from the lung and other sites, poorly differentiated sweat gland carcinoma, metastatic melanoma, and malignant lymphoma.105,296-298 Especially in the pediatric population, the Ewing sarcoma family of tumors (skeletal and extraskeletal Ewing sarcoma, PNET, Askin tumor), rhabdomyosarcoma, small cell desmoplastic tumor, lymphoblastic lymphoma, malignant rhabdoid tumors and organ-specific blastomas such Wilms tumor may be diagnostic considerations. The uniform small cells of a carcinoid tumor may resemble those of a primary adnexal tumor or glomus tumor.283,284,299,300 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Neuroblastomas may stain for neurofilaments and neural crest markers such as chromogranin A and synaptophysin.164,289,296-298 They are separated from other pediatric small round cell tumors by morphology, positive staining for these markers, and a failure to express vimentin and markers of muscle, lymphoid, and epithelial differentiation. Ewing sarcoma family tumors usually express vimentin, CD99, and FLI-1 but not muscle, lymphoid, and epithelial markers. Rhabdomyosarcomas often express muscle antigens such as muscle-specific actin and desmin and myogenic transcriptional regulatory proteins such as myogenin and Myo-D1. Carcinoid tumors usually stain with broad-spectrum anti-CK antibodies such as AE1/AE3 and low-molecular-weight anti-CK antibody CAM5.2 and neuroendocrine markers such as chromogranin A or synaptophysin.127,209,232,233 The primary site of neuroendocrine carcinomas, including carcinoid tumors, cannot be identified with certainty because tumors from different sites demonstrate phenotypic overlap. Merkel cell carcinomas have features of both neuroendocrine and epithelial differentiation. They demonstrate globular “dotlike” paranuclear staining with CAM5.2, AE1/AE3 and antibodies to CK20, and neurofilaments and sometimes stain with antibodies to EMA,

CK7, chromogranin A, and synaptophysin but not with antibodies to CEA or LCA. Positive staining for CK20 and neurofilaments in a paranuclear pattern and negative staining for CK7 and TTF1 favor Merkel cell carcinomas over metastatic small cell carcinoma of lung origin.99-101,117,120,222,223 A series of CK20-/CK7+ Merkel cell carcinomas has been reported. All of these tumors were TTF-1 negative,301 Small cell carcinomas from other locations, such as the gut, uterine cervix, and salivary glands, sometimes express TTF1 and CK20. Many neuroendocrine carcinomas, including primary neuroendocrine carcinomas of the lung and Merkel cell carcinomas, stain strongly with antibodies to CD56.100,224 Many Merkel cell carcinomas also stain with antibodies to TdT, a DNA polymerase that is usually considered to be sensitive and specific antibody for blastic hematologic malignancies.225

SARCOMAS Sarcomas metastasize to the skin in 3% of men and 2% of women with cutaneous metastases.5 Distant cutaneous metastases may also be seen from sarcomas that arise in the dermis, subcutaneous fat, or underlying soft tissue such as epithelioid cell sarcoma and atypical fibroxanthoma.88,89,302 The metastases occur on the scalp, trunk, and extremities. Most metastases of sarcomas occur after recognition of the primary lesion.4

CHAPTER 35 ■ CUTANEOUS METASTASES

many lung cancers. Positive staining for thyroglobulin and negative staining for CEA distinguish nonmedullary thyroid cancer from most lung cancers.94,127,128,209,267 Most metastatic papillary and follicular thyroid carcinomas stain for thyroglobulin and TTF-1. Medullary carcinomas of the thyroid usually express TTF-1, calretenin, and less specific neuroendocrine markers such as chromogranin and synaptophysin but not thyroglobulin. The origin of neuroendocrine and small cell carcinomas cannot be identified with certainty because tumors from different sites demonstrate a certain amount of phenotypic overlap with virtually every marker studied.

CLINICAL FEATURES Metastatic sarcomas in the skin are firm, skin-colored or redpurple nodules that may be ulcerated or painful.89,286 HISTOPATHOLOGIC FEATURES Leiomyosarcoma is often a well-demarcated or infiltrating nodule in the dermis or subcutaneous fat composed of fascicles of spindle cells with eosinophilic cytoplasms and varying degrees of cytological atypia (Fig. 35-8).303,304 Rhabdomyosarcomas are usually poorly differentiated tumors that may have large, atypical cells with abundant eosinophilic cytoplasms and multinucleated giant cells or small, hyperchromatic cells with scant cytoplasms, in which case they are included in the differential diagnosis of small, round, blue cell tumors.163,281,296,298,304,305 Elongated eosinophilic “strap cells” and recognizable rhabdomyoblasts with cross-striations in their cytoplasms are seen in some but not all rhabdomyosarcomas.

971

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 972

A

B

 FIGURE 35-8 Metastatic leiomyosarcoma. (A) Well-demarcated nodule of tumor in the subcutaneous fat with brightly eosinophilic cells. (B) Interlacing fascicles of eosinophilic spindle cells with nuclear pleomorphism.

Fibrosarcomas exhibit fascicles of spindle cells often arranged in a herringbone pattern with few polygonal and giant cells. Whereas better-differentiated tumors show more significant numbers of spindle cells and collagen production, poorly differentiated tumors manifest anaplastic cells and mitoses.304 Malignant fibrous histiocytoma (a controversial term that has been to some extent supplanted by undifferentiated pleomorphic sarcoma) has several variants that include storiform-pleomorphic, xanthomatous, inflammatory, myxoid, angiomatoid, and giant cell types.304 Chondrosarcomas are composed of undifferentiated round to spindle-shaped cells with malignant cartilage or chondroblasts in a myxoid matrix.304,306 Osteogenic sarcoma is composed of varying admixtures sof malignant osteoid and bone along with a spindle cell component that resembles fibrosarcoma or malignant fibrous histiocytoma.304,306 Ewing sarcoma family tumors are characterized by lobules of uniform small, round or oval cells, sometimes with perilobular fibrosis.106,306 Epithelioid sarcoma is composed of nodules of polygonal, epithelioid, and spindle cells with abundant eosinophilic cytoplasms and atypical nuclei that palisade around central areas of necrosis in association with lymphocytic infiltrates at the peripheries.89,307 DIFFERENTIAL DIAGNOSIS The definitive interpretation of the various sarcomas and their discrimination from other

spindle cell or round cell tumors of epithelial origin has been facilitated by the advent of immunohistochemistry. However, particular light-microscopic findings continue to be critical in the differential diagnosis of sarcomas and their distinction from epithelial tumors. The principal entity in the differential diagnosis of metastatic fibrosarcoma in the skin is primary dermatofibrosarcoma protuberans (DFSP). DFSP is centered in the reticular dermis and demonstrates uniform spindle cells and a more pronounced storiform pattern compared with fibrosarcoma.308-312 DFSP may show myxoid areas and extensive portions of the tumor indistinguishable from primary fibrosarcoma. Nodular fasciitis is a benign “pseudosarcomatous” lesion that may arise from the fascia and occasionally from the septa of the subcutaneous fat. Nodular fasciitis is characterized by generally uniform “tissue culture”–appearing fibroblasts and, in some cases, giant cells haphazardly arranged in a highly vascular, myxoid stroma.304 Some authors regard atypical fibroxanthoma as a superficial variant of malignant fibrous histiocytoma with less aggressive clinical behavior; however, atypical fibroxanthoma has traditionally been differentiated from malignant fibrous histiocytoma because of its smaller size and more superficial location.312-314 Well-differentiated metastatic leiomyosarcoma may have a similar infiltrative or well-demarcated pattern in the dermis or subcutaneous fat as that seen in

primary leiomyosarcomas or even leiomyomas.303,304 Metastatic leiomyosarcoma does not have a vascular origin, as observed in angioleiomyoma and many subcutaneous leiomyosarcomas. It is composed of smooth muscle cells that are more atypical than those of leiomyoma and often with significant mitotic activity. Anaplastic leiomyosarcomas with bizarre giant cells may resemble malignant fibrous histiocytoma. Rhabdomyosarcomas composed of small, round, blue cells need to be differentiated from other primary or metastatic tumors with similar morphologic features.163,164,304,305 Pleomorphic rhabdomyosarcomas with a storiform pattern and bizarre multinucleated cells may resemble malignant fibrous histiocytoma. As with rhabdomyosarcomas, Ewing sarcoma raises the differential diagnosis of small round cell tumors.164,298,304,315 Epithelioid sarcoma must be distinguished from infectious and palisading granulomas.89,304 Epithelioid sarcoma differs from malignant fibrous histiocytoma because of the absence of bizarre multinucleated cells and foam cells. SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY The immunohistochemistry of sarcomas are not covered in great detail here because cutaneous metastases of sarcomas usually bear a close clinical relationship to a known primary tumor.4 Epithelioid sarcoma is of special interest because it may be mistaken for granulomatous inflammation. These

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variant analyzed in a series of 23 cases. Am J Surg Pathol. 2007;31:1371-1377. Santa Cruz D: Tumors of the skin, in Fletcher C (ed). Diagnostic Histopathology of Tumors, vo1 2, 3rd ed. New York: Churchill Livingston; 2007:1423-1526. Soule E, Enriquez P: Atypical fibrous histiocytoma, malignant fibrous histiocytoma, malignant histiocytoma, and epithelioid sarcoma. A comparative study of 65 tumors. Cancer. 1972;30(1): 128-143. Silvis N, Swanson PE, Mannivel JCet al: Spindle-cell and pleomorphic neoplasms of the skin. A clinicopathologic and immunohistochemical study of 30 cases, with emphasis on “atypical fibroxanthomas.” Am J Dermatopathol. 1988;10(1):9-19. Izquierdo MJ, Pastor MA, Carrasco L, et al: Cutaneous metastases from Ewing’s sarcoma: report of two cases. Clin Exp Dermatol. 2002;27:123-128. Pai KK, Pai SB, Sripathi H, et al: Epithelioid sarcoma: a diagnostic challenge. Indian J Dermatol Venereol Leprol. 2006;72:446-448.

CHAPTER 35 ■ CUTANEOUS METASTASES

305.

neoplasms: another distinctive, previously unrecognized pattern in extraocular sebaceous carcinoma and sebaceoma. Am J Dermatopathol. 2005;27:195-203. Calder KB, Coplowitz S, Schlauder S, Morgan MB: A case series and immunophenotypic analysis of CK20/CK7+ primary neuroendocrine carcinoma of the skin. J Cutan Pathol. 2007; 34:918-923. Giuffrida T, Kligora, GD G: Localized cutaneous metastases from an atypical fibroxanthoma. Dermatol Surg. 2004;30: 1561-1564. Vandergriff T, Krathen RA, Orengo I: Cutaneous metastasis of leiomyosarcoma. Dermatol Surg. 2007;33:634-637. Fletcher C: Soft tissue tumors, in Fletcher C (ed). Diagnostic Histopathology of Tumors, vol 1, 3rd ed. New York: Churchill Livingston; 2007:1527-1592. Cessna MH, Zhou H, Perkins SL,, et al: Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol. 2001;25(9):1150-1157. Unni K, Inwards C: Tumors of the osteoarticular system, in Fletcher C (ed).

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5 PART

Disorders of Nails and the Oral Mucosa

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CHAPTER 36 Disorders of the Nail Apparatus Aldo González-Serva

MICROSCOPIC SIGNS OF NAIL DISEASES Relatively few histologic signs characterize nail disease.5,6 Some of the signs are noted in subungual horn and nail plate and thus may be diagnosed by noninvasive methods. Other signs are tissue based and need a biopsy for their detection. Excellent monographs and chapters of clinical and histologic features of nail diseases are available.7-10 The types of signs needed to secure a specific diagnosis should influence the choice of biopsy method. Many diseases can be diagnosed or strongly suspected from scrapings and clippings of the nail. Plate dystrophy, subungual hyperkeratosis, and gross pigmentary deposits are the most important. However, knowing the source of the latter requires tissue examination. This more invasive approach reveals epithelial changes such as epidermidalization, matrical hypergranulosis, or atypia. The presence of pigmented material or cells; atypical melanocytes; misplaced tissues; or neoplastic cells of other lineages, hemorrhage, and stromal changes (eg, cellular infiltrates and myxoid degeneration) requires tissue for histologic examination as well. More generalized skin disorders tend to be recognized in the perionychium because, essentially, this is skin with the

same characteristic response to disease as elsewhere.

RESOURCES FOR HISTOLOGIC DIAGNOSIS Most biopsies for the diagnosis of nail diseases are taken by shave of the cutaneous framework of the nail. Lately, shave biopsies of the matrix and bed have also been used. Punch biopsies are a satisfactory method for most nail diseases. Care should be exerted in also exploring the often detached nail plate core that is produced when the matrix or the bed are punched out. In demanding cases for diagnosis, a longitudinal nail biopsy may be the best solution. Regardless of the method of biopsy taking, the study of keratinous or tissue products of the nail with routine histology stained with hematoxylin and eosin is the mainstay of the diagnosis of nail diseases. Particularly helpful is the periodic acid-Schiff (PAS) stain, which should habitually accompany every study. For pigmentary disorders, iron, melanin, and hemoglobin stains are mandatory. Immunohistochemistry and electron microscopy are used sparingly in common diagnostic practice with the same frequency as in other areas of dermatopathology generally to define histogenetic and differentiation traits of neoplasms, deposits, or genodermatotic disorders.5 More recently, the approach to the diagnosis of some nail diseases is through the nail plate biopsy (NPB), a noninvasive technique that is gaining popularity. The mainstay of NPB is the search for fungi. In the past few years, there has been a clear shift from cultures to this method of detection of fungal pathogens. In addition, the use of the NPB to determine the presence, pattern, and percentage of melanin pigment within the plate has become an alternative to more invasive nail matrix biopsies. The following sections outline the principles of these methods.

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

The pervasive misunderstanding of the nail unit as a skin equivalent rather than as an adnexal unit such as the hair follicle has complicated the evaluation and diagnosis of nail diseases.1 After recognizing that the matrical and bed epithelia and stroma are not epidermis and dermis, a better understanding of the microscopic findings in nail diseases has emerged. The nail can be considered to resemble a flattened, cubist-like hair follicle that is asymmetric (Fig. 36-1). The plate is laminar and enclosed by lip-shaped sides of unequal length. The plate-forming matrix is lateralized rather than enclosing the nail root (Fig. 36-2A). The intermediary epithelia surrounding the matrix, especially the bed epithelium, are its products as well, as are ultimately the resulting cuticular keratins that ensheath the plate (Fig. 36-2B).2 Regarding the dynamics of migration of the nail components, every layer of the nail unit moves forward alongside the plate in unison. Thus, the plate does not glide over the bed epithelium but is firmly attached to it in a parallel course. The bed ends at a predetermined site (the onychodermal band, which may be recognized clinically; see Fig. 36-2C) and keratinizes fully in a zone known histologically as the solehorn. This keratinization may be described as onycholemmal keratinization.3 On the opposite side, the true cuticle, which originates on the ventral side of the proximal nail fold, apposes the plate as it emerges, thus sealing the virtual space that otherwise would occur. All of the described onychal structures are encircled by cutaneous structures more akin to epidermis, which intersects with the emerging plate and epithelial and keratinous coverings. The rim of epidermoid keratin above the plate and the true cuticle is the rough eponychium, a nonessential and disposable semilunar spur that has erroneously been called the cuticle. Beneath the site of plate launching, beyond the solehorn, is the product of the bed epithelium—the hyponychial horn (or ventral cuticle). The latter structure lies above an intermediate epithelium, closer

to epidermis, which is termed the hyponychium. Keratins of onychal and epidermoid origin are blended in this hyponychial angle. This area of collision of nail and cutaneous epithelia—a half ostium of sorts—is a reservoir of information about past events in the matrix and bed. The nail plate is also a mirror of the same events. This understanding facilitates the interpretation of nail diseases, from either scrapings or clippings of nail horn or plate, that had their initiation at some earlier point in time and may or may not be active at the time of the study. Thus, fungi of the bed will also be at the subungual or hyponychial horn. Pigment associated with keratins will reflect a pigment-forming lesion of the matrix or bed. The melanocytic system of the nail consists of inconspicuous, nonpigmented cells in both the matrix and bed, particularly in whites. In the matrix, whereas the functional melanocytes are more abundant in the distal matrix, even if functionally dormant, the total numbers of melanocytes predominate in the proximal matrix.4

NAIL PLATE BIOPSY IN SEARCH OF FUNGI

Definition A positive PAS stain result in an NPB in patients suspected to harbor onychomycosis is rewarding, but a negative result is vexing and may be falsely negative. Therefore, steps refining positivity or asserting true negativity are needed to insure that onychomycosis is not missed.

983

Anatomy of the Nail Eponychium (false cuticle)

Cuticle

Hyponychium* (space) Solehorn* (ventral cuticle)

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Onychodermal band

Lunula (distal matrix)

A

Fungal Morphology

Bed *Under nail plate

Histology/Anatomy of the Nail Proximal nail fold

Eponychium

Hyponychium Plate

Cuticle

Solehorn Onychodermal band

In positive nail plate biopsies, the fungal morphology (hypha, mold, yeast) directs the diagnosis and therapy, and their distribution and density allow an assessment of the type of treatment and likely therapeutic response. Table 36-1 shows a list of salient morphologic aspects of fungal and related pathogens inducing a similar “mycotic” nail appearance.

Additional Steps to Increase Yield of Diagnosis

Matrix

Bed

Pulp

Nail as homologue of hair follicle: Matrix produces, besides plate, nearby

B epithelia and ensheathing keratins (not proportionally depicted).

 FIGURE 36-1 (A) Clinical anatomy of the nail. The morphology of the plate is the result of intimate accommodation of the nail structures to the subjacent bone. The nail root rests over the proximal epiphysis of the distal phalanx, and the distal groove (at the site of onychodermal band and hyponychium) arches around (and actually inserts, by specialized nail ligaments, on) the tuberositas unguium. (B) Diagram of nail structures.

Flowchart The traditional flowchart for the search of fungi has started with direct microscopy (potassium hydroxide examination) followed by culture to either speciate or confirm the negative examination results. Histologic examination of nail material stained with PAS is emerging as the first line diagnostic test in this workup for onychomycosis.11

Rationale 984

double-observer examination of initially negative PAS stains and Giemsa (GMS) stain were added to the basic steps16 (Fig. 36-3). In the same series, the referring clinicians had an index of suspicion of onychomycosis varying between 49% and 94% with a median of 68%. These values closely equate the index of suspicion by the clinician to the harvest of positive PAS stains by the pathologist and establish that not every nail that looks mycotic is truly so. Unfortunately, the exact causes of those pseudomycotic appearances are not always clear. The quandary is whether occult onychomycosis is still present or if eczema, ischemic and trophic changes, trauma, bacteriosis, and psoriasis mimic it.

It is now obvious that PAS stain in nail clippings or curettages is more sensitive

and specific than direct microscopy or, surprisingly, than fungal cultures. Reported series of positivity for PAS vary from 33.3% to 92% in the rate of detection of fungi. Most series, though, approximate 48% success in demonstrating fungi in nails clinically suspected of harboring onychomycosis.12-15

Results The author and colleagues have recently reported a consistent 65% positive rate of fungal detection in a large series of more than 2561 nail clippings when

Microbial culture after a positive PAS stain may allow fungal speciation in nail plate biopsies. A second look at an initially negative PAS stain, possibly supplemented with GMS stain, should be the next steps in this histology-based flowchart. Microbial culture, even if culture is less sensitive than PAS, may even rescue on occasion some falsely negative PASor GMS-stained specimens (2.5%). Of those isolates, it is difficult to say which organisms other than dermatophytes (generally molds) are contaminants or true pathogens. Clinicopathologic correlation may then arbitrate the decision of treating the patient with potent antimycotic drugs or reinitiating the workup. Persistent negativity reassures the clinician that the pseudomycotic plate dystrophy is not infectious.

Rescue of False-Negative Cases of Onychomycosis Further steps to rescue occult cases of onychomycosis are the repeat of the NPB and the procurement of nail samples of increased quality, that is, those leading to high harvest of subungual horn, which is the seat of most infections. The use of still experimental, not

A

B

 FIGURE 36-2 Histology of the nail (in a newborn). (A) The matrix epithelium is stratified and produces an eosinophobic nail plate, mirrored by concurrent keratin of the ventral portion of the proximal nail fold (true cuticle). (B) The nail bed epithelium is less stratified than the matrical one, with relatively monotonous upper and lower keratinocytes. (C) The onychodermal nail band occurs where the bed epithelium clashes with the epidermis of the hyponychium. The entirety of the bed epithelium keratinizes and is extruded as the solehorn (ventral cuticle).

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

C

yet practical methods of fungal detection, such as confocal laser microscopy and molecular techniques, is not warranted in day-to-day practice.

MELANIN MAPPING OF THE NAIL PLATE AND MATRIX

Definition

 FIGURE 36-3 (A) and (B) Nail plate biopsy for fungi. A Giemsa stain can reinforce a negative periodic acid-Schiff stain or more starkly show the presence of hyphae. A preparation with low precipitation of silver granules is ideal but is often difficult to achieve.

The noninvasive mapping of the pattern of intralaminar melanin in an NPB mirrors the position and morphology of a melanin-producing melanocytic lesion in the ungual matrix.17 The analysis of the trail of intracorneal melanin present in some pigmented nail diseases in sections of the nail plate, unstained or stained with Fontana-Masson, is based on the fact that whereas the proximal matrix produces the most superficial sheets of the nail plate, the distal matrix produces the deepest sheets (Fig. 36-4).

985

Table 36-1 Morphology of Fungi With PAS Stain of the Nail Keratins FINDINGS

DISORDER Dermatophytes (91%): Trichophyton rubrum (71%), Trichophyton mentagrophytes (20%), Trichophyton tonsurans, and Epidermophyton floccosum (rare)

Yeasts (5%): Candida albicans

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Pityrosporum ovale (Malassezia furfur)

Nondermatophyte molds (4%) Scopulariopsis brevicaulis (most frequent)

Scytalidium dimidiatum (or hyalinum)

Aspergillus spp Pseudoonychomycosis (rare) Prototheca wickerhamii (or zopfii) (alga)

Corynebacterium minutissimum [bacterium]

In addition, the true cuticle and the subungual (hyponychial) horn are ultimately matrical products as well, as are the matrix-derived epithelia of the ventral proximal nail fold and the bed.

Slender septate cylindrical hyphae, 2-5 μm wide (if pigmented, T. rubrum nigricans), mainly at the lateral aspects of the nail plate Frequent sporulation, often at the midline under the nail plate; arthrospores, 2-4 μm wide, in regular chains Budding oval yeasts, 3-4 μm wide; pseudohyphae; septate hyphae (rare) Small, oval or bottle-shaped budding yeasts, 2-5 μm wide; truncate short hyphae are exceptional on the nail crevices (saprophyte vs. pathogen?) Masses of thin, short hyphae, 5-7 μm wide, with large lemon-shaped, rough-surfaced conidiospores Short, hyaline branched filaments, 2.5-7.0 μm wide, with thick walls and arthrospores (if pigmented, S. dimidiatum) Irregular septate hyphae, 2.5-3.5 μm wide, often branching dichotomously; heads and conidia Moruloid spherical, ovoid, or elliptical sporangia, 6-10 μm wide, with a crown of molded endospores around a central rounded one Irregular, minute rods and thin, fragmented filaments, 1 μm in diameter (gram+)

Premise Represented in the sheets of the plate are pigmented and keratinous reflections of events in matrical onychometameres. An onychometamere is the transversal file

of onychocytes that from one side to the other of the nail field conjointly produce each sheet of the plate. If the onychometameres are abnormal, the nail plate sheets will be equally abnormal. The number of matrical onychometameres, from nail root to the lunular border, equals the number of nail plate sheets. For example, 50 onychometameres—occupying one after another a matrix of approximately 1 cm or more in length—emit 50 plate sheets now compacted in a nail plate 1 mm or less in thickness. The thin plate is the product of a long matrix, only after matrical dynamics compresses the plate and forces it to grow forward horizontally and thinned down approximately 10 times the length of the matrix, rather than as an upward-bound and broad-based horn.

Analysis of Intralaminar Melanin The understanding that the matrix projects itself into the plate, leaving a trail of intralaminar melanin in nails with melanotic lesions, leads to the analysis of such lesions on the basis of the presence of pigment in few or all levels of the plate. The position of the melanin “smokestack” in the nail plate is paramount to predict the dimensions of a nevus or a melanoma. The pigment will occupy perpendicularly a space that is proportional to the area of the matrix occupied by the pigmented lesion. The portion of the melanin-containing plate will be representative of the matrical onychometameres producing melanin. In benign lesions, the abnormal matrical space tends to be small, but in a melanoma, the space is large and tends to occupy the whole length of the matrix (Fig. 36-5).

Percentage of Pigmented Plate and Calculation of Matrical Area

986

 FIGURE 36-4 Nail plate biopsy for melanin. The understanding that the most superficial sheets originate in the proximal matrix and the deepest ones from the distal matrix allows for “histographic mapping” of melanin pigment to the matrical onychometameres containing the pigment-producing lesion.

Besides the general position of the intralaminar melanin, the percentage of the nail plate containing melanin is of value. The “homunculus” of pigment reflected in the nail plate allows a noninvasive look at the dimensions and characteristics of a pigmented lesion in the matrix. Ideally, the dimensions of the pigment-producing lesion could be calculated combining the estimate in millimeters of the length of the melanocytic lesion that extrudes melanin into the plate given by this method and the width of the same lesion given by the width of the pigmented band determined clinically or histologically. If the position of the pigment is matrical and

Diseases of the Nail  FIGURE 36-5 Dimensions of a matrical melanocytic lesion by means of analysis of a nail plate biopsy (NPB). The percentage of matrix involved by a pigment-producing lesion is manifested in an NPB. Correlation with clinical or histologic width of the pigmented band allows for a full picture of matrical involvement. (A) The plate is a mirror of the matrix, although 10-13 times thinner. (B) A small proximal matrical lesion produces a limited focus melaninization of the upper plate sheets (eg, a lentigo). (C) A narrow but full-length matrical lesion will induce melanin throughout the entire vertical thickness of the plate (eg, a nevus). (D) A long and broad matrical lesion will give rise to a wide and full-thickness melanin trail in the plate (eg, melanoma). (The nail plate is depicted in the coronal view, matrix viewed en face [ie, from above]).

This chapter emphasizes the disorders that are likely to be diagnosed initially from histologic evaluation of the nail unit.20,21 Many other disorders not discussed here can be diagnosed from other cutaneous or systemic signs. It is important to recognize that the nail unit is a domain of the skin, rather than a region, that expresses a wide spectrum of disorders, even if not diagnosable specifically by means of a biopsy.22

Onychomycosis the percent of melanonychia is high, the melanin mapping of the NPB could predict the presence of a melanoma and leads to the taking of a punch or shave biopsy or, better, a longitudinal nail matrix biopsy (Fig. 36-6). This histopathologic mapping of melanin in the plate has lagged the dermatoscopists’ attempts to define through dermatoscopy, from above or across the leading edge of the plate, the position of matrical melanocytic proliferations producing melanin and thus be guided where to take a biopsy.18 The author anticipates that the histologic melanin mapping will become more popular as clinicians and pathologists clarify the correlations needed to achieve confident diagnoses by means of what essentially is “corneal exfoliative cytology” of sorts. In brief, the intralaminar melanotic mapping is a portrait in time (represented by the edge of the nail plate) of what has already occurred—but is likely to be still happening—in the nail matrix in times past when it produced the pigment that

then reached the distal plate. This mirroring in the plate of matrical events could become a crucial method in the difficult workup of melanonychia striata. Although not a full substitute for a biopsy, the NPB becomes the clear first-hand choice for a potentially broader workup of melanonychia, even if a biopsy is performed later.

DIAGNOSIS OF NAIL DISEASES The first issue to be addressed is whether the nail disorder is a plate dystrophy, a mass, or a pigmented lesion. Most biopsies are obtained for the evaluation of nail dystrophy. This is the most difficult group of diseases to diagnose specifically; fortunately, most specimens fall into the triad of tinea, psoriasis, and (much more rarely) lichen planus. Regarding pigmentation of the plate or adjoining tissues, the quandary is often the discrimination between melanin or hemoglobin deposition. A more difficult problem is posed by longitudinal melanonychia because the distinction

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

between benign and malignant pigment-producing lesions is difficult in the nail field, given the restrained ability for a biopsy of the nail tissues to be ample and free of artifacts and to show to good advantage all criteria to reach a diagnosis of early malignancy (ie, malignant melanoma in situ). The workup of a mass in the nail unit is more frequently related to evaluation of a verrucous papule than to a deeper soft or hard tissue tumor. When this is the situation, the distinction is between verruca and more serious tumors such as keratoacanthoma or squamous cell carcinoma. Fortunately, reliable criteria for these microscopic diagnoses now are available,19 but not every case is readily solved by biopsy alone. In those dilemmas, observation, clinicopathologic correlation, and repeat biopsy by a more invasive method become paramount.

Synonyms: Tinea unguium, dermatophytosis, nail ringworm Fungal infections of the nail, the most frequent cause of nail disease, can be dermatomycetic (encompassing the cited synonyms), nondermatomycetic (eg, mold infections), and yeast-related infections (mostly candidiasis).23 CLINICAL FEATURES Regardless of the etiologic agent, the onychomycoses have been grouped as distal or lateral subungual, superficial white or black, proximal subungual, total dystrophic, and (more recently) endonyx (nail plate only without any other changes). The type of dystrophy may suggest the type of onuchomycosis involved.15 Candidal onychomycosis stands apart. Isolation of the agent may be difficult, even if direct microscopy shows positive findings. HISTOPATHOLOGIC FEATURES The findings on direct microscopy may help to broadly identify organisms in nail plate or other nail tissue biopsies.13,24-26 Besides the presence of the fungi, the nail tissues undergo

987

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

C

988

A

D

B

 FIGURE 36-6 Nail plate biopsy for melanin in melanoma in situ. (A) Low power and (B) Higher power Fontana-Masson stain shows full-thickness involvement by coarse melanin granules, most noticeable in the lower 87% of the plate. (C) and (D) Low and high power respectively Longitudinal nail biopsy with immunoperoxidase stain for MART-1 reveals malignant melanoma in situ, extending as Hutchinson sign into the proximal nail fold.

plate dystrophy and variable degrees of psoriasiform onychitis. The hyphae of dermatophytes are tubular, colorless, often refractile, and usually septate. In contrast, those of nondermatophytes are thinner; more irregular and tortuous; and occasionally, tan-brown. Conidia can also be seen with the latter infection. If this type of infection is suspected, fungal culture should be used for confirmation. Yeasts occur as pseudohyphae and spores. In recent years, the biopsy of the plate alone, as clippings, has burgeoned as the method of choice for fast recognition leading to early treatment of onychomycosis.27,28 Fungi in tunnels containing air variably penetrate the plate, but more reliably, the subungual horn invariably contains most organisms. PAS stain suffices in most cases for confirmation. If a biopsy is done, the skin or epidermalized bed epithelium shows hyperkeratosis, both ortho- and parakeratotic, with Munro-like intracorneal microabscesses. Other than the presence of the fungi, the changes are similar to those of psoriasis (Fig. 36-7). In superficial white onychomycosis, short and

A

B

 FIGURE 36-7 Onychomycosis. Nail plate dystrophy, Munro’s microabscess and epidermidalization of the nail bed epithelium are identical to psoriasis, (A) except for the presence of hyphae with periodic acid-Schiff stain. (B) This type of biopsy has been superseded in tinea unguium by the increasing use of more conservative nail plate biopsies.

gnarled fungi are present in the superficial sheets of the plate. In contrast, fungi are present throughout the plate in proximal subungual onychomycosis and dystrophic onychomycosis. Candida also involves the whole thickness of the plate, but pseudohyphae are distinct and accompanied by spores.

 FIGURE 36-8 Psoriasis. The receding hyponychium, now occupying the space of former nail bed (onycholysis), is epidermidalized and hyperkeratotic. Besides keratinocytic pallor and agranulosis of the epithelium and papillomatosis of the bed stroma, there is a microabscess within the horn. No fungi are demonstrated with special stains.

Psoriasis Synonyms: Pustular psoriasis, acrodermatitis continua of Hallopeau CLINICAL FEATURES Involvement of the nail is seen commonly in up to 50% of patients with psoriasis and is even more prevalent in patients with psoriatic arthropathy.32 The abnormalities are zonal and related to the involved portion of the nail apparatus. Pits, transverse grooves, and other surface irregularities in the plate are related to damage to the matrix. An affected nail bed may exhibit discolorations, onycholysis, and splinter hemorrhages. If the nail bed and hyponychium are involved, subungual hyperkeratosis will be prominent. HISTOPATHOLOGIC FEATURES The histopathologic alterations depend on the site of the disease, which may involve any part of the nail33,34 (Fig. 36-8). However, the basic pattern is that of psoriasiform onychitis with spongiform pustulation. In the proximal nail fold, the process is similar to psoriasis elsewhere in the skin. Matrical involvement results in pits, which are dislodged psoriatic scalelike islands of variable width and length, according to the breadth and duration of injury to the proximal matrix. If these parakeratotic islands with neutrophils originate in papules of the middle and distal matrix, punctate leukonychia will follow. The matrical damage will result in an overall thick, crumbly plate. When

the matrix and nail bed are affected, the spongiform pustulation will be the basis for the salmon patch and onycholysis. Involvement in the bed will produce epidermalization of its epithelium with resulting subungual hyperkeratosis. If the longitudinally oriented ectatic vessels of the bed exude erythrocytes, splinter hemorrhages will ensue. Many of these changes will be reflected in changes in the plate that are recognizable through clippings alone. DIFFERENTIAL DIAGNOSIS The main differential diagnosis is onychomycosis. The microscopic changes may be identical, but psoriasis is usually more parakeratotic. The mainstay of the discrimination is the finding of fungi in onychomycosis. Another distinction is with eczematous onychitis, given that psoriasis in the nail may show eczematoid features. Other psoriasiform disorders, such as Reiter syndrome and parakeratosis pustulosa, are either indistinguishable or very hard to separate from psoriasis.

Eczematous Onychitis Synonyms: Trachyonychia (20-nail dystrophy), eczematous dermatitis The ubiquitous eczematoid changes in nail biopsies point to the recognition as an entity of eczematous onychitis, even if such processes may precede or be

concurrent with more distinct nail inflammatory conditions. CLINICAL FEATURES Among the entities that clinically resemble onychomycosis, spongiotic or psoriasiform onychitides are frequently seen after fungal infection has been ruled out. This is due to the fact that onchomycosis entails eczematoid features as part of its clinical and histologic spectrum of features, which accounts for the clinical overlap with the dermatitides. Moreover, nail dystrophy is relatively common (16%) in atopic dermatitis of the hand.35 Trachyonychia is the most widely recognized expression of eczema in the nail unit, which is also associated with Beau lines, subungual hyperkeratosis, and onycholysis, among other manifestations.9,36

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

DIFFERENTIAL DIAGNOSIS The most important differential diagnosis, before recognizing the fungal agents, is that of psoriasis. After this relatively simple distinction is reached, one should realize that most fungal organisms identified in nails are not causing true infection. Commensal fungi can be seen in many biopsies, but the role of small yeasts (now mostly identified as Malassezia furfur) is being reevaluated as possibly pathogenetic.29 Even secondarily colonizing fungi may be observed in nonmycotic disorders such as lichen planus and psoriasis. Unusual pathogens, such as Prototheca spp and Corynebacterium minutissimum, replicate the histologic signs of onychomysis.30,31

HISTOPATHOLOGIC FEATURES In addition to nail plate dystrophy and subungual orthokeratosis, eczematous onychitis shows extensive subungual parakeratosis, often admixed with sometimes large pools of spongiotic (serum-like) fluid (Fig. 36-9). Smaller subungual “scale-crusts” are also noted. The nail matricolectual epithelium may exhibit spongiosis or psoriasiform hyperplasia, depending on the phase of the process. DIFFERENTIAL DIAGNOSIS Onychomycosis is the main distinction because without

989

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

nonspecific end stage. The most diagnostic pattern is one that is similar to lichen planus in skin, namely, lichenoid onychitis with a bandlike lymphocytic infiltrate near vacuolated basal keratinocytes. There is also hyperkeratosis with hypergranulosis. Plasma cells may be present. If burnt out, the nail field will become atrophic and epidermalized, often permanently, and difficult to discriminate from that resulting from external trauma.

A

Paronychia B  FIGURE 36-9 (A) and (B) Eczematous onychitis. Low and high power respectively. Many changes of onychomycosis, minus the presence of fungi with periodic acid-Schiff or Giemsa stains or in cultures, are shared by eczematous disease of the nail field, perhaps a kindred of dyshidrotic dermatitis. This entity is probably more common than previously thought and may explain cases clinically suggestive of onychomycosis that are repeatedly negative for fungi. However, the presence of fungi may amplify a concomitant eczematous component in some cases of tinea unguium, making differential diagnosis on hematoxylin and eosin–stained sections of these entities nearly impossible.

the presence of fungal mycelia, the histologic changes are practically identical.

Lichen Planus

990

DIFFERENTIAL DIAGNOSIS If the highly characteristic features of lichen planus are identified, few other differential diagnoses need to be considered. The main problem is with healed lichen planus, in which the residual changes will be less than pathognomonic and essentially indistinguishable from lichen simplex chronicus of the nail after external rubbing or other mechanical trauma. If onychomycosis supervenes, care should be taken not to overlook lichen planus that may be obscured by infection. Other lichenoid disorders, such as lichen striatus, graft-versus-host disease, and even lichen sclerosus, may histologically mimic lichen planus.42-44

CLINICAL FEATURES Onychal lichen planus may occur in 1% to 10% of patients with lichen planus elsewhere but may rarely be confined to the nails, particularly in children.37,38 The disorder varies in intensity, extension, and number of nails or portions of nails involved. Besides the common presentation, hypertrophic and ulcerative variants are recognized, as is the recently described nail degloving (shedding of nail plate and nearby tissues).39,40 Onychomycosis can supervene in lichen planus of the nail.

HISTOPATHOLOGIC FEATURES The most devastating clinical features result from involvement of the matrix41 (Fig. 36-10). According to the severity of damage, only dystrophic plates may develop, or in many cases, complete destruction of the matrix eventuates in a loss of the nail plate with scarring and adhesion of the proximal nail fold to the nail mesenchyme (pterygium) (see Fig. 36-4). If damage is limited, the impairment of the matrix will produce thinner or shorter plates. When the process is intermittent in the matrix, pits and irregularities are noticeable (20-nail dystrophy). Microscopic findings may not be sufficient for an unequivocal diagnosis because the disease evolves into a relatively

Paronychia is infectious onychitis of the nail folds. Acute paronychia is bacterial, secondary to Staphylococcus aureus. Chronic paronychia is a disorder often associated with Candida albicans infection. Contact irritants may exacerbate the appearance and persistence of paronychia.45 Pseudomonas spp may be an offender, either primary or supervening on a psoriatic nail.46 CLINICAL FEATURES The features of acute paronychia are those of acute pyogenic infection, namely, an abscess or cellulitis. Chronic paronchia combines the proliferative elements of fibrosing granulation tissue with foci of suppuration. Children are affected frequently.47 HISTOPATHOLOGIC FEATURES In acute paronchia, a collection of purulent exudate is situated near a disrupted lateral or proximal fold (Fig. 36-11). A hangnail may be a preceding event. Interstitial neutrophilic exudate may be seen as well. Chronic paronchia has minimal or variable epidermal hyperplasia with spongiosis and scale-crust. The dermal infiltrate is composed of lymphocytes, histiocytes, and numerous plasma cells. Dilated vessels in an edematous stroma are prominent. If Candida organisms are present, they are located in the cornified

Traumatic Onychitis

 FIGURE 36-10 Lichen planus. The epidermidalized nail bed epithelium, appearing under dystrophic plate, is associated with a lichenoid lymphocytic infiltrate.

 FIGURE 36-11 Acute paronychia. The proximal nail fold, which is protuberant and crusted (similar to a hangnail), contains mixed inflammatory cell infiltrate (mostly suppurative) along with a fibrosing granulation tissue reaction.

layer and are neither invasive nor associated with granulomas. DIFFERENTIAL DIAGNOSIS Each paronychia has to be distinguished on the basis of etiology. Chronic paronychia can

conceivably be bacterial, and candidal paronychia may be acute. Some tumors, including amelanotic melanoma, may mimic paronychia. Rarely, fixed drug eruption may clinically resemble paronychia,48 as may Langerhans cell histiocytosis.49

HISTOPATHOLOGIC FEATURES Hemorrhage can be recognized histologically by extravasation of erythrocytes in the matrical-bed stroma and beneath or within the plate. Hematoidin (negative for iron stain), rather than hemosiderin, is identified. Benzidine stain may be used to detect disintegrated red blood cells and their products.51 Lichenification is a common final pathway to many disorders of the nail unit (Figs. 36-12 and 36-13). Whether it is derived from associated external trauma or, possibly, from self-perpetuating damage by abnormal epidermoid horn of various inflammatory disorders lodged between the plate and epithelia, the process is the same and may be erroneously taken for the primary disorder. The macerated lichenification of heloma durum, with clavus-like hyperkeratosis, is the equivalent of cutaneous picker’s nodule. Scar results from mechanical damage tearing the tissues. A protruding scar in the matrix will result in a split nail plate. If present in the bed or in the proximal nail fold, a scar also will induce dystrophic change in the plate. In fact, deformity of the nail bed is the most common result of serious nail trauma. Nail degloving, the partial or total shedding of the plate and neighboring tissues, has been recently described as an effect of trauma (besides other inducers such as other insults, dermatologic diseases, and drug reactions).40 DIFFERENTIAL DIAGNOSIS Nail hemorrhage is the common differential diagnosis for pigmented lesions. An NPB will usually discriminate between blood and melanin. The former may be freshly extravasated erythrocytes or hemolyzed products and pigments in or under the nail plate. Melanin, in contrast, can be discerned

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

CLINICAL FEATURES The results of trauma in the nail field include hemorrhage, lichenification, and scar. Nail hemorrhage may be of splinter type or more overt and of an acute nature, such as intralaminar hemorrhage (within the plate) and subungual hematoma. The effects of trauma can be enhanced by an abnormal protuberance of bone or cartilage under the nail plate, as in the case of a subungual corn (heloma durum) above an exostosis or osteochondroma. Other complications of external trauma are Beau lines, plate dystrophy, misplacement of the matrix, pyogenic granulomas, anomalous growth of a new nail plate, and even longitudinal melanonychia.50

991

by evidence of mechanical trauma such as hemorrhage or fibrosis. A scar must be distinguished from sclerosing conditions of the lamina propria of the nail, such as that that occurs after lichen planus or inherent to lichen sclerosus.

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Verruca CLINICAL FEATURES This human papillomavirus (HPV)–induced lesion can be either periungual or subungual. If under the nail plate, the latter can be minimally affected. Trauma may contribute to persistence and refractoriness to treatment. HISTOPATHOLOGIC FEATURES The ungual wart is similar to verruca vulgaris of skin. There is prominent digitated epithelial hyperplasia with koilocytotic (clear cell) changes of the upper strata and hyperkeratosis. The cytopathic changes are less pronounced than in palmoplantar verruca. The lesion may become inflamed after trauma.  FIGURE 36-12 Traumatic onychitis (lichen simplex chronicus onychalis). The lichenified bed epithelium, now with mature squamous metaplasia (epidermidalization), is orthokeratotic. The bed stroma (inaccurately referred to as the dermis) is fibrotic, reflecting a subjacent scar.

easily in the plate as opaque brown granules that are argyrophilic. Hemorrhages from other causes, such as subacute bacterial endocarditis, cholesterol embolism,

and antiphospholipid syndrome, should be kept in mind.52,53 Lichenification, when secondary to protracted trauma, is usually accompanied

DIFFERENTIAL DIAGNOSIS Besides the common wart, there is an autochthonous variety of verruca known as the onycholemmal horn.54 This lesion develops at the proximal and lateral folds and shows onycholemmal differentiation, namely, a proliferation of large polygonal keratinocytes without a granular layer, resembling that of trichilemmal and onycholemmal cysts. A much rarer entity that may be warty is mucinous syringometaplasia of the distal bed.55 This process is characterized by a focal invagination lined by squamous epithelium. Eccrine coils and ducts are present with mucinous cells. The ducts drain into the epidermoid invagination. Finally, the verrucous lesions of incontinentia pigmenti56 and epidermal nevus must be distinguished from viral warts. Another condition to be excluded when a “wart” is noted clinically is Bowen disease.57

Cysts

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 FIGURE 36-13 Traumatic onychitis (above exostosis). The macerated bed epithelium, also epidermidalized and hyperkeratotic, shows hydropic swelling and degeneration of keratinocytes. Subungual hyperkeratosis also indicates compression trauma of nail structures against the hard nail plate (and shoe).

The cysts in the nail are a broad group of lesions that differ in histogenesis and clinical expression. They may be minuscule and subclinical, such as subungual epidermoid inclusions (epidermoid buds), or similar to epidermoid buds but with nail dystrophy. Others are indistinguishable from so-called epidermal inclusion cysts of the skin and are known as implantation epidermoid cysts (keratin cyst, squamous epithelial cyst, traumatic cyst).58

associated with longitudinal melanonychia and may harbor onychomycosis.63 Some giant presentations of the neoplasm are known,64 as is a very rare occurrence in a child.65

 FIGURE 36-14 Onycholemmal cyst. In a subungual location, a cyst resembling a trichilemmal (pilar) cyst is identified. The content is parakeratotic, not separated from the epithelium by a granular layer.

CLINICAL FEATURES Cysts of sufficient size will produce a subungual mass. Some of them involve subjacent bone. A history of trauma is almost always elicited, except in the incidentally found subungual epidermoid inclusions. HISTOPATHOLOGIC FEATURES The implantation epidermoid cyst is unilocular, lined by thin epidermoid epithelium, and filled with orthokeratin. Subungual epidermoid inclusions are protrusions of the bed epithelium into the uppermost bed stroma. Although often asymptomatic, many of them may be associated with marked hyperplasia of the bed epithelium. This disorder results in subungual hyperkeratosis; onycholysis; and rarely, a shortened dystrophic nail plate. Calcification of the cyst contents may be also present.59 Finally, some cysts may contain epithelium that resembles that of the nail bed (and trichilemmal cysts) and hence are called onycholemmal cysts (Fig. 36-14).

CLINICAL FEATURES This neoplasm produces a markedly overcurved plate (in transverse fashion) with excessive longitudinal ridging and a yellow longitudinal band. When the plate is avulsed, the exophytic tumor in the matrix is digitated and filiform, being encased in a curved plate that offers a mirror-like funnel to the exuberant proliferation. It may be

DIFFERENTIAL DIAGNOSIS Unlike onychomatricoma, a verruca is epidermoid rather than basaloid and matrical. It also shows prominent keratinization and thick epithelium. The invaginated fibrokeratoma with matrix differentiation is mainly composed of a broad-based stromal fibrous nodule.69 However, this and even the more common fibrokeratoma of the nail bed may bear a superficial resemblance to onychomatricoma.70

Fibroma This is a complex group of hamartomas and benign neoplasms that overlap and

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

HISTOPATHOLOGIC FEATURES Microscopically, the neoplasm is matrical, of lobular pattern, formed by basaloid keratinocytes (Fig. 36-15). At the base of the lobules are narrow columns of densely arranged elongated cells with dark nuclei (similar to those in the matrical keratogenous zone). If these columns become dislodged, invaginations resembling hair follicle infundibula replace the formerly solid cores in the endophytic columns of cells.66,67 According to the predominance of epithelium or stroma in the tumor, the terms unguioblastoma and unguioblastic fibroma have been proposed.68

DIFFERENTIAL DIAGNOSIS Some malignant neoplasms may be partly or largely cystic, such as the malignant proliferating onycholemmal cyst.60 When solid, the tumor has now been termed onycholemmal carcinoma.61,62

Onychomatricoma Synonym: Filamentous tufted tumor in the matrix of a funnel-shaped nail

 FIGURE 36-15 Onychomatricoma. The matrical epithelium is digitated and lines stalks of stroma. No significant proliferation of either is noted other than the abnormal fingerlike projection impaling the nail plate.

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

are sometimes difficult to distinguish unequivocally. CLINICAL FEATURES The periungual fibromas and fibrokeratomas are sessile or filiform masses that occur in digital skin or around the nail field, as well as in nail tissues, where they arise in the proximal or distal nail fold or under the plate. A true fibroma, in contrast, is nodular and deep and always endophytic, even though it may be protuberant. However, it does not exhibit hyperkeratosis or epidermal collarettes, as observed in fibrokeratomas and periungual fibromas. Recently, multiple acral fibromas, either periungual or subungual, have been associated not only with tuberous sclerosis71 and neurofibromatosis but also with familial retinoblastoma.72 HISTOPATHOLOGIC FEATURES The periungual fibroma is essentially an angiofibroma. The accompanying epidermal hyperplasia is ancillary. On the other hand, the fibrokeratoma is a fibrotic proliferation, with numerous fibroblasts, lined by prominent epidermal hyperplasia with hyperkeratosis. This lesion may be very large and invaginated.69,73 Collagenous, cellular (fibroblastic), and edematous patterns are known. The true fibroma is composed of dense and hyaline collagen bundles, both aligned irregularly and interspersed among few fibroblasts. Elastic fibers are often few in numbers or absent. It is a deep and poorly circumscribed nodule located in reticular dermis or nail stroma. DIFFERENTIAL DIAGNOSIS The most important differential diagnosis of each fibroma of this taxonomically confusing group is with the other entities in this group, given the subtle variations that distinguish each one. It is noteworthy that periungual warts may resolve as relatively persistent angiofibromatous papules. A fibrokeratoma differs from a supernumerary digit in that the latter contains nerve trunks in its core, mainly near the base of the lesion. Infantile digital fibromatosis is richly spindle celled, with frequent paranuclear inclusion bodies in up to 2% of fibroblasts. Table 36-2 summarizes the spindle cell tumors that are worthy of consideration in the ungual field.

Digital Myxoid Pseudocyst Synonyms: Synovial cyst, dorsal finger cyst, cutaneous myxoid or mucoid cyst

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CLINICAL FEATURES This common disorder occurs in the proximal nail fold or

under the proximal matrix (see Chapter 16).93 They can be subungual and multiple.94 Attachment, through a stalk, to the distal interphalangeal joint has been proposed and found occasionally. This is not, however, sufficient evidence to claim herniation of synovium as the source of the cavity of the pseudocyst. It may just reflect the ganglion-like degeneration of nail stroma or a surrogate of tenosynovial tissue or of nearby real tenosynovial structures. HISTOPATHOLOGIC FEATURES The lesion is a pseudocyst without a genuine epithelial or even synovial lining. Some alignment and compression of marginal fibroblasts may give the impression of pseudosynovial lining, but the changes are not those of pseudosynovial metaplasia elsewhere. An ill-defined wall of fibroconnective tissue surrounds the lesion. The cavity is filled with mucoid material. The area initially is traversed by cobweb-like, loose myxomatous tissue with few fibroblasts before cavitation. If the tense mucin-filled cavity erodes upward, the epidermis or the nail epithelia may rupture, and evacuation of mucin may occur. Resealing of the defect and ongoing myxoid degeneration of soft tissues will be responsible for recurrence of the lesion unless it is fully treated. DIFFERENTIAL DIAGNOSIS A resolving abscess from chronic paronychia may enter into the differential diagnosis. If the mucin is drained, the resulting changes may suggest a scar. When epithelial necrosis occurs above a myxoid cyst, the traumatic changes may resemble those overlying exostosis or osteochondroma. A true myxoma or superficial acral fibromyxoma is never cavitated and contains numerous and prominent stellate fibroblasts.

Superficial Acral Fibromyxoma CLINICAL FEATURES This relatively recently described benign tumor of the hand and, most commonly, feet has a predominant location in the nail field. It can be slow growing and reach a large size, up to 5 cm. Most are around 1.75 cm, however,88 and could rarely erode the distal phalanx. Complete surgical excision is generally curative, but recurrence or persistence occurs in fewer than 10% of cases. HISTOPATHOLOGIC FEATURES The neoplasm is composed of spindle and stellate cells, only occasionally multinucleated, embedded in a myxoid or collagenous

matrix with increased vascularity and scattered mast cells.86 Atypia can be noted, at least in substantial grade in near 10% of cases. Mitoses, however, are absent or infrequent (Fig. 36-16). The tumor cells can be positive for CD34, epithelial membrane antigen, and CD99 but not every such marker is expressed in individual tumors. DIFFERENTIAL DIAGNOSIS Besides other benign soft tissue tumors with spindle or stellate cells, at least two malignant conditions should be excluded: dermatofibroma protuberans and acral myxoinflammatory fibroblastic sarcoma, a low-grade neoplasm of usually greater size and higher degree of atypia.92 Besides myxoid neurofibroma,95 another benign myxoid tumor to be considered is perineurioma.91

Osteocartilaginous Tumors This group of entities is related because of common clinical signs and histologic features. It includes exostosis, osteochondroma, enchondroma, osteoid osteoma, and solitary bone cyst. The first two conditions constitute the bulk of the presentations. Recently, it has been suggested that osteochondromas are exostoses and that either is a posttraumatic reactive process. CLINICAL FEATURES The classic triad for exostosis (pain, nail deformity, and radiographic abnormalities) may apply to the rest of these entities. A history of trauma is often noted.96 Exostosis is an exophytic lesion, either single or multiple (as in the multiple exostosis syndrome). Osteochondroma, enchondroma, osteoid osteoma, and solitary bone cyst are intraosseous disorders.97,98 The former may be multiple (as in Ollier dyschondroplasia and Maffucci syndrome, in which there are also multiple vascular malformations in soft tissue). HISTOPATHOLOGIC FEATURES The exostosis is a protuberant proliferation of mature bone surmounted by a fibrocartilaginous cap. An osteochondroma, not clearly distinguished from exostosis, is also a sessile or polypoid tumor of mature bone capped by mature cartilage. The enchondroma is a nodule of hyaline cartilage with haphazardly disposed chondrocytes that are often pleomorphic. The osteoid osteoma contains a nidus of disarrayed thick bone trabecules. The very rare subungual bone cyst is cavitated reparative fibrotic tissue with giant cells.

Table 36-2 Differential Diagnosis of Spindle Cell Tumors of the Nail Unit Propera SUBTYPE I. Mainly Fibrous Tumors Periungual or subungual fibroma71,72,74-77 Subungual pleomorphic fibroma4

Solitary sclerotic fibroma75

II. Both Fibrous and Epithelial Tumors Acquired periungual or subungual fibrokeratoma21,69,73,79,80

Unguioblastic or matrix fibroma68

III. Tumors with Myxoid Stroma Superficial acral fibromyxoma81-88

Cellular digital fibroma74,82

Sclerosing perineurioma89,90

Myxoinflammatory fibroblastic sarcoma92

IMMUNOHISTOCHEMISTRY

Polypoid or sessile tumor with dense collagenous matrix containing few fibroblasts (Also known as Koenen tumor or angiofibroma) Pleomorphic, hyperchromatic cells or giant multinucleated cells embedded in a collagenous stroma

Factor XIIIa+

Well-circumscribed dermal storiform nodule of sparse spindle cells with alternating wavy collagen fibers resembling the sclerotic ones in Cowden syndrome (Probable variants: subungual pleomorphic fibroma; storiform collagenoma6) Hypocellular, ill-defined nodule composed of dense collagen bundles and reduced elastic fibers and resembling DF elsewhere in the skin (very rarely, more cellular and sclerosing hemangioma-like) Hyperkeratotic large tumor, carrot shaped, with thick collagen bundles arrayed along the axis of the tumor and pseudo-nail plate formation above an accessory germinal matrix Invaginated fibrokeratoma69: variant occurring at the proximal nail fold, parallel but more proximal than the normal matrix Stroma-rich variant of onychomatricoma

(1) Dermal or subcutaneous proliferation of spindle and stellate cells (occasionally multinucleated) with slight nuclear atypia, arranged in a random, loose storiform or partly fascicular patterns (2) Slight to mild nuclear atypia (substantial atypia rarely) and infrequent mitoses (3) Myxoid stroma with mildly to moderately increased small blood vessels and scattered mast cells Intersecting fascicles of thin delicate bland spindle cells in the superficial reticular dermis with a fibrotic-to-slight myxoid stroma (Variant of superficial acral fibromyxoma?74,82) Other nail-located variant: tendon sheath fibroma-like91 Potential variants: storiform, intraneural, extraneural, reticular, and plexiform (1) Vaguely lobular architecture and oval, spindle, and epithelioid neoplastic cells with scattered, focally aggregated inflammatory cells (2) Bizarre giant cells (some resembling Reed-Sternberg cells, lipoblasts or ganglion cells) with large, lobulated, or multiple nuclei containing distinct nucleoli or intranuclear inclusions (3) Myxoid areas in variable proportions

(a) Vimentin+ (b) S-100, cytokeratin, smooth muscle actin, factor XIIIa, CD34: negative (a) CD34+ and O13+ (b) CD31, S-100, and CD68: negative (c) Factor XIIIa+ (storiform collagenoma) (a) Factor XIIIa variably + (b) CD34-

(a) Cd34+ and factor XIII+ (in some cells) (b) Vimentin+ and actin+ (one case) (a) CD34+ (b) EMA, actin, desmin, keratins, S100 protein, CD99, and HMB45 all negative

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

Fibrous dermatofibroma75,78

HISTOLOGIC FEATURES

(a) CD34: +strongly in spindle cells in all cases (b) Factor XIIIa:+ only scattered stromal cells (a) EMA, vimentin, type IV collagen and laminin: positive (b) Perineurial markers claudin-1 and GLUT-1 + Vimentin+; CD68+ and CD34+ (some cells)

a

Tumors near the nail unit, such as infantile digital fibromatosis, keloid, giant cell tumor and fibroma of the tendon sheath, and juvenile hyaline fibromatosis, have not been expressly reported in the journal literature as ungual proper but are dealt with in nail textbooks.6,8

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

HISTOPATHOLOGIC FEATURES Squamous cell carcinoma in situ is similar to that noted in skin, namely, a keratinizing proliferation of atypical keratinocytes throughout the epithelium of the periungual epidermis, nail bed, or matrix. It may be pigmented. Squamous cell carcinoma consists, as in other sites, of a bulky and invasive proliferation of atypical keratinocytes with anaplasia and dyskeratosis. The invasion of nearby stroma is jagged and irregular and more infiltrative than pushing. Verrucous carcinoma (epithelioma cuniculatum) is an exo- or endophytic neoplasm with deep burrows and fistulas that are strikingly well differentiated and deeply invasive, with expansive and pushing rather than classically infiltrating margins. Bone invasion is noted frequently.107  FIGURE 36-16 Superficial acral fibromyxoma. The neoplasm is composed of spindle and stellate cells, only occasionally multinucleated, embedded in a myxoid or collagenous matrix with increased vascularity and scattered mast cells.

DIFFERENTIAL DIAGNOSIS First of all, exostosis and osteochondroma must be distinguished, but this is difficult histologically because both may have cartilaginous caps (fibrocartilaginous and hyaline, respectively), although mature exostoses lose their cartilaginous caps. Enchondroma must be differentiated cytologically from chondrosarcoma (the latter is a distinct yet rare complication of osteochondroma and enchondroma). Osteoid osteoma is identical histologically to benign osteoblastoma.97 If protuberant, any of the ossified and, therefore, calcified tumors may be mimicked by occasional subungual calcifications of the nail bed or nearby soft tissues and by circumscribed calcinosis cutis.

HISTOPATHOLOGIC FEATURES This wellcircumscribed and encapsulated solid tumor is biphasic and highly organoid. Besides afferent arterioles and efferent venules, there are numerous vessels enmeshing small and round cuboidal cells. The cells are uniform and contain dark nuclei and comparatively pale cytoplasm. Many nerves are also present. DIFFERENTIAL DIAGNOSIS Other vascular tumors may resemble the glomus tumor on cursory examination. Among them, angioleiomyoma may have a complex net of vessels as well, but eosinophilic spindle-shaped smooth muscle bundles define the latter.101

Squamous Cell Carcinoma Glomus Tumor This rare tumor is observed mostly in the hand, particularly in the subungual area.

996

CLINICAL FEATURES The glomus tumor is a small (<1 cm), bluish red, and intensely painful lesion.99 Some tumors may produce slight plate deformity with ridging and fissuring. A history of trauma is frequent. After surgical excision, recurrence is relatively high (10%-20% of cases). Some cases may be associated with neurofibromatosis.100

CLINICAL FEATURES Squamous cell carcinoma in situ (Bowen disease) may be polydactilous,102 usually involving the hands more often than the feet. Rarely, pigmented bands are noted. Much more frequently, invasive squamous cell carcinoma, as other tumors of the nail unit, may give rise to a painful subungual or periungual mass or swelling that may mimic traumatic and primarily inflammatory disorders.103,104 This tumor can be associated with HPV infection or be preceded by psoriasis.105,106

DIFFERENTIAL DIAGNOSIS Squamous cell carcinoma in situ has to be distinguished from verrucae displaying atypia or from the nearby in situ component of an invasive squamous cell carcinoma.57 Squamous cell carcinoma presents few problems in recognition. The distinction from keratoacanthoma probably remains the most important one. Verrucous carcinoma108 must be distinguished from keratoacanthoma, verrucae, pseudoepitheliomatous hyperplasia, and conventional squamous cell carcinoma. Finally, metastatic tumors may mimic, besides infections or cysts, squamous cell carcinoma.109

Keratoacanthoma CLINICAL FEATURES This entity may be subungual or periungual, either as solitary or multiple painful lesions.110 It should be emphasized that subungual keratoacanthoma (KA) does not behave like or even morphologically resemble cutaneous KA. It is of longer duration (>1 year), rapidly erodes bone, and often does not regress, except exceptionally.111 HISTOPATHOLOGIC FEATURES Subungual KA has a narrow, more vertically oriented profile than common KA but otherwise is composed of deeply infiltrating aggregates of large pale (glassy) keratinocytes with keratohyalin granules and prominent dyskeratosis21 (Fig. 36-17). The structure is centered around a keratin-plugged crater delimited by prominent lips. Compared with conventional KA, it is less inflamed (with fewer neutrophils and eosinophils), does not show fibrosis at the base, and readily infiltrates the subjacent bone. Even following these criteria, a

 FIGURE 36-17 Keratoacanthoma. A cluster of glassy keratinocytes, one among many, is identified. Prominent dyskeratosis and a small neutrophilic abscess are noted toward the center of the cluster.

confident distinction from conventional squamous cell carcinoma is difficult.110 DIFFERENTIAL DIAGNOSIS Given the peculiar features of subungual KA, its distinction from squamous cell carcinoma can be difficult. Despite a similar gender distribution (male > female) to that of squamous cell carcinoma, KA often presents as a mass, occurs in a younger population, is rarer, grows faster, and is of shorter duration than squamous cell carcinoma. It may also be multiple, may erode bone (which may be reconstituted), and is rarely associated with a history of trauma. The tumors of incontinentia pigmenti are indistinguishable those of from KA.112 Histologically, the well-differentiated appearance of large keratinocytes arranged in large aggregates with central dyskeratosis and at the base of a crater favors KA. The occasionally progressive course of KA raises the differential diagnosis of endophytic—rather than more easily recognized exophytic—verrucous carcinoma. In the author’s opinion, some KAs that do not regress but rather destroy structures inexorably are, in fact, verrucous carcinomas, an idea posed several years ago.113 More recently, transition from KA to verrucous carcinoma has been suggested.114 An important point is that the subungual tumors associated with incontinentia pigmenti are indistinguishable from keratoacanthoma.112

Typical Melanocytic Proliferations (Benign Melanocytic Hyperplasia), Including Ephelis, Simple Lentigo, and Melanocytic Nevi These entities are very frequent causes of longitudinal melanonychia. The latter feature results from melanin granules in the growing plate derived from the segment of matrix involved by the melanocytic activation or proliferation.115 Dermatoscopy has gained ground in the management of longitudinal bands, but a biopsy is the gold standard in definitively excluding malignant melanoma.116,117 CLINICAL FEATURES Longitudinal melanonychia is a brown-black band that indicates a melanin-producing lesion of the matrix. The same type of lesion in the bed, a non–plate-forming portion of the nail, results in a pigmented spot that is discrete and immobile. All of the preceding entities may produce a band that is narrow, sharply circumscribed, and homogeneous.118 The current workup of melanonychia includes careful clinical assessment, dermatoscopy, and one of three types of matrical biopsy (punch, shave or lateral longitudinal).116,119 HISTOPATHOLOGIC FEATURES The description of microscopic findings in pigmented longitudinal bands has been relatively unchanged for many years. Melanocytic hyperplasia or macule, which may be the

DIFFERENTIAL DIAGNOSIS The longitudinal melanonychia derived from neoplastic disorders (lentigo and nevus) must be distinguished from the same phenomenon secondary to the freckle-like lesions with hyperactive melanocytes. The latter lesions may be related to ethnicity (Africans and Asians), may be spontaneous or congenital, may develop after trauma (such as friction or radiation), or may be associated with the LaugierHunziker-Baran syndrome.125 These benign causes of longitudinal melanonychia have, in turn, to be distinguished from early melanoma, also characterized by a pigmented band. However, this band usually is wider, darker or variegated, and less well circumscribed than a benign pigmented band. It reflects a larger, more irregular, and heterogeneous neoplasm of the matrix.

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

equivalent of an ephelis (freckle), shows hyperpigmentation either with or without a (functional) slightly increased numbers of melanocytes. It is essentially a well-demarcated pigmented macule in the matrix.120 A simple lentigo exhibits an increased number of melanocytes singly disposed in a variably hyperplastic epithelium. These two entities tend to appear early in life.121 The acquired or congenital melanocytic nevus, which is uncommon in the nail unit, contains nests of melanocytes in variably hyperpigmented rete ridges. Most of the ungual nevi are junctional and only rarely compound.122 Blue nevus shows up very rarely in subungual location,123 where a regressed melanoma may mimic it.124

Atypical Melanocytic Proliferation, Including Melanoma in Situ Under this rubric are included the atypical melanocytic proliferations and the early stage of melanoma in situ. Also included is recurrent or persistent melanocytosis with histologic features that simulate melanoma. CLINICAL FEATURES The early phase of acral melanoma may present as longitudinal melanonychia that is broader than 5 mm and associated with nail dystrophy, a bleeding mass,118 and Hutchinson sign (spread of pigmentation in the nail folds). HISTOPATHOLOGIC FEATURES On biopsy of the nail plate, the melanin granules are distributed broadly and, more important, throughout the whole thickness of the plate. This is a reflection of the usually wide and lengthy extension of the primary lesion. A problem in its

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

recognition is the relatively uniform pattern of melanocyte proliferation near the junction of the matrix (practically always the source of melanoma in situ). However, the process may be cellular, and nuclear pleomorphism and other signs of malignancy may be obvious (prominent nucleoli, increased or abnormal mitoses, longitudinally branching dendritic melanocytes). A suprabasal location of melanocytes throughout the lower half of the matrix has been described.126 If nests are formed, they are usually small, only slightly pleomorphic, and almost always nevoid. The latter characteristics account for the relative reluctance of pathologists to accept such a subtle proliferation as malignant. Regardless of the terminology applied to such a lesion, complete removal of the lesion is mandatory. However, dermatoscopy has been claimed as a means of follow-up in some instances.116 Hutchinson sign may be seen histologically as the continuation of the same matrical or bed-extended proliferation of melanocytes in the epidermoid epithelia of epo- and hyponychium or the epidermis of the nail folds. The diagnostic utility of Hutchinson sign is limited by its presence in some nevi, so far only dermatoscopically proven,127 or the existence of a pseudo-Hutchinson sign given by pigmented Bowen disease or by overly transparent nail folds that would appear falsely pigmented.128 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes the entities discussed previously, namely ephelis, lentigo, nevus, and invasive melanoma. As mentioned earlier, the diagnosis of these various lesions is based on the frequency, disposition, and degree of atypia of melanocytes (see Chapter 27).

Melanoma

998

CLINICAL FEATURES Besides the predominant acral lentiginous pattern, malignant melanoma may be nodular and, less frequently, desmoplastic or even neurotropic (see also Chapter 27).129-131 Although early melanomas may present with a longitudinal melanotic streak, more advanced tumors may give rise to a fully pigmented flat or tumorous mass in the nail field and periungual tissues. The pigmented band usually has the same characteristics as in melanoma in situ.118 More advanced melanomas may be amelanotic and may be accompanied by destruction of the plate, ulceration, and occasional longitudinal erythronychia.132 Melanotic whitlow (Hutchinson

 FIGURE 36-18 Melanoma, microinvasive. In the matrical epithelium, mostly basally located, are small yet hyperchromatic melanocytes that are irregularly arranged as single cells and in variably confluent nests. Few melanocytes are subtly present in the bed stroma.

sign) is found very frequently at advanced stages of the disease.128 HISTOPATHOLOGIC FEATURES As discussed in Chapter 27, the criteria for diagnosis include variable degrees of the following: a lesion of sufficient breadth, asymmetry, poor circumscription, increased numbers of atypical basilar melanocytes reaching confluence (Fig. 36-18), aggregates of atypical melanocytes that are irregularly sized and shaped, and pagetoid spread.132 The presence of microscopic Hutchinson sign in proximal or lateral nail fold epithelia, but not so in the hyponychium (which is still part of the matrical stream of cells and keratins), is a valuable microscopic sign of melanoma. Extension of atypical melanocytes into subungual epidermoid inclusions (adnexal-like extension) may show greater relative thickness than actual malignant melanocytes in the subungual stroma. DIFFERENTIAL DIAGNOSIS The main pitfall is the misdiagnosis of melanoma as a simple lentigo, nevus, or atypical intraepithelial melanocytic proliferation. The false-negative diagnosis of one of those entities, particularly misconstrued diagnostically as an “atypical melanocytic proliferation,” is always involved when a delay in the diagnosis of malignant melanoma happens. Another pitfall is the erroneous assumption, for example, that melanoma is not an occurrence in

children, although such diagnoses should always be carefully made.133,134

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CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

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Dermatology, 2nd ed. New York: Mosby Elsevier; 2008:1019-1036. Sobera JO, Elewski BE. Fungal diseases, in Bolognia JL, Jorizzo JL, Rapini RP (eds). Dermatology, 2nd ed. New York: Mosby Elsevier; 2008:1135-1163. Grover C, Reddy BS, Chaturvedi KU: Onychomycosis and the diagnostic significance of nail biopsy. J Dermatol. 2003;30(2):116-122. Reisberger EM, Abels C, Landthaler M, Szeimies RM: Histopathological diagnosis of onychomycosis by periodic acid-Schiff-stained nail clippings. Br J Dermatol. 2003;148(4):749-754. Weinberg JM, Koestenblatt EK, Jennings MB: Utility of histopathologic analysis in the evaluation of onychomycosis. J Am Podiatr Med Assoc. 2005;95(3):258263. Walling HW, Sniezek PJ: Distribution of toenail dystrophy predicts histologic diagnosis of onychomycosis. J Am Acad Dermatol. 2007;56(6):945-948. Hernández M, Harrist TJ, GonzálezServa A: Flowcharting the nail plate biopsy in search of fungi [abstract]. Am J Dermatopathol. 2007;29(5):503. González-Serva A: Pigmented sheets in a nail-plate biopsy: Mirrors of melaninproducing onychometameres [abstract]. Am J Dermatopathol. 2007;29(2):204. Braun RP, Baran R, Saurat JH, Thomas L: Surgical pearl: dermoscopy of the free edge of the nail to determine the level of nail plate pigmentation and the location of its probable origin in the proximal or distal nail matrix. J Am Acad Dermatol. 2006;55(3):512-513. Grover C, Nanda S, Reddy BS, Chaturvedi KU: Nail biopsy: assessment of indications and outcome. Dermatol Surg. 2005; 31(2):190-194. Holzberg M: Common nail disorders. Dermatol Clin. 2006;24(3):349-354. Baran R, Richert B: Common nail tumors. Dermatol Clin. 2006;24(3):297-311. Kovich OI, Soldano AC: Clinical pathologic correlations for diagnosis and treatment of nail disorders. Dermatol Ther. 2007;20(1):11-16. Gupta AK, Ryder JE, Summerbell RC: Onychomycosis: classification and diagnosis. J Drugs Dermatol. 2004;3(1):51-56. Gupta AK, Ricci MJ: Diagnosing onychomycosis. Dermatol Clin. 2006;24(3): 365-369. Cabral A, Berger TH, Middag-Broekman JH, Boon ME: Unequivocal morphological diagnosis of fungi in morphologically abnormal nails. Histopathology. 2006; 48(7):862-867. Karimzadegan-Nia M, Mir-AminMohammadi A, Bouzari N, Firooz A: Comparison of direct smear, culture and histology for the diagnosis of onychomycosis. Australas J Dermatol. 2007; 48(1):18-21. Chang A, Wharton J, Tam S, et al: A modified approach to the histologic diagnosis of onychomycosis. J Am Acad Dermatol. 2007;57(5):849-853. Machler BC, Kirsner RS, Elgart GW: Routine histologic examination for the diagnosis of onychomycosis: an evaluation of sensitivity and specificity. Cutis. 1998;61(4):217-219. Chowdhary A, Randhawa HS, Sharma S, et al: Malassezia furfur in a case of

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the nailbed. Am J Dermatopathol. 2001; 23(1):36-40. Ruiz-Villaverde R, Blasco-Melguizo J, Hernandez-Jurado I, et al: Bilateral and multiple periungual fibromas as an oligosymptomatic form of tuberous sclerosis. Dermatology. 2004;209(2):160-161. Dereure O, Savoy D, Doz F, et al: Multiple acral fibromas in a patient with familial retinoblastoma: a cutaneous marker of tumour-suppressor gene germline mutation? Br J Dermatol. 2000;143(4):856-859. Hashiro M, Fujio Y, Tanaka M, Yamatodani Y: Giant acquired fibrokeratoma of the nail bed. Dermatology. 1995;190(2):169-171. McNiff JM, Subtil A, Cowper SE, et al: Cellular digital fibromas: distinctive CD34-positive lesions that may mimic dermatofibrosarcoma protuberans. J Cutan Pathol. 2005;32(6):413-418. Mahmood MN, Salama ME, Chaffins M, et al: Solitary sclerotic fibroma of skin: a possible link with pleomorphic fibroma with immunophenotypic expression for O13 (CD99) and CD34. J Cutan Pathol. 2003;30(10):631-636. Hsieh YJ, Lin YC, Wu YH, et al: Subungual pleomorphic fibroma. J Cutan Pathol. 2003;30(9):569-571. Tosti A, Cameli N, Peluso AM, et al: Storiform collagenoma of the nail. Cutis. 1999;64(3):203-204. Kinoshita Y, Kojima T, Furusato Y: Subungual dermatofibroma of the thumb. J Hand Surg [Br]. 1996;21(3):408-409. Carlson RM, Lloyd KM, Campbell TE: Acquired periungual fibrokeratoma: a case report. Cutis. 2007;80(2):137-140. Saito S, Ishikawa K. Acquired periungual fibrokeratoma with accessory germinal matrix. J Hand Surg [Br]. 2002; 27(6):549-555. Oteo-Alvaro A, Meizoso T, Scarpellini A, et al: Superficial acral fibromyxoma of the toe, with erosion of the distal phalanx. A clinical report. Arch Orthop Trauma Surg. 2008;128(3):271-274. Guitart J, Ramirez J, Laskin WB: Cellular digital fibromas: what about superficial acral fibromyxoma? J Cutan Pathol. 2006;33(11):762-764. Abou-Nukta F, Fiedler P, Parkash V, Arons J: Superficial acral fibromyxoma of the distal phalanx of the thumb. J Hand Surg [Br]. 2006;31(6):619-620. Quaba O, Evans A, Al-Nafussi AA, Nassan A: Superficial acral fibromyxoma. Br J Plast Surg. 2005;58(4):561-564. Meyerle JH, Keller RA, Krivda SJ: Superficial acral fibromyxoma of the index finger. J Am Acad Dermatol. 2004; 50(1):134-136. Andre J, Theunis A, Richert B, de SaintAubain N: Superficial acral fibromyxoma: clinical and pathological features. Am J Dermatopathol. 2004;26(6):472-474. Kazakov DV, Mentzel T, Burg G, Kempf W: Superficial acral fibromyxoma: report of two cases. Dermatology. 2002; 205(3):285-258. Fetsch JF, Laskin WB, Miettinen M: Superficial acral fibromyxoma: a clinicopathologic and immunohistochemical analysis of 37 cases of a distinctive soft tissue tumor with a predilection for the fingers and toes. Hum Pathol. 2001; 32(7):704-714.

89. Smith K, Skelton H: Cutaneous fibrous perineurioma. J Cutan Pathol. 1998; 25(6):333-337. 90. Mentzel T, Kutzner H: Reticular and plexiform perineurioma: clinicopathological and immunohistochemical analysis of two cases and review of perineurial neoplasms of skin and soft tissues. Virchows Arch. 2005;447(4):677-682. 91. Baran R, Perrin C: Perineurioma: a tendon sheath fibroma-like variant in a distal subungual location. Acta Derm Venereol. 2003;83(1):60-61. 92. Jurcic V, Zidar A, Montiel MD, et al: Myxoinflammatory fibroblastic sarcoma: a tumor not restricted to acral sites. Ann Diagn Pathol. 2002;6(5):272-280. 93. de Berker D, Goettman S, Baran R: Subungual myxoid cysts: clinical manifestations and response to therapy. J Am Acad Dermatol. 2002;46(3):394-398. 94. Kivanc-Altunay I, Kumbasar E, Gokdemir G, et al: Unusual localization of multiple myxoid (mucous) cysts of toes. Dermatol Online J. 2004;10(1):23. 95. Baran R, Haneke E: Subungual myxoid neurofibroma on the thumb. Acta Derm Venereol. 2001;81(3):210-211. 96. Lee SK, Jung MS, Lee YH, et al: Two distinctive subungual pathologies: subungual exostosis and subungual osteochondroma. Foot Ankle Int. 2007;28(5):595-601. 97. Ekmekci P, Bostanci S, Erdogan N, et al: A painless subungual osteoid osteoma. Dermatol Surg. 2001;27(8):764-765. 98. Bostanci S, Ekmekci P, Ekinci C, et al: Subungual osteochondroma: a case report. Dermatol Surg. 2001;27(6):591-593. 99. Maalla R, Hmid M, Mellouli O, Klila M: [Glomus tumours of the hand. About 10 cases]. Tunis Med. 2007;85(6):469-472. 100. Okada O, Demitsu T, Manabe M, Yoneda K: A case of multiple subungual glomus tumors associated with neurofibromatosis type 1. J Dermatol. 1999; 26(8):535-537. 101. Baran R, Requena L, Drape JL: Subungual angioleiomyoma masquerading as a glomus tumour. Br J Dermatol. 2000; 142(6): 1239-1241. 102. Koch A, Schonlebe J, Haroske G, et al: Polydactylous Bowen’s disease. J Eur Acad Dermatol Venereol. 2003;17(2):213-215. 103. Figus A, Kanitkar S, Elliot D: Squamous cell carcinoma of the lateral nail fold. J Hand Surg [Br]. 2006;31(2):216-220. 104. Dalle S, Depape L, Phan A, et al: Squamous cell carcinoma of the nail apparatus: clinicopathological study of 35 cases. Br J Dermatol. 2007;156(5):871-874. 105. Zabawski EJ Jr, Washak RV, Cohen JB, et al: Squamous cell carcinoma of the nail bed: is finger predominance another clue to etiology? A report of 5 cases. Cutis. 2001;67(1):59-64. 106. Dobson CM, Azurdia RM, King CM: Squamous cell carcinoma arising in a psoriatic nail bed: case report with discussion of diagnostic difficulties and therapeutic options. Br J Dermatol. 2002;147(1):144-149. 107. Tosti A, Morelli R, Fanti PA, et al: Carcinoma cuniculatum of the nail apparatus: report of three cases. Dermatology. 1993;186(3):217-221. 108. Van Geertruyden JP, Olemans C, Laporte M, Noel JC: Verrucous carcinoma of the nail bed. Foot Ankle Int. 1998;19(5):327-328.

109. Cohen PR: Metastatic tumors to the nail unit: subungual metastases. Dermatol Surg. 2001;27(3):280-293. 110. Baran R, Mikhail G, Costini B, et al: Distal digital keratoacanthoma: two cases with a review of the literature. Dermatol Surg. 2001;27(6):575-579. 111. Sinha A, Marsh R, Langtry J: Spontaneous regression of subungual keratoacanthoma with reossification of underlying distal lytic phalynx. Clin Exp Dermatol. 2005;30(1):20-22. 112. Baran R, Goettmann S: Distal digital keratoacanthoma: a report of 12 cases and a review of the literature. Br J Dermatol. 1998;139(3):512-515. 113. Scarani P, Ghigi G, Bertarelli C, Eusebi V: Subungual keratoacanthoma: a variant of verrucous squamous cell carcinoma of the skin. Appl Pathol. 1983;1(6):339-342. 114. Baran R, Tosti A, De Berker D: Periungual keratoacanthoma preceded by a wart and followed by a verrucous carcinoma at the same site. Acta Derm Venereol. 2003;83(3):232-233. 115. Andre J, Lateur N: Pigmented nail disorders. Dermatol Clin. 2006;24(3):329-339. 116. Braun RP, Baran R, Le Gal FA, et al: Diagnosis and management of nail pigmentations. J Am Acad Dermatol. 2007; 56(5):835-847. 117. Thomas L, Dalle S: Dermoscopy provides useful information for the management of melanonychia striata. Dermatol Ther. 2007;20(1):3-10. 118. Haneke E, Baran R: Longitudinal melanonychia. Dermatol Surg. 2001;27(6): 580-584. 119. Jellinek N: Nail matrix biopsy of longitudinal melanonychia: diagnostic algorithm including the matrix shave biopsy. J Am Acad Dermatol. 2007;56(5):803-810. 120. Husain S, Scher RK, Silvers DN, Ackerman AB: Melanotic macule of nail unit and its clinicopathologic spectrum. J Am Acad Dermatol. 2006;54(4):664-667. 121. Goettmann-Bonvallot S, Andre J, Belaich S: Longitudinal melanonychia in children: a clinical and histopathologic study of 40 cases. J Am Acad Dermatol. 1999;41(1):17-22. 122. Tosti A, Baran R, Piraccini BM, et al: Nail matrix nevi: a clinical and histopathologic study of twenty-two patients. J Am Acad Dermatol. 1996;34 (5, pt 1):765-771. 123. Causeret AS, Skowron F, Viallard AM, et al: Subungual blue nevus. J Am Acad Dermatol. 2003;49(2):310-312. 124. Yang CH, Yeh JT, Shen SC, et al: Regressed subungual melanoma simulating cellular blue nevus: managed with sentinel lymph node biopsy. Dermatol Surg. 2006;32(4):577-580; discussion 580-581. 125. Moore RT, Chae KA, Rhodes AR: Laugier and Hunziker pigmentation: a lentiginous proliferation of melanocytes. J Am Acad Dermatol. 2004;50(5 suppl): S70-S74. 126. Tomizawa K: Early malignant melanoma manifested as longitudinal melanonychia: subungual melanoma may arise from suprabasal melanocytes. Br J Dermatol. 2000;143(2):431-434. 127. Kawabata Y, Ohara K, Hino H, Tamaki K: Two kinds of Hutchinson’s sign, benign and malignant. J Am Acad Dermatol. 2001;44(2):305-307.

128. Baran R, Kechijian P: Hutchinson’s sign: a reappraisal. J Am Acad Dermatol. 1996; 34(1):87-90. 129. Parodi PC, Scott CA, De Biasio F, et al: Desmoplastic melanoma of the nail. Ann Plast Surg. 2003;50(6):658-662. 130. Tan KB, Moncrieff M, Thompson JF, et al: Subungual melanoma: a study of 124 cases highlighting features of early lesions, potential pitfalls in diagnosis, and guidelines for histologic reporting. Am J Surg Pathol. 2007;31(12):1902-1912.

131. Cohen T, Busam KJ, Patel A, Brady MS: Subungual melanoma: management considerations. Am J Surg. 2008;195(2):244248. 132. Harwood M, Telang GH, RobinsonBostom L, Jellinek N: Melanoma and squamous cell carcinoma on different nails of the same hand. J Am Acad Dermatol. 2008;58(2):323-326. 133. Antonovich DD, Grin C, Grant-Kels JM: Childhood subungual melanoma in situ in diffuse nail melanosis beginning as

expanding longitudinal melanonychia. Pediatr Dermatol. 2005;22(3):210-212. 134. Motta A, Lopez C, Acosta A, Penaranda C: Subungual melanoma in situ in a Hispanic girl treated with functional resection and reconstruction with onychocutaneous toe free flap. Arch Dermatol. 2007;143(12):1600-1602.

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CHAPTER 37 Disorders of the Oral Mucosa

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Mark A. Lerman Sook-Bin Woo Oral and maxillofacial pathology is the specialty of dentistry and pathology that concerns itself with the study, diagnosis, and management of developmental, inflammatory, infectious, neoplastic, and metabolic diseases relating to the teeth, the maxilla and mandible, the major and minor salivary glands, and the oral mucosa. This chapter focuses on the more common oral mucosal diseases encountered in a pathology practice. As in the practice of dermatopathology, the importance of a thorough understanding of the clinical aspects and dynamic evolution of each entity cannot be overemphasized.

DEVELOPMENTAL CONDITIONS

Fordyce Granules Synonym: Ectopic sebaceous glands. Fordyce granules are intraoral sebaceous glands that are present in approximately 80% of the population1 and are viewed as a normal anatomic variation. They become prominent after puberty because of hormonal influences. CLINICAL FEATURES They occur as yellow to white papules measuring 1 to 3 mm in diameter and present symmetrically on the buccal mucosa, upper and lower labial mucosa, lip vermilion, and the retromolar areas. Rarely, they also may be seen on the tongue, gingiva, and palate. HISTOPATHOLOGIC FEATURES They consist of normal sebaceous glands that may communicate with the surface epithelium via a duct. Occasionally, there may be hyperplasia of the sebaceous acini, retention of secretions with pseudocyst formation, and even adenomatous change.2 In one report, a hair follicle and hair shaft were present.

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DIFFERENTIAL DIAGNOSIS Most Fordyce granules are diagnosed on clinical findings alone, and there is usually no need for a biopsy. Some salivary gland neoplasms (especially those in the major

glands) may exhibit focal sebaceous differentiation within an obviously neoplastic process.

White Sponge Nevus Synonyms: Leukoedema exfoliativum mucosae oris, congenital leukokeratosis mucosa oris, naevus spongiosus albus mucosae. White sponge nevus is an uncommon mucosal condition transmitted in an autosomal dominant fashion with a high degree of penetrance and variable expressivity that affects primarily the oral mucosa, although genital, anal, laryngeal, and esophageal mucosal involvement also has been documented. There are no concomitant skin lesions and ocular coloboma have been described in one report. White sponge nevus is the result of abnormal keratinization and faulty desquamation. This condition is caused by a mutation in differentiation-specific keratins K4 (on chromosome 12q) and/or K13 (on chromosome 17q) in a domain critical for keratin filament stability.3 CLINICAL FEATURES Onset is in early childhood. The buccal mucosa is thickened, boggy, and white with soft, spongy folds and creases. Involvement is usually bilateral and the labial mucosa, alveolar ridge mucosa, floor of the mouth, and tongue may show similar changes. It is asymptomatic and may undergo periods of exacerbation and remission. Tetracycline and penicillin have been reported to improve lesions. HISTOPATHOLOGIC FEATURES There is parakeratosis, spongiosis in the absence of inflammation, epithelial hyperplasia with cytoplasmic clearing of the spinous cells, and eosinophilic para- and perinuclear condensations. These condensations are the most characteristic feature of white sponge nevus (Fig. 37-1). Some spinous cells may exhibit nuclear degeneration and anucleation. Bacterial colonization is a result of chronic trauma. The lamina propria is usually devoid of inflammation. Rarely, epidermolytic changes are noted. Ultrastructurally, the cells show segregation of organelles with some areas being completely devoid of organelles. There is abnormal aggregation of tonofilaments into dense clumps corresponding to the para- and perinuclear condensations, and the superficial cells contain Odland bodies (membrane-coating granules) but without transfer of granules into the intercellular space.

DIFFERENTIAL DIAGNOSIS Leukoedema does not show para- and perinuclear eosinophilia. Hereditary benign intraepithelial dyskeratosis (HBID) also lacks eosinophilic condensations and often demonstrates a “cell-within-a-cell” phenomenon, in which an epithelial cell appears to be surrounded or engulfed by an adjacent epithelial cell.4 Chronic bite injury is characterized by hyperparakeratosis with superficial bacterial colonization, acanthosis, and intrakeratinocyte edema without eosinophilic condensations. In some cases of white sponge nevus, there may be a component of chronic cheek chewing present histologically because the lesions protrude and may be traumatized inadvertently.

Leukoedema Leukoedema is a fairly common mucosal condition reported to be present in 4% to 90% of the general population and therefore sometimes considered a normal variation.5 This wide variation in prevalence figures is likely a reflection of the variation in criteria used for diagnosis, differences in examination conditions, and differences in population groups and oral habits. The prevalence of leukoedema may appear to be higher in African Americans than in other races because the pigmented nature of their mucosa contrasts more sharply with this white lesion. Its occurrence has been associated with the use of tobacco products, chewing of coca leaves, and smoking of cannabis.6 It is believed that leukoedema occurs as a result of local insult to the mucosa because in some cases cessation of smoking results in resolution of the lesions.7 CLINICAL FEATURES The condition affects both children and adults. The buccal mucosa and sometimes the labial mucosa have a pale milky white or gray opalescent appearance with crinkly folds and wrinkles. When the mucosa is stretched, the white crinkly appearance diminishes or disappears.5 HISTOPATHOLOGIC FEATURES The mucosa may or may not be thinly parakeratotic. There is acanthosis with the formation of broad rete ridges. The midlevel spinous cells are swollen and vacuolated (Fig. 37-2). The cells in the outermost layer are vacuolated and ballooned and usually anucleate; outlines of plasma membranes have a “jigsaw puzzle” effect. Ultrastructurally, the swollen cells of the midepithelium contain clumped

glycogen-like material and abnormal mitochondria. The superficial ballooned cells have membrane-bound spaces that contain fragmented organelles, abnormal keratohyalin-like granules, and dispersed tonofilaments. These features have been interpreted as reversible degenerative changes in the midepithelium and irreversible degenerative changes in the superficial cells.

Oral Lymphoepithelial Cyst

 FIGURE 37-1 White sponge nevus. Keratinocytes exhibit perinuclear eosinophilic condensations.

Oral lymphoepithelial cysts are cystic structures that develop most commonly on the ventrolateral tongue, the soft palate, the floor of the mouth, or within the tonsils. Their etiology is unknown, but they may develop from inflammation of, or trauma to, deep tonsillar crypts.9 CLINICAL FEATURES Lymphoepithelial cysts are seen most commonly in young adults. They are generally yellow in color and approximately 1 cm in diameter. They present as asymptomatic mucosal masses that may be either soft or firm to palpation. They have occasionally been reported in association with epidermoid cysts.10

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

DIFFERENTIAL DIAGNOSIS Biopsies of the linea alba may be identical to leukoedema, supporting superficial mucosal injury as an etiologic factor. A similar histology is noted in the sucking pads of neonates.8 Chronic bite injury (morsicatio mucosae oris) also exhibits leukoedema but in addition shows marked hyperparakeratosis with fissures and clefts rimmed by bacteria (impetigination).

HISTOPATHOLOGIC FEATURES The lumen is usually filled with parakeratin. They are lined by parakeratinized stratified squamous epithelium and exhibit lymphocyte exocytosis. The wall of the cyst contains diffuse sheets of lymphocytes, often demonstrating germinal center formation (Fig. 37-3).11 DIFFERENTIAL DIAGNOSIS Papillary cystadenoma lymphomatosum (Warthin tumors) are benign salivary gland tumors that also feature an epithelial lining and prominent lymphoid component. However, this tumor is seen primarily within the parotid gland and exhibits multiple papillary infoldings and oncocytic metaplasia of the epithelium.

Gingival Cyst of the Adult  FIGURE 37-2 Leukoedema. Ballooned cells, compact cells, and superficial, degenerated, and anucleate cells are demonstrated.

The gingival cyst of the adult is a developmental odontogenic cyst that is believed to be derived from rests of the dental

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patients with this condition rarely demonstrate candidiasis elsewhere in the mouth, and the clinical lesion persists even after treatment with antifungal medications.

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

CLINICAL FEATURES This condition is rare in children and is present in 0.1% to 1.0% of adults. The lesion presents as a slightly painful, oval to rhomboidal, discrete, erythematous, depapillated, often nodular area in the midline posterior dorsum of the tongue anterior to the circumvallate papillae.

 FIGURE 37-3 Lymphoepithelial cyst. A keratin-filled lumen is surrounded by stratified squamous epithelium and lymphoid tissue.

lamina or from junctional epithelium within the gingival sulcus.12 It is to be distinguished from the gingival (dental lamina) cyst of the newborn, a common cyst which resolves spontaneously very early in life. CLINICAL FEATURES Gingival cysts of the adult develop primarily on the facial mandibular gingiva in the canine-premolar region. They present as soft tissue nodules that are typically asymptomatic and colored pink to blue. There is a slight female predilection and they are noted most often in the fifth or sixth decade.13

Median rhomboid glossitis represents a form of erythematous candidiasis that involves the posterior midline tongue dorsum.14 It is unclear why this particular area is predisposed to candidal infection. A previous theory of this being a developmental anomaly has fallen into disfavor. However, it is possible that this is a developmental malformation that facilitates candidal colonization since

HISTOPATHOLOGIC FEATURES There is atrophy of the filiform papillae with parakeratosis and the presence of spongiotic pustules associated with candidal hyphae (Fig. 37-4). There is psoriasiform epithelial hyperplasia with confluent rete ridges, papillary edema, and a variable chronic inflammatory infiltrate in the connective tissue. Some biopsies, if deep and taken from the midline, may contain the median raphe of the tongue, a homogeneously hyalinized, hypocellular, and avascular band into which the muscle fibers of the tongue decussate. DIFFERENTIAL DIAGNOSIS Benign migratory glossitis and oral psoriasis will show psoriasiform mucositis but will not contain evidence of candidal infection unless secondarily infected.15

HISTOPATHOLOGIC FEATURES Gingival cysts of the adult are classically lined by a thin layer of squamous or cuboidal epithelium 4 to 5 cells thick. Within the lining may be noted focal epithelial plaques containing glycogen-rich clear cells arranged in a whorling pattern. DIFFERENTIAL DIAGNOSIS A lateral periodontal cyst features identical histopathology but develops within the alveolar bone. Glandular odontogenic cysts demonstrate a similar thin lining of odontogenic epithelium with epithelial plaques, but also exhibit numerous mucous cells and duct-like structures.

INFECTIOUS CONDITIONS

Median Rhomboid Glossitis 1004

Synonym: Central papillary atrophy of the tongue.

 FIGURE 37-4 Median rhomboid glossitis. A hyalinized band (median raphe) underlies elongated rete ridges and inflammatory cells. Spongiotic pustules are noted within the surface epithelium.

Oral Hairy Leukoplakia

CLINICAL FEATURES The ventrolateral border of the tongue is the most frequently involved site, sometimes with extension onto the dorsum. Less commonly, the buccal and labial mucosae are involved. Hairy leukoplakia occurs as a painless white plaque that has a corrugated, shaggy (“hairy”) surface with parallel furrows running at right angles to the lateral tongue border. When on the dorsum or the buccal mucosa, the condition may appear as a homogeneous dense white plaque. HISTOPATHOLOGIC FEATURES OHL demonstrates corrugated parakeratosis and acanthosis as well as clusters of pale-staining cells in the superficial epithelium subjacent to the keratin. These pale cells exhibit condensation of chromatin against the nuclear membrane and dense Cowdrytype nuclear inclusions (Fig. 37-5).19 This “chromatin beading” is an important and consistent finding in OHL. There is no evidence of dysplasia and inflammation in the lamina propria is insignificant. EBV is demonstrated by immunohistochemical stains, in situ hybridization, or polymerase chain reaction (PCR) within the superficial keratinocytes.20 Candidal hyphae are present in the keratin layer in 80% of patients and, importantly, are usually unassociated with spongiotic pustules.21 DIFFERENTIAL DIAGNOSIS Vacuolated cells are seen in leukoedema, chronic bite injury, or white sponge nevus, but chromatin beading and nuclear inclusions are absent in these entities. Candidal colonization, when present, is a secondary phenomenon, and the lack of spongiotic

 FIGURE 37-5 Oral hairy leukoplakia. Ballooned cells show nuclear condensations and eosinophilic dense nuclear inclusions.

pustules should raise the suspicion for hairy leukoplakia.

Squamous Papilloma Squamous papillomas are common benign epithelial proliferations exhibiting a verrucous or papillary surface. They are often associated with human papillomavirus (HPV) types 6 and 11, though the exact nature of the relationship is unclear. CLINICAL FEATURES Papillomas may occur at any age and on any oral mucosal surface; they are seen most commonly on the palate or tongue. They are typically pedunculated exophytic lesions that are white but may be red or normal in color, depending on their extent of keratinization.22 They generally do not exceed 0.5 cm in size. HISTOPATHOLOGIC FEATURES Papillomas demonstrate an exophytic, papillary proliferation of stratified squamous epithelium. Subjacent fibrovascular connective tissue cores may show hyalinization. Koilocytes representative of HPV infection may be noted in the

surface epithelium. Lesions on the soft palate often exhibit prominent intracellular edema, while those on the tongue are often thickly keratinized.

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

Synonym: Viral leukoplakia. First described in human immunodeficiency virus (HIV)–infected individuals, oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV) infection of the mucosa that also occurs in non-HIVinfected immunocompromised individuals, particularly organ transplant recipients, and rarely in immunocompetent individuals.16,17 In OHL, EBV is found in epithelial cells, which is unusual for this primarily lymphotrophic virus. In HIV infection, hairy leukoplakia is predictive of AIDS, which generally develops within 2 years of the diagnosis of hairy leukoplakia.18 OHL is a benign process and should not be mistaken for true oral leukoplakia (discussed later), a clinical entity often associated with premalignant changes and progression to carcinoma.

DIFFERENTIAL DIAGNOSIS Verruca vulgaris is distinguished by marked hyperkeratosis, coarse keratohyaline granules, axially inclined rete ridges, and more prominent koilocytes. Condylomas are sessile and display rete ridges that are broader than those of papillomas; koilocytes are consistently present. Verrucous hyperplasia demonstrates a proliferation of hyperkeratotic and acanthotic surface epithelium arranged in prominent papillary projections.23

Focal Epithelial Hyperplasia Synonyms: Heck disease, multifocal papillomavirus epithelial hyperplasia. Focal epithelial hyperplasia is a squamopapular mucosal disorder caused by HPV-13 and/or 32. It has been reported frequently in Inuit and native American populations, Africans, Cape Malays, Caucasians, and Arabs. The prevalence rate varies from 7% to 13% of susceptible populations. Up to 25%

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

of patients may have another member of the household similarly affected, and in general, most afflicted individuals come from a low socioeconomic group, suggesting horizontal transmission.24 It also has been reported in patients infected with HIV.25 CLINICAL FEATURES Although most often noted in children, adults also may be affected. The disorder presents as multiple mucosa-colored or pale pink papules with smooth or slightly papillary surfaces. Individual papules may coalesce to form larger plaques.24 The labial mucosa, buccal mucosa, and tongue are frequently involved. The lesions regress after a few months or years. HISTOPATHOLOGIC FEATURES There is an exophytic squamous epithelial proliferation with only slight surface undulations. Hyperparakeratosis, if present, is mild. Rete ridges are usually broad and may be confluent at their tips. Koilocytes are noted superficially, as in other HPV-associated lesions. The so-called “mitosoid figures” represent nuclear degeneration and karyorrhexis due to HPV infection. Identification of HPV-13 or HPV-32 clinches the diagnosis. DIFFERENTIAL DIAGNOSIS Condylomas and papillomas have obviously papillary surfaces, and acanthosis is much more pronounced in condylomas than in focal epithelial hyperplasia. Oral bowenoid papulosis and koilocytic dysplasia may exhibit similar nuclear changes, but significant epithelial atypia is present.26,27

REACTIVE AND IMMUNEMEDIATED CONDITIONS

Recurrent Aphthous Ulcer

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Synonyms: Canker sore, aphthous stomatitis. Aphthous ulcers of the minor variety constitute a recurrent ulcerative condition of the mouth that afflicts approximately 20% of the population and is the most common cause of oral ulcers in North America. Predisposing local and systemic conditions include trauma, hypersensitivity to food, hematinic deficiencies, inflammatory bowel disease, immunoglobulin deficiencies, Behçet disease, neutropenia, and some collagenvascular disorders.28 In addition, HIV infection is associated with major aphthous ulcers. One variant of minor aphthous ulcers occurs in early childhood as part of the FAPA (fever, adenitis, pharyngitis, aphthae) syndrome.29 Aphthous

ulcers are likely associated with mild immune dysregulation and may be linked to mucocutaneous and rheumatologic disorders, a condition referred to as complex aphthosis. Cross-reaction of antigens of Streptococcus mutans with a mitochondrial heat shock protein may play role in ulcer development.30 Helicobacter pylori has not been found to be associated with this condition.31

the patients. The term Riga-Fede disease refers to tongue ulcers in infants and young children caused by the trauma of rubbing the tongue against erupting teeth.33 It is also seen in patients with familial dysautonomia who are indifferent to pain.34 Unlike traumatic ulcers or even aphthous ulcers, the inflammation is deeply penetrating and results in muscle damage and chronicity.

CLINICAL FEATURES The minor form occurs in teenagers and adults. Lesions are evanescent, painful, discrete ulcers, single or multiple, that are less than 1 cm in diameter with an erythematous border, occur on the nonkeratinized mucosa, and heal within 1 to 2 weeks. Common sites are the buccal and labial mucosa, ventral/lateral tongue, and soft palate—all areas of the mouth that are not normally keratinized. The herpetiform type occurs in crops of many small ulcers, whereas major ulcers measure greater than 1 cm and take weeks, if not months, to heal, often with scarring.

CLINICAL FEATURES TUG affects males 2 to 5 times more often than females. It occurs both in infants, during eruption of the primary dentition (Riga-Fede disease), and in adults. Although most traumatic ulcers of the oral mucosa heal within a 2-week period, TUG may persist for more than 1 month, raising the suspicion for a carcinoma, especially if the lesion is painless. The tongue is affected in 50% to 75% of patients; the lip and buccal mucosa are the next most frequently involved sites. TUG may present as an indurated ulcer or as a rapidly enlarging ulcerated mass. It heals uneventfully after biopsy or on its own, although it may take several weeks. Lesions may be multifocal or relapsing.

HISTOPATHOLOGIC FEATURES The ulcer base contains granulation tissue with acute and chronic inflammatory cells and an overlying fibrin clot that contains many neutrophils unless the patient is neutropenic. The adjacent epithelium may exhibit reactive atypia. Underlying skeletal fibers, if penetrated by inflammatory cells, exhibit myositis. Vasculitis, if present, is usually a secondary phenomenon. DIFFERENTIAL DIAGNOSIS If there is significant stromal eosinophilia associated with myositis and proliferation of large mononuclear histiocyte-like cells, a diagnosis of traumatic ulcerative granuloma should be made (see the following section). The presence of true vasculitis may be seen in the oral ulcers of Behçet disease.32 A search for herpes simplex virus (HSV) and cytomegalovirus (CMV) should be made in biopsies from ulcerated lesions in HIV-seropositive individuals.

Traumatic Ulcerative Granuloma Synonyms: Traumatic ulcerative granuloma with stromal eosinophilia, traumatic eosinophilic granuloma/ulcer of the tongue, granuloma eosinophilium diutinum, Riga-Fede disease. Traumatic ulcerative granuloma (TUG) is a condition that is most likely of traumatic origin because a clinically and histologically identical lesion has been reproduced experimentally in rat tongues after crush injury. However, a history of trauma may be present in less than half

HISTOPATHOLOGIC FEATURES Beneath the ulcerated epithelium is a mass of granulation tissue that may be exuberant and exophytic. There is a polymorphous inflammatory infiltrate with many eosinophils that extends deep into the tissues, often into the muscle and salivary gland. A large number of large mononuclear histiocyte-like cells with pale vesicular nuclei and eosinophils is a typical finding. These histiocyte-like cells stain for CD68 or factor XIIIa.35 Clusters of CD30+ lymphocytes may be noted within these infiltrates.36 In almost all cases, degenerating muscle fibers are also identified.37 DIFFERENTIAL DIAGNOSIS The atypical histiocytic granuloma contains sheets of transformed lymphocytes and centroblasts, often with cellular pleomorphism and mitoses, resembling a lymphoma. The presence of CD30+ lymphocytes has led to speculation that some lesions that resemble TUG clinically may histologically represent a low-grade lymphoproliferative disorder.38 For the most part, TUGs are polyclonal and self-limiting, and CD30+ cells have also been noted in benign lesions. The cells in TUG do not stain for S100 or CD1a and they lack the grooved nuclei typical for Langerhans cell histiocytosis.

Chronic Bite Injury Synonyms: Morsicatio mucosae oris, pathominia mucosae oris, morsicatio buccarum. The term chronic bite injury should be reserved for lesions that result from chronic mucosal chewing or a biting habit. Histologic changes of secondary chronic bite trauma may occur as an incidental finding in a localized fashion associated with another lesion such as a fibroma.

HISTOPATHOLOGIC FEATURES Chronic bite injuries are characterized by varying degrees of hyperparakeratosis that may be marked; the surface of the keratin is shaggy and irregular with fissures and clefts rimmed by many bacterial colonies and rarely candidal hyphae in the absence of intraepithelial inflammation. There is benign epithelial hyperplasia, variable papillomatosis, and intracellular edema. Dysplasia is never present in primary chronic bite injury. DIFFERENTIAL DIAGNOSIS Biopsies of the linea alba are identical to lesions of chronic bite injury because they share a similar etio-pathogenesis; the difference is in clinical presentation. Linea alba presents clinically as a white line along the mid-buccal mucosa bilaterally at the level of the occlusal plane and shows milder histologic changes. Primary leukoedema does not show hyperparakeratosis or surface bacterial colonization but will exhibit benign epithelial hyperplasia and intracellular edema. Unlike oral hairy leukoplakia, there is no clumping of the chromatin against the nuclear membrane, and EBV is not identified.

Oral Lichen Planus Oral lichen planus (OLP) is a common immunologically mediated condition of the mucosa with a prevalence rate of 1% to 2%. Although many cases are idiopathic, a lichenoid mucosal reaction (similar clinically and histologically) may be seen in mucosal drug eruptions and in contact stomatitides associated

CLINICAL FEATURES Females are affected twice as often as males, and most are adult or middle aged. Concurrent skin lesions are present in 4% to 44% of patients. Three clinical types have been identified, to wit: reticular/papular, erythematous/erosive/atrophic, and ulcerative/bullous types, associated with increasing symptomology. The bullous type is

rare because most bullae in the mouth rupture within a short time after their appearance. Many patients have combinations of these types, and generally, reticular white areas suggestive of Wickham striae are present at the periphery of erythematous and ulcerative lesions. Stress may cause exacerbations. Involvement of the vulva has been reported in the vulvovaginal-gingival syndrome. Any part of the mucosa may be affected by OLP, with the favored sites being buccal mucosa, labial mucosa, tongue, and gingiva; dorsal tongue lesions may not be reticulated. Desquamative gingivitis (DG) is a clinical term used to describe an erythematous condition of the gingiva that represents one of several pathologic entities, most commonly erosive OLP or mucous membrane pemphigoid. DG exhibits a 4:1 female predilection. The gingiva is painful and diffusely erythematous with areas of vesiculation, erosion, and desquamation, often covered by a white membrane that may represent a fibrin clot or the roof of a collapsed bulla. A positive Nikolsky sign may be present. OLP and mucous membrane pemphigoid represent up to 80% of DG followed by hypersensitivity reactions and other autoimmune conditions such as pemphigus vulgaris, linear IgA disease and epidermolysis bullosa acquisita.47,48 HISTOPATHOLOGIC FEATURES OLP demonstrates hyperorthokeratosis or even parakeratosis in the oral cavity. The epithelium is attenuated or eroded in the atrophic/erosive type, often with small ulcerations, and somewhat hyperplastic in the reticular/papular type. There is leukocyte exocytosis, an increase in the number of Langerhans cells, and variable numbers of colloid (Civatte) bodies. Sawtooth rete ridges may be seen. The basal cells are degenerated, and the basement membrane is thickened. A bandlike lymphohistiocytic infiltrate hugs the connective tissue-epithelium interface (Fig. 37-6).49 Some lesions exhibit subepithelial bullae formation or complete desquamation of the epithelium. Melanophages and incontinent melanin may be present in the lamina propria and plasma cells are prominent if there is overlying ulceration. Eosinophils are not usually encountered. In some cases, nodular peri- and paravascular lymphocytic aggregates may be a prominent feature, sometimes with lymphoid follicles within the lymphoid band. Some but not all of such cases are

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

CLINICAL FEATURES Chronic chewing habits are encountered in the teenage years and adulthood and patients may be unaware of the habit. The most common locations are the buccal and labial mucosa and lateral tongue, all sites readily traumatized by teeth. The lesion is typically nontender and appears as grayish white papules and plaques with irregular, shaggy, peeling surfaces, focal erosions, erythema, and sometimes ulcerations.

with dental restorations.39 The use of cinnamon-flavored products may result in the occurrence of oral lichenoid reactions, although more commonly they present as painful erythematous areas with only faint peripheral lichenoid striations. Among the drugs that have been implicated are antihypertensive agents, nonsteroidal anti-inflammatory drugs, cholesterol-lowering medications, and drugs used to treat rheumatologic conditions. Discoid lupus erythematosus and chronic oral graft-versus-host disease may result in oral lesions that are clinically and histologically similar to oral lichen planus. There may be an association of lichen planus with hepatitis C in some cases. There is an increased incidence of HLA-Bw57, HLA-DR1, HLADR2, HLA-DR3, HLA-DR9, and HLADR10 as well as a decreased incidence of HLA-DQ1 in some patients.40-42 Allele HLA-DR6 has been significantly expressed in patients with lichen planus and HCV infection.43 The rate of malignant transformation of lichen planus has been reported to be between 0.4% and 6.0%. Some investigators believe that oral lichen planus has an innate premalignant potential. Others believe that preexisting lesions previously misdiagnosed as OLP are actually premalignant epithelial dysplasias with lichenoid features that subsequently progress to carcinomas. Supporting this latter theory is the finding that many of the patients with reported malignant transformation have a history of tobacco use. Among all lichenoid lesions, loss of heterozygosity on chromosome arms 3p, 9p, and 17p is only found in those that also exhibit epithelial dysplasia.44,45 OLP results from a complex interplay between cellular and molecular signals that begin with alteration of keratinocyte antigens by an endogenous or exogenous agent that subsequently are ingested by Langerhans cells. T-lymphocytes migrate to the area, facilitated by adhesion molecules and cytokines (such as tumor necrosis factor alpha) secreted by mast cells and endothelial cells. Basal cell lysis ensues, and continued recruitment of cells and secretion of cytokines lead to progression and chronicity.46

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

developing oral cancer among snuff dippers compared to non-tobacco users is 4.2.57 Snus, a form of smokeless tobacco commonly used in Sweden, appears to be associated with no increased risk of oral cancer, although it was found to be a risk factor for pancreatic cancer.58

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CLINICAL FEATURES Early lesions of STK appear as asymptomatic gray or white macule or plaque that may be fissured, usually in the mandibular vestibule where the tobacco is placed. Long-standing lesions have a leathery or velvety feel and represent leukoplakia arising within STK and are less likely than early lesions to regress upon cessation of the habit.

 FIGURE 37-6 Lichen planus. Para- or orthokeratin, saw-tooth rete ridges, squamatization of basal cells, and a bandlike inflammatory cell infiltrate characterize oral lichen planus.

associated with hypersensitivity reactions to cinnamon-flavored products. Direct immunofluorescence (DIF) studies reveal fibrinogen in a stalactite pattern in the basement membrane zone and IgM in apoptotic cells.50 There are rare reports of circulating antibodies against basal cells, but how important these antibodies are to the pathogenesis of lichen planus has been a subject of debate.51,52 DIFFERENTIAL DIAGNOSIS In mucous membrane pemphigoid, the basal cells are intact, and the lymphocytic band is usually not as dense. Lupus erythematosus shows hydropic degeneration of the basal cells, alternating epithelial atrophy and hyperplasia of rete ridges, perivascular lymphocytic infiltrates, and patchy subepithelial periodic acid-Schiff (PAS)positive deposits. Both these entities exhibit linear IgG (and/or C3 in the case of mucous membrane pemphigoid) deposition at the basement membrane zone with DIF studies. The epithelial changes are less marked, and the lymphocytic infiltrate is sparse in oral chronic graftversus-host disease because of systemic immunosuppression. Lichenoid dysplasias represent epithelial dysplasias that incite a lichenoid tissue reaction. An entity that clinically and histologically resembles erosive lichen planus called chronic ulcerative stomatitis exhibits speckled nuclear anti-IgG deposits on DIF directed against a 70-kDa chronic ulcerative stomatitis protein (CUSP).53,54

Nicotine (Nicotinic) Stomatitis This is a rare benign reactive lesion of the hard palate that is associated with excessive heat, typically generated by pipes or cigars.55Although it is almost always seen in smokers, it appears to have no premalignant potential. CLINICAL FEATURES Nicotine stomatitis is seen most often in older men because this population accounts for the majority of cigar and pipe smokers. The palatal mucosa appears white; red papules within these hyperkeratotic areas represent inflamed minor salivary gland duct orifices.56

HISTOPATHOLOGIC FEATURES STK is characterized by slight hyper ortho or parakeratosis, often with keratin spires called “chevrons.” More typically, beneath the keratin is a band of degenerated cells of varying thickness that exhibit intracellular edema or hydropic degeneration with loss of nuclei. Epithelial dysplasia may be seen in long-standing lesions where the keratin layer is usually more pronounced. Amyloid-like material may be seen in the lamina propria and within interstitium of minor salivary glands. This represents altered collagen and is not congophilic. DIFFERENTIAL DIAGNOSIS In its early stages, STK represents direct topical injury to the mucosa, producing the superficial layer of degenerated cells. Leukoedema does not exhibit chevron formation and does not have the distinct band of degenerated cells. Other noxious contactants such as aspirin usually result in ulceration.

Benign Migratory Glossitis HISTOPATHOLOGIC FEATURES Hyperkeratosis and acanthosis are characteristic findings, as is an inflammatory cell infiltrate surrounding the salivary gland excretory ducts that usually exhibit squamous metaplasia.56 Epithelial dysplasia is generally not present. DIFFERENTIAL DIAGNOSIS Necrotizing sialometaplasia exhibits necrosis of the salivary gland acini and squamous metaplasia is often more pronounced and pseudoepitheliomatous in nature.

Smokeless Tobacco Keratosis Smokeless tobacco keratosis (STK) typically presents as an area of leukoplakia and is seen in patients who use snuff or chewing tobacco. The relative risk of

Synonyms: Geographic tongue, erythema areata migrans, erythema circinata, migratory stomatis. This evanescent inflammatory tongue condition occurs in between 1% and 25% of the population.59 Patients with generalized pustular psoriasis and Reiter syndrome may exhibit lesions of migratory glossitis in 7% to 10% of cases.60 An atopic diathesis has been suggested as a contributory factor in its development.61 A recent study suggested that benign migratory glossitis (BMG) is not associated with diabetes, as had been previously reported, and is inversely associated with cigarette smoking.62 There is an increased incidence of HLA-Bw62, HLA-Bw63, HLA-Cw6, and HLA-B13 with a reduced incidence of HLA-Cw4.63

CLINICAL FEATURES This condition affects adults in a male-to-female ratio of 1:2. The tongue presents with irregular maplike areas of depapillation and atrophy that are erythematous, often but not invariably outlined by a slightly raised, yellow-white serpiginous or circinate border. The lesions wax and wane, and there may be pain, burning, and sensitivity to acidic and spicy foods. When located on mucosa other than the tongue, the term erythema areata migrans, migratory stomatitis, or ectopic geographic tongue is used. Usage of the term erythema areata migrans is independent of site.64

DIFFERENTIAL DIAGNOSIS Candidiasis, oral psoriasis, and the edge of ulcers often exhibit spongiotic pustulosis; stains for fungi should be performed routinely.

This is a rare, nonautoimmune, pustular and vegetating mucosal disorder that is associated with inflammatory bowel disease (most often ulcerative colitis) in 50% to 70% of patients and is thought to represent the mucosal counterpart of pyodermatitis vegetans. There is also an association with liver diseases including sclerosing cholangitis.66 Approximately 90%of cases are associated with peripheral blood eosinophilia.67 CLINICAL FEATURES Multiple painful small yellowish-white papules, ulcers, and pustules appear on the mucosa, sometimes with a linear, serpentine, or “snail track” configuration and sometimes in clusters and crops.66 The surrounding mucosa may be markedly erythematous and friable with nodular excrescences and vegetative plaques. Generally, the bowel symptoms precede the oral lesions by about 1 year, although oral lesions may appear first. Skin lesions are present in approximately 50% of cases. HISTOPATHOLOGIC FEATURES There is epithelial hyperplasia with marked spongiosis and the formation of suprabasilar clefts. Intraepithelial abscesses composed of neutrophils and numerous eosinophils are characteristic, and often there are similar abscesses in the edematous connective tissue papillae. A polymorphous inflammatory infiltrate is present in the

 FIGURE 37-7 Benign migratory glossitis. Parakeratosis, atrophy of filiform papillae, and spongiotic pustules (in the absence of candida) characterize migratory glossitis.

lamina propria, sometimes in a perivascular distribution. Direct immunofluorescence studies may reveal weak, patchy, and granular positive staining for IgG and C3.68 It has been suggested that such immunoreactivity may be a secondary phenomenon owing to vascular leakage. DIFFERENTIAL DIAGNOSIS Pemphigus vegetans may be histologically indistinguishable from pyostomatitis vegetans, but DIF studies usually are strongly positive for intercellular deposition of IgG in pemphigus lesions and weak to absent in pyostomatitis vegetans. The epithelial hyperplasia may be so florid that the differential diagnosis of acantholytic squamous cell carcinoma may be suggested. The latter would show cytologic atypia and pleomorphism beyond the range encountered in reactive lesions, and DIF studies are negative.

Orofacial Granulomatosis Synonyms: Cheilitis granulomatosa, Miescher disease, Melkersson-Rosenthal syndrome. Some investigators use this term to refer only to granulomatous inflammation not associated with other systemic conditions such as Crohn disease or sarcoidosis, whereas others use it to designate a condition characterized by orofacial swelling that histologically consists of noninfectious granulomatous inflammation regardless of whether there is a known systemic eiotlogy. Oral manifestations of the systemic conditions may predate systemic findings. Orofacial granulomatosis has been attributed to an abnormal immune response to a variety of antigens, including food, and food additives including cinnamon products.69 There may be a genetic predisposition (increased HLA-A3, HLA-B7 and HLA-DR2 expression), and many patients have been reported to be atopic.70 CLINICAL FEATURES The most common clinical presentation is painless, persistent swelling of the upper and/or lower lips. If only the lips are involved, the clinical diagnosis of cheilitis granulomatosa is made. If the patient presents with the triad of cheilitis granulomatosa, fissured tongue, and facial nerve palsy, the diagnosis of Melkersson-Rosenthal syndrome applies. Some consider cheilitis granulomatosa alone as the oligosymptomatic form of Melkersson-Rosenthal syndrome. In addition, patients may present with gingival swelling (up to 30%), erythema, and erosions, not unlike what may be seen in oral Crohn disease.71

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

HISTOPATHOLOGIC FEATURES There is atrophy of the filiform papillae on the tongue dorsum with or without parakeratosis. Spongiotic pustules and sometimes microabscesses unassociated with candidal hyphae are present and may involve one-third to one-half the epithelium (Fig. 37-7). The epithelium is acanthotic, with leukocyte exocytosis and often confluence of the rete ridges at the bases. There is edema of the papillary lamina propria, thinning of the suprapapillary epithelium, vascular ectasia, and a variable lymphoplasmacytic infiltrate, all features of a psoriasiform mucositis.65

Pyostomatitis Vegetans

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

HISTOPATHOLOGIC FEATURES Within the lamina propria are nonnecrotizing granulomas often containing multinucleated giant cells. These granulomas usually are present in small numbers and may be poorly formed, so multiple sections may be needed before they can be identified definitively. The surrounding tissues may be edematous and contain scattered chronic inflammatory cells, often in a peri- and paravascular location.72 Dilated lymphatics may be present superficially. If salivary glands are present, granulomas should be sought within the gland parenchyma. Stains for organisms are negative, and the granulomas should contain no identifiable foreign material. Since the condition may wax and wane, the appearance of granulomas may not be demonstrable in all patients. DIFFERENTIAL DIAGNOSIS The granulomas of orofacial granulomatosis are indistinguishable from those of Crohn disease, and the patient should be evaluated for gastrointestinal signs and symptoms. Granulomas of sarcoidosis usually contain asteroid bodies and tend to be well formed. ANCA-associated granulomatous vasculitis (Wegener granulomatosis) presents clinically with “strawberry gingivitis” and histologic features of pseudoepitheliomatous hyperplasia, vasculitis, geographic necrosis, abscesses, and a mixed inflammatory infiltrate in addition to subtle granulomas.73 Foreign material eliciting a chronic granulomatous reaction should be ruled out.

may be present. The lamina propria contains sheets of plasma cells that do not display atypia and are polyclonal with immunohistochemical studies. Dilated capillaries and scattered lymphocytes are noted in areas where the plasma cell infiltrate is less dense. Eosinophils are not a feature.75,76 DIFFERENTIAL DIAGNOSIS Monoclonality of the plasma cell infiltrate must be ruled out because the differential diagnosis includes extramedullary plasmacytoma. An intense plasmacytic infiltrate in the gingival tissues and periodontium is not uncommon in severe chronic gingivitis and periodontal disease but would not resemble plasma cell gingivitis clinically. Such lesions may form masses known as plasma cell granulomas.77 Foreign-body gingivitis is associated with a dense lymphocytic or plasmacytic infiltrate, nonnecrotizing granulomas, and particulate foreign material, which usually represents dental abrasives.78

Mucocele Synonym: Mucous escape reaction. This is a common condition caused by mucous extravasation and pooling in the interstitium as a result of traumatic disruption of the integrity of the excretory salivary duct. Floor of mouth lesions are instead referred to as ranulas. If a distal

obstruction causes retention of mucous within the cystically dilated duct, the appropriate terms are salivary duct cyst, mucous retention cyst or mucous cyst. CLINICAL FEATURES The mucocele occurs as a dome-shaped, sessile, bluish, translucent, usually painless swelling on any site that has underlying salivary glands, in particular the lower labial mucosa, ventral tongue or floor of mouth. There may be a history of the cyst repeatedly increasing and decreasing in size. Superficial mucoceles are 2 to 3 mm blister-like lesions located on the hard and soft palate.79 HISTOPATHOLOGIC FEATURES In the mucocele of mucous escape etiology, a pool of mucinous material containing muciphages and often neutrophils is present in the interstitium, sometimes abutting the epithelium. It is surrounded by condensed granulation tissue containing muciphages and variable numbers of chronic inflammatory cells and is therefore not a true cyst (Fig. 37-8). A portion of the salivary duct, often exhibiting squamous metaplasia, may be present at the periphery, and the associated minor salivary glands exhibit varying degrees of chronic inflammation, ductal ectasia, acinar atrophy, and interstitial fibrosis (all signs of obstruction). In late stages, only a nodule of granulation tissue with occasional muciphages remains. Salivary duct cysts consist

Plasma Cell Stomatitis Synonyms: Plasma cell gingivitis, mucous membrane plasmacytosis This condition was first described in the early 1970s, and its etiology was putatively ascribed to a hypersensitivity reaction to a component of chewing gum.74 Sporadic cases continue to be reported. CLINICAL FEATURES The gingiva (usually in the anterior maxilla) is markedly erythematous, edematous, and painful. Ulceration is unusual. In the original chewing gum–associated cases, there was concomitant cheilitis and glossitis. In some idiopathic cases, there is accompanying supraglottic and laryngeal involvment with accompanying hoarseness and/or sore throat.75

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HISTOPATHOLOGIC FEATURES The epithelium is markedly hyperplastic with spongiosis and sometimes superficial microcyst and pustule formation in a psoriasiform pattern. Dyskeratotic cells

 FIGURE 37-8 Mucocele. A cystlike cavity is filled with mucous and surrounded by granulation tissue and histiocytes.

of cystically dilated excretory ducts filled with mucus; they usually exhibit squamous, oncocytic, and/or mucous cell metaplasia of the lining epithelium; they are termed oncocytic sialocysts if oncocytes are prominent and are more common in the upper labial mucosa, where they may be associated with sialoliths. DIFFERENTIAL DIAGNOSIS The partially organized mucocele may be mistaken for a minor salivary gland or a histiocytic tumor. The absence of proliferation of ductal, myoepithelial, epidermoid, mucous or clear cells differentiate a mucocele from a neoplastic process.

Necrotizing sialometaplasia is an uncommon inflammatory condition characterized by ulceration of the mucosa overlying infarcted salivary glands. It is believed to result from ischemia to the gland.80 Such vascular compromise has been variably attributed to local trauma, epinephrine from local anesthetics, Raynaud phenomenon, adjacent tumors impinging on the blood supply, and bulemia.81 Nevertheless, many cases occur idiopathically. It may be confused with a malignant process because of rapid onset, the clinical appearance, and histopathology. CLINICAL FEATURES There is a slight 2:1 male predilection, and it tends to occur in middle age. The mucosa of the posterior hard palate and associated glands is affected in 70% to 80% of patients, with two-thirds of cases occurring unilaterally.82 Necrotizing sialometaplasia also may occur in the labial mucosa, retromolar pad, tongue, major salivary glands, and upper respiratory tract. The lesion usually begins as a swelling that ulcerates; pain may or may not be present. After a few weeks, a sizable mass of necrotic tissue may exfoliate, and rapid healing ensues. The average duration of the ulcer is 5 weeks. HISTOPATHOLOGIC FEATURES The salivary glands exhibit preservation of their usual lobular architecture, and this is a very important feature present in all lesions, provided that an adequate biopsy is obtained. Early lesions feature coagulative necrosis of salivary glands but with preservation of the acinir outlines (Fig. 37-9). There may be extensive mucous pooling around acini even in early lesions with accompanying acute and chronic inflammation. In more advanced lesions, squamous metaplasia of the ducts and pseudoepitheliomatous hyperplasia of

 FIGURE 37-9 Necrotizing sialometaplasia. Minor salivary gland acini undergo necrosis with preservation of their outlines; squamous metaplasia is also noted.

the overlying mucosa may be pronounced.82 The islands of squamous epithelium usually are cytologically bland with occasional evidence of reactive atypia. Small vessels in the area often exhibit thrombosis and occlusion. DIFFERENTIAL DIAGNOSIS The preservation of the normal lobular architecture of the glands is the single most important histologic parameter that helps to distinguish necrotizing sialometaplasia from mucoepidermoid carcinoma and squamous cell carcinoma. In mucoepidermoid carcinoma, there is proliferation of mucous and squamous cells in a disorganized fashion, forming islands of tumor cells that vary in shape and size with infiltration of the adjacent structures. Squamous cell carcinoma exhibits significant cytologic atypia and pleomorphism with infiltration of the adjacent tissues. In subacute necrotizing sialadenitis, the glands are diffusely infiltrated by a mixed inflammatory infiltrate with focal necrosis and little metaplasia.83

Cheilitis Glandularis This is an unusual inflammatory condition of the lip (usually lower) of unknown etiology, although there is an association with actinic cheilitis, atopic diatheses, and factitial injury. CLINICAL FEATURES Cheilitis glandularis (CG) is a disorder of adults, typically

elderly men. Three clinical forms are recognized: simple, superficial suppururative (Baelz disease), and deep suppurative (cheilitis glandularis apostematosa). In all cases, the lip is enlarged and often everted with areas of nodularity.84 In the simple type, crusting may occur with associated beads of mucus on the lip surface. Pain and crusting are more prominent in the suppurative type, and ductal orifices may exude purulent material. Up to one-third of cases have been associated with the development of squamous cell carcinoma, although this may be a reflection of increased exposure to the sun because of lip eversion and tobacco products rather than cheilitis glandularis, representing a premalignant process.

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

Necrotizing Sialometaplasia

HISTOPATHOLOGIC FEATURES The glands contain a chronic interstitial inflammatory infiltrate with acinar atrophy, sialodochitis, and often a purulent exudate within dilated and metaplastic ducts.85 In the simple type, the findings are less severe, and suppuration is usually absent. In many cases, actinic cheilitis may be concurrently present. The finding of hyperplasia of the mucous glands has been disputed.86 DIFFERENTIAL DIAGNOSIS Distal obstruction of the salivary glands of the upper lip by sialoliths may cause similar histologic changes of a chronic sclerosing sialadenitis. In such cases, the sialoliths

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are identified in the ducts. CG may be misdiagnosed as papillary cystadenoma based on the presence of tortuous ductlike spaces.87

noted. Although some fibromas may contain a few lipocytes, others contain significant amounts of fat, in which case a diagnosis of “fibrolipoma” is appropriate.

Fibromas

DIFFERENTIAL DIAGNOSIS The giant cell fibroma often has a papillary surface configuration and usually exhibits epithelial hyperplasia in the form of spiky rete ridges. Numerous plump stellate-shaped and often bi- or multinucleated giant fibroblasts are scattered throughout (Fig. 37-10B). Occasionally, the nuclei may have a wreath-like configuration. These giant cells stain for vimentin, occasionally for factor XIIIa, but not for S100 protein or CD68.88 Ultrastructurally, the giant fibroblasts have been noted to contain microfilaments, dense bodies, and junctional complexes, thus resembling myofibroblasts. Sclerotic fibromas are sharply circumscribed tumors that exhibit thick collagen bundles arranged in a storiform pattern and separated by prominent clefts. Mast cells are present throughout the stroma. The tumor demonstrates CD34 and factor XIIIa reactivity.89

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Synonyms: Fibrous hyperplasia, fibroepithelial polyp, bite fibroma, irritation fibroma. A fibroma a very common condition of the oral mucosa and occurs at sites that are commonly traumatized. It is not a true neoplastic process, but rather a reactive proliferation of fibrous scar tissue. CLINICAL FEATURES Fibromas usually present on the buccal mucosa, lower labial mucosa, or lateral border of the tongue, all common sites of bite trauma. The nodule usually is dome-shaped, sessile or pedunculated, soft, mucosa-colored, and may show areas of ulceration and/or whiteness. A variant of fibroma called the giant cell fibroma tends to be located on the gingiva or tongue and often has a papillary surface clinically.88 Giant cell fibromas on the lingual gingiva near the mandibular canines are termed retrocuspid papillae. HISTOPATHOLOGIC FEATURES There is a proliferation of fibrous tissue, usually with low cellularity, and scattered blood vessels; occasionally the collagen may appear keloidal. The overlying epithelium may be attenuated or hyperplastic, and there is usually hyperkeratosis (Fig. 37-10 A). Focal areas of myxoid degeneration and mucinous change may be encountered, and scattered lymphocytes are occasionally

A

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Epulis Fissuratum

obvious reasons, occurs in older individuals. There are papulous and ridged folds of soft tissue, usually in the buccal maxillary and mandibular sulci, and often with a prominent central fissure into which the denture flange fits. The surface may have papillary, ulcerated, or erythematous areas.90 HISTOPATHOLOGIC FEATURES The overlying epithelium is often hyperplastic and pseudoepitheliomatous hyperplasia is not unusual. There may be parakeratosis, focal ulcerations, and areas of candidal infection. The bulk of the tissue consists of hyperplasia of fibrous tissue, sometimes with many ectatic vessels. A lymphocytic infiltrate is invariably present; sometimes, lymphoid nodules, minor salivary glands, and osseous and cartilagenous metaplasia also may be noted, the latter especially in the maxilla.90 Salivary glands, if present, may demonstrate chronic sialadenitis. DIFFERENTIAL DIAGNOSIS Pseudoepitheliomatous hyperplasia may be mistaken for squamous cell carcinoma in this elderly population, but there is a lack of atypia, true invasion, or mitotic activity.

Synonyms: Inflammatory fibrous hyperplasia, denture-associated epulis. The benign overgrowth of fibrous tissue that characterizes this condition is caused by an ill-fitting denture sliding on and traumatizing the soft tissues at the edges of a denture flange.

Inflammatory Papillary Hyperplasia of the Palate

CLINICAL FEATURES There is a female predilection for this condition that, for

CLINICAL FEATURES The palatal mucosa under the denture is covered by soft,

This condition is caused by wearing an ill-fitting maxillary denture and/or wearing a denture continuously, even when asleep at night.

B

 FIGURE 37-10 (A) Fibroma. Fibrous scar tissue proliferates in the absence of significant inflammation. (B) Giant cell fibroma. Tapered rete ridges overlie dense collagen. Stellate-shaped giant fibroblasts are present within the connective tissue.

pebbly, fibrous nodules that coalesce, resulting in a cobblestone appearance. The tissue often appears erythematous secondary to candidiasis. HISTOPATHOLOGIC FEATURES This is essentially similar to the histopathology of epulis fissuratum except that the fibrous hyperplasia has a papillary configuration. Candida organisms may be noted in the superficial epithelium. DIFFERENTIAL DIAGNOSIS See “Epulis Fissuratum,” earlier in this chapter.

The term “epulis” refers to any growth on the gingiva or alveolar mucosa. Six of the most common gingival lesions are

A

may be mucosa-colored when small. Larger ones are usually erythematous and/or ulcerated. Drug-induced hyperplasias affect the gingiva diffusely over time and occur in 15% to 50% of patients taking phenytoin, calcium channel blockers, and cyclosporine.91-93 Nongingival soft tissue hyperplasia induced by cyclosporine administration has also been reported in patients taking this medication for chronic graft-versus-host disease.94 The mechanism is unclear but believed to be related to an alteration of collagen metabolism mediated by transforming growth factor beta 1, which promotes synthesis of extracellular matrix components and inhibits degradation.95 The parulis usually occurs on attached or nonattached gingiva at a distance from

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

Other Gingival Epulides

the fibroma (discussed previously), pyogenic granuloma (granuloma gravidarum if the patient is pregnant), peripheral giant cell granuloma, peripheral ossifying fibroma, drug-induced gingival hyperplasia, and parulis (Fig. 37-11 A to C). Each of the first four entities arises as a reparative process in response to chronic irritation from deposits of dental calculus, poorly adapted dental restorations, orthodontic braces, or other local factors. They often occur on the marginal gingiva with at least a portion of the lesion resting against the teeth. Histopathologically, it is not unusual to see combinations of pyogenic granuloma, peripheral ossifying fibroma, and peripheral giant cell fibroma within one lesion. All present as nodules varying in size from a few mm to 1 to 2 cm. They

B

C  FIGURE 37-11 (A) Pyogenic granuloma. There is a proliferation of granulation tissue; the overlying epithelium may be intact or ulcerated. (B) Peripheral giant cell granuloma. Multinucleated giant cells are present within a vascular stroma. (C) Peripheral ossifying fibroma. A cellular proliferation of fibroblasts deposits foci of metaplastic osteoid or woven bone.

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Table 37-1 Gingival Nodules ENTITY

CLINICAL FEATURES

HISTOPATHOLOGIC FEATURES

DIFFERENTIAL DIAGONIS

Pyogenic granuloma

Often seen during pregnancy; may regress postpartum Marginal gingiva

Proliferation of endothelial cells and capillaries Cellular fibroblast-like proliferation with deposition of osteiod, woven bone or cementum-like droplets Proliferation of multinucleated giant cells of osteoclast-type, mononuclear cells in stroma, siderophages, dilated capillaries; “Grenz” zone may be present Proliferation of fibrous tissue and some granulation tissue with variable inflammation. In dilantin hyperplasia, elongated “test tube” ridges may be present Edematous granulation tissue, acute and chronic inflammation and microabscesses, may see neutrophil “tract”

Capillary hemangiomas are similar histologically A bony spicule is composed of lamellar bone with periosteum and no spindle cell proliferation Central giant cell granuloma eroding through bone; lack of foreign material and epithelioid histiocytes excludes other granulomatous proceses

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Peripheral ossifying fibroma

Peripheral giant cell granuloma

May rest in a cup-shaped depression in the bone; 10% recurrence rate; unlike intraosseous counterpart, no association with hyperparathyroidism

Drug-induced fibrous hyperplasia

Usually involves gingiva diffusely and rare in edentulous areas; dilantin, cyclosporine and Ca2++ channel blockers are common etiologic agents Usually not on marginal gingiva; indicates tooth has pulpal or periodontal infection

Parulis

the teeth. Its presence almost always indicates an underlying odontogenic infection within the bone. Table 37-1 summarizes the clinical and histologic findings, as well as the differential diagnoses of these lesions.

Essential to the diagnosis of VX are numerous CD68+ foamy macrophages within the connective tissue papillae (Fig. 37-12). Rarely, these macrophages extend beyond the tips of the rete ridges.

Gingival fibromatoses is similar histologically but tends to be hereditary and presents at an early age Lack of mucin and muciphages as well as location excludes mucocele

DIFFERENTIAL DIAGNOSIS Squamous papillomas, condylomas, and verruca vulgaris lack the presence of foamy macrophages. Papillary squamous cell carcinoma demonstrates features of cytologic atypia.

Verruciform Xanthoma Verruciform xanthoma (VX) is a rare reactive lesion primarily seen in the oral cavity that was first described in 1971. The etiology is unclear, but it is believed that epithelial breakdown releases lipids that draw xanthoma cells to the site. An association with human papillomavirus has not been identified.96 Cases have been associated with pemphigus vulgaris, graft-versus-host disease, epidermolysis bullosa, warty dyskeratoma, and lichen planus.97-99 CLINICAL FEATURES Most VXs are seen on the gingiva and palatal mucosa. They typically present as papillary or verrucous lesions that may be pink, red, or white. Most examples are no larger than 2 cm in size.

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HISTOPATHOLOGIC FEATURES VX characteristically exhibits bright orange hyperparakeratosis, loose keratin squames ,and keratin plugging between papillary projections. Rete ridges extend to a uniform depth within the lamina propria.

 FIGURE 37-12 Verruciform xanthoma. Beneath a papillary proliferation of the squamous epithelium, foamy macrophages are situated within the connective tissue papillae.

PIGMENTED CONDITIONS

Amalgam Tattoo Amalgam used in dental restorations is the most common cause of exogenous pigmentation in the oral cavity. It is usually inadvertently traumatically implanted during placement or removal of a restoration or retrograde root canal filling or may fall from an extracted tooth into its socket.

HISTOPATHOLOGIC FEATURES Dark brownto-black, coarse and/or fine granules are present in three patterns. Most commonly, fine particles are disposed parallel to and along the reticulin and elastic fibers within the stroma, the basement membranes of blood vessels, the epithelium, and sometimes endoneurium and endomysium, while larger particles are found within foreign body giant cells and macrophages. Less commonly, the fibers are stained golden brown without particulate deposition.101 (Fig. 37-13). Fibrosis/scarring is a common finding. DIFFERENTIAL DIAGNOSIS Graphite tattoos are often seen in the palatal mucosa of children who fall with pencils held between the teeth. The particles tend to be coarser and do not stain the reticulin fibers. In cases where the diagnosis is not immediately apparent, energy dispersive x-ray microanalysis of the content of the particles may be helpful.102

 FIGURE 37-13 Amalgam tattoo. The silver in dental amalgam stains the basement membrane of blood vessels and epithelium and stains collagen fibers.

of melanin in the basal cells, especially at the tips of the rete ridges (Fig. 37-14).103 Melanocytic hyperplasia, if present, is usually very mild with no atypia and no nesting, and is not lentiginous. Melanin is present in the lamina propria, and there

are variable numbers of melanophages and scattered lymphocytes. DIFFERENTIAL DIAGNOSIS Unlike ephelides, oral melanotic macules are not related to sun exposure, and the color varies

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

CLINICAL FEATURES The most common locations for amalgam tattoos are the gingiva and the buccal mucosa adjacent to a restoration.100 The tattoo is macular and appears uniformly black or slate gray; it may have discrete or ill-defined borders.

Oral Melanotic Macule This is a common condition of the oral mucosa caused by increased deposition of melanin and occasionally very mild melanocytic hyperplasia. It may represent post-inflammatory hypermelanosis. CLINICAL FEATURES This occurs mainly in adults with a male-to-female ratio of 1:2. Approximately one-third of cases occur on the vermilion of the lower lip (labial melanotic macule); other sites include the gingiva, buccal mucosa, and palate. They are discrete, usually solitary, evenly tan-brown or black macules that are less than 1 cm in diameter. HISTOPATHOLOGIC FEATURES There is absent or mild hyperkeratosis and usually insignificant or mild epithelial hyperplasia. There is an increase in the amount

 FIGURE 37-14 Oral melanotic macule. Melanin is present within basal cells, accentuated at the tip of rete ridges, and in the superficial lamina propria.

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little throughout the year. Unlike lentigo and melanoacanthosis, they show minimal melanocytic hyperplasia and insignificant epithelial hyperplasia. Malignant melanoma is characterized by a proliferation of atypical melanocytes. The melanotic macule may be indistinguishable from oral pigmentation associated with postinflammatory hypermelaninosis and from the pigmented macules of PeutzJegher, Albright, and Addison diseases and the Laugier-Hunziker syndrome.104

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Oral Melanoacanthosis Synonym: Oral melanoacanthoma. Oral melanoacanthosis is a reactive hypermelaninosis of the oral mucosa that has a characteristic clinical presentation. The original reports refer to it as “oral melanoacanthoma”105 and it shares some histologic similarities with skin melanoacanthoma. However, unlike skin melanoacanthomas, oral melanoacanthosis is macular, occurs in young adult African American females, and is self-remitting. CLINICAL FEATURES This is a condition that is most commonly encountered in young African American adults with a 1:3 male-to-female ratio. Typically, the lesion presents as a solitary dark brown macule on the buccal or labial mucosa that may have a slightly roughened surface.106 It spreads laterally and may grow several centimeters within a few weeks. It does not ulcerate and is not indurated. It regresses spontaneously or after removal of offending physical irritants, but may recur. HISTOPATHOLOGIC FEATURES There is acanthosis and increased deposition of melanin in the basal cells and hyperplasia of benign pigment-laden dendritic melanocytes throughout the thickness of the epithelium. Rarely, there may be spongiosis. A lymphocytic infiltrate is present in the lamina propria with scattered melanophages, eosinophils, and vascular ectasia.107 DIFFERENTIAL DIAGNOSIS Oral melanotic macules do not exhibit the marked acanthosis and dendritic melanocytic hyperplasia and trans-epithelial melanocytic migration seen in melanoacanthosis. The benign appearance of the melanocytes differentiates this entity from atypical melanocytic lesions and melanoma.

Medication-Associated Pigmentation 1016

Pigmentation of the oral mucosa has been associated with admininstration of

antimalarial medications, tetracyclines and minocycline. Chelation of melanin and/or hemosiderin to drug metabolites and/or pigmented metabolites of the associated medication have all been implicated as causes. Some of the reports of pigmentation caused by medications are likely post-inflammatory hypermelaninoses secondary to lichenoid and interface stomatitides. CLINICAL FEATURES The color and distribution of the pigmentation varies with the offending medication, but is generally bilateral and symmetrical. With the administration of antimalarials, the hard palate often takes on a characteristic slate-gray appearance. Tetracycline pigmentation primarily affects the bone (since tetracycline is avidly taken up by bone) and shows through the gingival or palatal mucosa as grayish discoloration. HISTOPATHOLOGIC FEATURES Drug metabolites chelate melanin or iron, and the resulting granules may appear 2 to 4 μm in size with a round and regular configuration, typically arranged in linear array between collagen fibers. They may be distributed within the lamina propria and within macrophages and may stain for melanin and/or iron. DIFFERENTIAL DIAGNOSIS Hemosiderin particles tend to be slightly larger, coarser, more orange, and less regular in appearance than melanin. Moreover, melanin does not usually have the characteristic linear configuration between collagen fibers.

DYSPLASTIC AND NEOPLASTIC CONDITIONS

Leukoplakia Synonym: Leukokeratosis. Leukoplakia is a clinical entity that the World Health Organization (WHO) defines as “any white patch that does not rub off and cannot be characterized clinically or pathologically as any other disease and is not associated with a physical or chemical agent except tobacco.”108,109 It is the most common premalignant mucosal lesion. The prevalence of leukoplakia in the general population ranges from 2% to 4%, and leukoplakia occurs in up to 14% of smokers. More than 70% of patients who have leukoplakia use tobacco products.110 CLINICAL FINDINGS Leukoplakia is twice as common in adult males as females, although smoking may account for this

discrepency. Several different clinical forms are recognized: homogeneous, speckled (erythroleukoplakia), verrucous, and nodular.111 Very often a plaque will exhibit combinations of these forms. Early leukoplakic plaques tend to be grayish white, and established lesions tend to be densely opaque with verrucous and/or nodular areas. Erythroleukoplakia (speckled leukoplakia) is associated with an even greater risk of dysplasia and malignant change.112,113 Although any oral site may present with leukoplakia, the two most common sites are the buccal mucosa and gingiva. Though encountered less commonly, lesions on the floor of mouth, ventral tongue, and soft palate have a higher association with dysplasia or carcinoma. Malignant transformation occurs in up to 24% of all patients with long-term follow-up and in 36% of patients with preexisting epithelial dysplasia.113 There is a form of extensive leukoplakia that tends to occur in elderly women called proliferative verrucous leukoplakia, of which only half the cases are associated with tobacco use. These extensive lesions develop over 10 or 20 years from homogeneous leukoplakias. 80% to 100% of cases develop squamous cell or verrucous carcinoma on long-term follow-up.114 HISTOPATHOLOGIC FEATURES Since at least 9% to 34% of all leukoplakias exhibit dysplasia, carcinoma in situ, or invasive carcinoma, all leukoplakias must be evaluated for epithelial dysplasia. There is usually hyperpara- or orthokeratosis with varying degrees of acanthosis. Architectural features of dysplasia include endophytic growth, significant papillomatosis and bud- or teardropshaped rete ridges. Cytologic features include maturation disarray, basal cell hyperplasia, increased nuclear to cytoplasmic ratio, pleomorphism, and increased mitotic activity. The convention is to grade the dysplasia mild if less than one-third of the epithelium is involved, moderate if more than onethird but less than two-thirds is involved, and severe if more than twothirds is involved. Full-thickness involvement is diagnosed as carcinoma in situ. Some use the term squamous intraepithelial neoplasia (SIN) or oral intraepithelial neoplasia (OIN) to designate such dysplasias.115,116 Koilocytic dysplasia exhibits histologic features of conventional oral epithelial dysplasia as well as those of HPV infection including koilo-cytosis. HPV infection has recently been recognized

DIFFERENTIAL DIAGNOSIS Inflammatory epithelial atypia may be seen in association with candidiasis and at the edge of ulcers. A lichenoid lymphocytic reaction to epithelial dysplasia should not be mistakenly underdiagnosed as lichen planus.

Erythroplakia Synonym: Erythroplasia. Erythroplakia (similar to erythroplasia of Queyrat) is another clinical entity that, like leukoplakia, cannot be attributed to any specific oral condition and is simply described as a clinical red plaque. CLINICAL FEATURES This is an uncommon condition of older men characterized by a discrete erythematous plaque that has a velvety surface. It is more often seen adjacent to or admixed with a leukoplakia (erythroleukoplakia or speckled leukoplakia).112,118 HISTOPATHOLOGIC FEATURES Most erythroplakias are nonkeratinized and may demonstrate epithelial atrophy. Up to 90% of patients exhibit epithelial dysplasia, carcinoma in situ, or squamous cell carcinoma at the time of biopsy.112,118 The criteria for diagnosis of epithelial dysplasia have been discussed in the previous section.

DIFFERENTIAL DIAGNOSIS This is similar to leukoplakia.

Oral Submucous Fibrosis This condition is associated with chewing betel quid (composed of areca nut, slaked lime, tobacco, and spices wrapped in betel leaf), which is a habit common in populations from the Indian subcontinent and southeast Asia. The areca nut stimulates collagen synthesis and inhibits degradation of collagen, leading to fibrosis. In populations that exclude tobacco from this preparation, early studies showed no increased risk of oral cancer. More recently, however, a link has been established between carcinogenesis and chewing betel quid in the absence of tobacco, believed to be releated to the presence of the areca nut alkaloid arecoline.119,120 CLINICAL FEATURES Submucous fibrosis involves the lips, buccal mucosa, retromolar areas and soft palate. Patients develop progressive limitation of mouth opening and a burning sensation. The mucosa develops a marble-like pallor and palpable fibrous bands. HISTOPATHOLOGIC FEATURES Early lesions may show little more than a mild inflammatory cell infiltrate within the lamina propria. Later-stage disease is characterized by atrophic epithelium overlying densely collagenized fibrous connective tissue with reduced vascularity. Epithelial dysplasia or carcinoma may be seen in 15% to 38% of cases at the time of biopsy. DIFFERENTIAL DIAGNOSIS Systemic sclerosis featurs positive serologic markers for autoimmune disease. Hyalinization associated with amyloidosis will stain with Congo red.

Squamous Cell Carcinoma Squamous cell carcinoma (SCCa) accounts for more than 90% of all intraoral malignancies and constitute 3% of all malignancies diagnosed in the United States. Many of them occur in the setting of preexisting leukoplakias or erythroplakias. Tobacco and areca nut use (in specific populations) are two of the most important risk factors for the occurrence of intraoral carcinoma; this risk is greatly increased by the synergistic effect of alcohol. Oral HPV infection is strongly associated with oropharyngeal cancer. Additional risk factors include ultraviolet light and immunocompromise.121,122

CLINICAL FEATURES The prevalence of SCCa increases with age. It presents most often as either a nonhealing ulcer, leukoplakia, erythroplakia, or a rapidly growing, fungating mass. The most common sites are the posterior tongue, the floor of the mouth, the soft palate, and the gingiva/alveolar mucosa. HISTOPATHOLOGIC FEATURES SCCas of the oral cavity may be well, moderately, or poorly differentiated with increasing anaplasia and decreasing production of keratin. There is variable pleomorphism, and stromal invasion must be present. Invasion on a broad front with large, broad pushing rete ridges carries a better prognosis than infiltration in small cords or single-cells.123 Perineural and bone invasion is associated with a poorer prognosis.124,125 Like melanomas, the thickness of the tumor may have some prognostic significance, with thickness less than 4 mm correlating with increased risk of metastasis and reduced survival.124,126 Low levels of E-cadherin expression has also been associated with late cervical metastasis. Sentinel node biopsy in patients without evidence of cervical disease found occult metastases in 20% to 50% of patients.123,127-139 Allelic imbalance and loss of heterozygosity involving in particular chromosome 3p, 9p, 11q, 13a, and 17p have been associated with squamous cell carcinoma.130 A high frequency of p53 mutations has been noted in patients with oral squamous cell carcinoma. There are many histologic variations of SCCa. It is sometimes difficult to differentiate between papillary well-differentiated squamous cell and verrucous carcinomas that are strongly associated with smokeless tobacco use. In the latter, there is marked hyperparakeratosis with parakeratin plugging, prominent endophytic frondlike epithelial proliferations (blunt invasion) and minimal cytologic atypia.23 Keratin pearl formation, especially in the depths of the tumor, occurs rarely, if at all, and there should be no evidence of individual cell invasion of the stroma. This should not be confused with papillary well-differentiated squamous cell carcinoma, which is papillary, may form abundant keratin, and usually exhibits single-cell infiltration of the stroma and significant atypia and pleomorphism. The papillary squamous cell carcinoma of the upper aerodigestive tract exhibits infiltration of the stroma and portions of it resemble a squamous papilloma with carcinoma in situ.131 Other less common variations of squamous cell carcinomas include the

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

as a risk factor for the development of oropharyngeal squamous cell carcinoma. Papillomatosis is a constant feature of the entity verrucous hyperplasia that is a precursor to verrucous carcinoma or papillary well-differentiated squamous cell carcinoma.23 The term lichenoid dysplasia has been used to describe epithelial dysplasia associated with a lichenoid lymphocytic band at the interface. To avoid confusion, it is preferable to diagnose such cases as “epithelial dysplasia with an associated lichenoid infiltrate.” Some believe that these represent malignant transformation of oral lichen planus, though it is more likely that the lichenoid infiltrate is an immunologically mediated reaction to the epithelial dysplasia. Alterations in the cell cycle regulatory pathways led by the p53 gene and the Rb gene have been identified in oral carcinomas. Increased expression of p53 and cyclin D1, inactivation of p16 and pRb, and increased telomerase activity have been reported in dysplastic cells of leukoplakia.117 Alterations in the Rb pathway correlate with a worse prognosis.

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sarcomatoid (spindle cell) carcinoma, adenosquamous carcinoma, adenoid squamous carcinoma, and basaloid squamous cell carcinoma. In all these cases, a typical squamous cell carcinoma is always present, and the overlying surface epithelium is usually dysplastic. Half of all sarcomatoid carcinomas occur on the lower lip; the tongue is the second most common site, where it is often polypoid. There is a proliferation of spindled cells in a fasciculated configuration. The spindle cells stain for both vimentin and keratin but are uniformly S100-negative.132-134 Adenosquamous carcinoma consists of a combination of a surface squamous cell carcinoma and an adenocarcinoma that often, but not invariably, stains for mucin intracytoplasmically; the adenosquamous carcinoma resembles a mucoepidermoid carcinoma.135 Most adenoid squamous cell carcinomas (also known as pseudoglandular or acantholytic squamous cell carcinoma) arise on the lower lip vermilion. The tumor forms ductlike structures within islands of tumor cells as a result of acantholysis and marked dyscohesion of tumor cells.136 Unlike adenosquamous carcinoma, these are not true ducts; tumor cells do not contain mucin. Basaloid squamous cell carcinoma arises primarily in the base of the tongue and pharynx and consists of islands of basaloid cells usually with comedonecrosis, microcystic spaces filled with PAS-positive material and stromal hyalinization; a cribriform pattern may be present. In addition to being keratinpositive, the tumor cells also are often EMA- and CEA-positive; S100 and NSE positivity may be weak.137

noted in close proximity to skeletal muscle, GCTs were originally referred to as granular cell myoblastomas. Nearly half of GCTs display pseudoepitheliomatous hyperplasia. The cells stain for both S100 protein and CD68 because the granules represent lysosomes. DIFFERENTIAL DIAGNOSIS Superficial biopsies that capture only the pseudoepitheliomatous hyperplasia and not the granular cells may be mistaken for squamous cell carcinoma, though GCTs lack cytologic atypia. The congenital granular cell tumor (congenital epulis of the newborn) is rare tumor that presents as a red or pink nodule on the alveolar ridge of neonates; there is a 1:9 male-to-female ratio. They are unencapsulated but circumscribed lesions composed of large round or polyhedral cells with granular cytoplasm, but the stain for S100 protein is usually negative since these are not of neural differentiation.140,141 The primitive polypoid granular tumor (non-neural granular cell tumor) does not exhibit positive staining for S100 protein and may show pleomorphism.142,143

Ectomesenchymal Chondromyxoid Tumor This rare benign tumor seen primarily on the anterior tongue was first

described in 1995.144 Its histogenesis is uncertain; although many believe these represent a distinct entity,145 it has been suggested that ECTs may represent a variant of myoepitheliomas that are derived from minor salivary glands or from non-salivary gland-derived myoepithelial cells.146 CLINICAL FEATURES Ectomesenchymal chondromyxoid tumors (ECTs) are slow-growing painless nodules typically found on the anterior tongue. There is no sex predilection. A single case has been reported on the palate. HISTOPATHOLOGIC FEATURES These tumors are well-circumscribed nodules with lobules separated by fibrous septations. Tumor cells are arranged in sheets and cords, vary from spindled or polygonal, and are set in a myxoid background that may display chondroid areas (Fig. 37-15). Ductal structures are absent. ECTs exhibit variable positivity with keratin markers and generally stain for GFAP and S100 protein.147-149 DIFFERENTIAL DIAGNOSIS Pleomorphic adenomas of the minor salivary glands always contain ductal structures. Soft tissue myxomas lack chondroid features and GFAP positivity and they are hypocellular with abundant connective tissue mucin.

Granular Cell Tumor A granular cell tumor (GCT) is a benign soft tissue tumor of neural origin; more than half occur in the oral cavity. CLINICAL FEATURES The most common location for a GCT is the dorsal surface of the tongue, although some lesions are noted on the buccal mucosa. It typically presents as a deep-seated firm mass that varies in color from pink to yellowish. It is generally less than 2 cm in size. Although rare, some patients have multifocal lesions.138,139

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HISTOPATHOLOGIC FEATURES GCTs are characterized by sheets of polygonal cells that have finely granular eosinophilic cytoplasm. Cells have indistinct borders and small nuclei. Because they are often

 FIGURE 37-15 Ectomesenchymal chondromyxoid tumor. A well-circumscribed nodule contains polygonal and spindle-shaped cells set in a myxoid background.

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120. Yang YH, Lien YC, Ho PS. The effects of chewing areca/betel quid with and without cigarette smoking on oral submucous fibrosis and oral mucosal lesions. Oral Dis. 2005;11(2):88-94. 121. Johnson NW, Warnakulasuriy S, Tavassoli M. Hereditary and environmental risk factors; clinical and laboratory risk matters for head and neck, especially oral, cancer and precancer. Eur J Cancer Prev. 1996;5(1):5-17. 122. Scully C, Bagan JV. Recent advances in oral oncology. Oral Oncol. 2007;43(2):107-115. 123. Taylor RJ, Wahl RL, Sharma PK, et al. Sentinel node localization in oral cavity and oropharynx squamous cell cancer. Arch Otolaryngol Head Neck Surg. 2001; 127(8):970-974. 124. Shingaki S, Suzuki I, Nakajima T, Kawasaki T. Evaluation of histopathologic parameters in predicting cervical lymph node metastasis of oral and oropharyngeal carcinomas. Oral Surg Oral Med Oral Pathol. 1988;66(6):683-688. 125. Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29(2):167-178. 126. Yuen AP, Lam KY, Wei WI, et al. A comparison of the prognostic significance of tumor diameter, length, width, thickness, area, volume, and clinicopathological features of oral tongue carcinoma. Am J Surg. 2000;180(2):139-143. 127. Shoaib T, Soutar DS, MacDonald DG, et al. The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 Neck. Cancer. 2001;91(11):2077-2083. 128. Hart RD, Nasser JG, Taylor M, Trites JT, Barnes D, Bullock MD. Sentinel lymph node biopsy in N0 squamous cell carcinoma of the oral cavity and oropharynx. Arch Otolaryngol Head Neck Surg. 2005;131(1):34-38. 129. Payoux P,Dekeister C, Lopez R, Lauwers F, Esquerre JP, Paoli JR. Effectiveness of lymphoscintigraphic sentinel node detection for cervical staging of patients with squamous cell carcinoma of the head and neck. J Oral Maxillofac Surg. 2005;63(8): 1091-1095. 130. Scully C, Field JK, Tanzawa H. Genetic aberrations in oral or head and neck squamous cell carcinoma 3: clinicopathological applications. Oral Oncol. 2000;36(5): 404-413. 131. Crissman JD, Kessis T, Shah KV, Fu YS, Stoler MH, Zarbo RJ. Squamous papillary neoplasia of the adult upper aerodigestive tract. Hum Pathol. 1988;19(12): 1387-1396. 132. Zarbo RJ, Crissman JD, Venkat H, Weiss MA. Spindle-cell carcinoma of the upper aerodigestive tract mucosa. An immunohistologic and ultrastructural study of 18 biphasic tumors and comparison with seven monophasic spindle-cell tumors. Am J Surg Pathol. 1986; 10(11):741-753. 133. Ellis GL, Langlos JM, Heffner DK, Hyams VJ. Spindle-cell carcinoma of the aerodigestive tract. An immunohistochemical analysis of 21 cases. Am J Surg Pathol. 1987;11(5):335-342.

134. Takata T, Ito H, Ogawa I, Miyauchi M, Ijuhin N, Nikai H. Spindle cell squamous carcinoma of the oral region. An immunohistochemical and ultrastructural study on the histogenesis and differential diagnosis with a clinicopathological analysis of six cases. Virchows Arch A Pathol Anat Histopathol. 1991; 419(3):177-182. 135. Gerughty RM, Hennigar GR, Brown FM. Adenosquamous carcinoma of the nasal, oral and laryngeal cavities. A clinicopathologic survey of ten cases. Cancer. 1968;22(6):1140-1155. 136. Ferlito A, Devaney KO, Rinaldo A, Milroy CM, Carbone A. Mucosal adenoid squamous cell carcinoma of the head and neck. Ann Otol Rhinol Laryngol.1996;105(5):409-413. 137. Coppola D, Catalano E, Tang C-K, Elfenbein IB, Harwick R, Mohr R. Basaloid squamous cell carcinoma of floor of mouth. Cancer. 1993;72(8): 2299–2305. 138. Lamey PJ,. Rennie JS, James J. Multiple granular cell tumors of the palate. Int J Oral Maxillofac Surg. 1987;16(2):236-238. 139. Goodstein ML, Eisele DW, Hyams VJ, Kashima HK. Multiple synchronous granular cell tumors of the upper aerodigestive tract. Otolaryngol Head Neck Surg. 1990;103(4):664-668. 140. Kaiserling E,Ruck P, Xiao JC. Congenital epulis and granular cell tumor: a histologic and immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;80(6):687-697. 141. Lapid O, Shaco-Levy R, Krieger Y, Kachko L, Sagi A. Congenital epulis. Pediatrics 2001;107(2):E22. 142. Basile JR, Woo SB. Polypoid s-100-negative granular cell tumor of the oral cavity: a case report and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96(1):70-76. 143. Lerman M, Freedman PD. Nonneural granular cell tumor of the oral cavity: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(3):382-384. 144. Smith BC,Ellis GL, Meis-Kindblom JM, Williams SB. Ectomesenchymal chondromyxoid tumor of the anterior tongue. Nineteen cases of a new clinicopathologic entity. Am J Surg Pathol. 1995;19(5):519-530. 145. Carlos R,Aguirre JM,Pineda V. Ectomesenchymal chondromyxoid tumor of the tongue. Med Oral. 1999; 4(1):361-365. 146. Woo VL, Angiero F, Fantasia JE, Myoepithelioma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99(5):581-589. 147. De Visscher JG, Kibbelaar RE, Van Der Waal I. Ectomesenchymal chondromyxoid tumor of the anterior tongue. Report of two cases. Oral Oncol. 2003;39(1):83-86. 148. Kaplan I, Anavi Y, Calderon S. Ectomesenchymal chondromyxoid tumour of the anterior tongue. Int J Oral Maxillofac Surg. 2004;33(4):404-407. 149. Goveas N, Ethunandan M, Cowlishaw D, Flood TR. Ectomesenchymal chondromyxoid tumour of the tongue: unlikely to originate from myoepithelial cells. Oral Oncol. 2006;42(10):1026-1028.

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

109.

mucocutaneous pigmentation (LaugierHunziker syndrome): a clinical, histopathological and ultrastructural review of 12 cases. Oral Dis. 1999;5(1):80-86. Schneider LC, Mesa ML, Haber SM. Melanoacanthoma of the oral mucosa. Oral Surg Oral Med Oral Pathol. 1981; 52(3):284-287. Goode RK, Crawford BE, Callihan MD, Neville BW. Oral melanoacanthoma. Review of the literature and report of ten cases. Oral Surg Oral Med Oral Pathol. 1983;56(6):622-628. Contreras E, Carlos R. Oral melanoacanthosis (melanoachantoma): report of a case and review of the literature. Med Oral Patol Oral Cir Bucal. 2005; 10(1):9-12. Axell T, Pindborg JJ, Smith CJ, van der Waal I. Oral white lesions with special reference to precancerous and tobaccorelated lesions: conclusions of an international symposium held in Uppsala, Sweden, may 18-21 1994. International collaborative group on oral white lesions. J Oral Pathol Med. 1996;25(2):49-54. Van Der Waal I, Schepman KP, Van Der Meij EH, Smeele LE. Oral leukoplakia: a clinicopathological review. Oral Oncol. 1997;33(5):291-301. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006;42(5):461-474. Jaber MA, Porter SR, Speight P, Eveson JW, Scully C. Oral epithelial dysplasia: clinical characteristics of western European residents. Oral Oncol. 2003; 39(6):589-596. Shafer WG, Waldron CA. Erythroplakia of the oral cavity. Cancer. 1975;36(3): 1021-1028. Silverman S, Bhargava K, Mani NJ, Smith LW, Malaowalla AM. Malignant transformation and natural history of oral leukoplakia in 57,518 industrial workers of Gujarat, India. Cancer. 1976; 38(4):1790-1795. Zakrzewska JM Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82(4):396-401. Crissman JD, Visscher DW, Sakr W. Premalignant lesions of the upper aerodigestive tract: pathologic classification. J Cell Biochem Suppl.1993;17f:49-56. Kuffer R. Lombardi T. Premalignant lesions of the oral mucosa. A discussion about the place of oral intraepithelial neoplasia (oin). Oral Oncol. 2002. 38(2): 125-130. Soni S, Kaur J, Kumar A, et al. Alterations of Rb pathway components are frequent events in patients with oral epithelial dysplasia and predict clinical outcome in patients with squamous cell carcinoma. Oncology. 2005;68(4-6):314-325. Mashberg A. Erythroplasia: the earliest sign of asymptomatic oral cancer. J Am Dent Assoc. 1978;96(4):615-620. Chung CH, Yang YH, Wang TY, Shieh TY, Warnakulasuriva S. Oral precancerous disorders associated with areca quid chewing, smoking, and alcohol drinking in southern Taiwan. J Oral Pathol Med. 2005;34(8): 460-466.

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APPENDIX 1 Stem Cells and the Skin

APPENDEX 1 ■ STEM CELLS AND THE SKIN

Laurence Verneuil Anne Janin Raymond L. Barnhill

EPIDERMIS, HAIR FOLLICLE, AND EPIDERMAL STEM CELLS Stem cells (SCs) reside in the discrete microenvironment of the hair follicle bulge (Fig. A1-1) and give rise to several cell types in the hair follicle.1 During the hair cycle, bulge SCs are stimulated to exit the SC niche, proliferate, and differentiate along the lines of various cell types of mature HFs. In addition to serving as a source of various cell types during HF regeneration, the bulge SC is a reservoir for multipotent SCs that may be recruited during wound healing to reconstitute the epidermis.2 There is conflicting evidence as to whether follicular SCs contribute to the wounded epidermis only transiently, ultimately being replaced by the progeny of SCs derived from the original epidermal compartment before wounding or on a long-term basis. Ito M et al.3 suggest that SCs in the hair follicle bulge do not normally contribute cells to the epidermis, which is organized into epidermal proliferative units, as previously

Placode

Hair Germ

described. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound in a striking radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most appear to be eliminated from the epidermis over several weeks, indicating that bulge SCs respond rapidly to epidermal wounding by generating short-lived “transient amplifying” cells responsible for acute wound repair.3 In contrast, Levy et al.4 have reported that follicular cells participate in the initial resurfacing of the wound, and their progeny seem to persist in the wound epidermis months after wound healing. Levy et al.4 conclude that the follicular cells seem to undergo reprogramming to become long-term repopulating epidermal progenitors after wounding.4 In summary, hair follicle SCs have at the very least a dual function: continuous hair follicle remodeling and epidermal regeneration whenever skin integrity is severely compromised.5 Although it has not been clearly established whether other multipotent SCs are present in adult skin, substantial evidence shows that unipotent SCs exist in other cutanous locations.2 Thus, the question arises as to the relationship between the SCs of the bulge and those residing within the basal layer of the epidermis. One possibility is that multipotent bulge cells periodically migrate from their niche to populate the basal layer of the epidermis, the hair matrix, and sebaceous gland. What triggers a bulge cell to move upward or downward and execute a

Hair Peg

Mature Follicle

Sebaceous gland

Dermal condensate Bulge

Matrix (Mx) Dermal papilla (DP)

Inner root sheath (IRS)

Outer root sheath (ORS) Melanocytes (Mc)

1022

FIGURE A1-1 Epidermal and other stem cells reside in the bulge area of the hair follicle.

particular differentiation program? Although the answer to this question is still uncertain, some new information has emerged from studies on hair lineage. It seems likely that the process of activating bulge SCs depends on factors that are both intrinsic and extrinsic to the bulge cells themselves. Surrounded by a dermal sheath that is richly innervated and vascular, the bulge dwells in a fertile milieu of signaling networks. An attractive model is that some environmental cue stimulates bulge cells to divide asymmetrically, replenishing the bulge SCs and generating daughter cells that are less adhesive to the niche. Although not yet demonstrated for skin epithelial SCs, asymmetric divisions have been documented for some SCs.6-8 In this model, a reduction in the expression of integrins or cadherins could facilitate the departure of non–stem daughter cells from the niche.

MELANOCYTE STEM CELLS Although stem cells for melanocytes have been difficult to identify, there has been much greater interest in such stem cells recently. For example, a recent study demonstrated that melanocyte SCs (MSCs) may reside in the area of the hair follicle.9,10 These MSCs proliferate and migrate to the bulbar area to generate pigmented hair shafts, and the exhaustion or incomplete maintenance of this cellular populace from this region results in a loss of hair shaft pigmentation and gray hairs.10 Other studies have shown that related cells with broad differential potential, including expression of neuronal, glial, smooth muscle, keratinocytic, and melanocytic differentiation, originate from the hair follicular bulge and appear to be neural crest derived. 9 These apparent neural crest–related cells also express nestin, an intermediate filament protein in neural stem and progenitor cells, and Sox10, a neural crest SC marker. Thus, increasing evidence suggests that MSCs are present in the hair follicle bulge region. The cells may self-renew or migrate from the bulge niche and differentiate into melanocytes in the bulb of the hair follicle. In addition, other cell populations such as Merkel cells11 and Langerhans cells12 have also been detected in the bulge area, further indicating the importance of bulge environment in the homeostasis of the skin.13

TUMOR STEM CELLS AMONG HAIR FOLLICLE STEM CELLS

Hair Follicle Stem Cells are Uniquely Interesting Targets for Regenerative Medicine Adult SCs may have tremendous therapeutic potential, and the skin epithelium represents an enormous source of accessible SCs for generating cells to replace diseased tissue. In addition, the skin is an excellent model for studying the basic biology of organ regeneration and translational approaches to regenerative medicine. Because of the accessibility of the skin, a long history of regenerative approaches already exists. Identifying the commonalities between skin regeneration and the regeneration of other organs could provide major breakthroughs in regenerative medicine.

REFERENCES 1. Taylor G, Lehrer MS, Jensen PJ, et al: Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell. 2000;102:451-461. 2. Blanpain C, Fuchs E: Epidermal stem cells of the skin. Ann Rev Cell Devel Biol. 22:339-373.

3. Ito M, Liu Y, Yang Z, et al: Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005;11(12):1351-1354. 4. Levy V, Lindon C, Zheng Y, et al: Epidermal stem cells arise from the hair follicle after wounding. FASEB J. 2007; 21(7):1358-1366. 5. Tiede S, Kloepper JE, Bodò E, et al: Hair follicle stem cells: walking the maze. Eur J Cell Biol. 2007;86(7):355-376. 6. Knoblich JA: Asymmetric cell division during animal development. Nat Rev Mol Cell Biol. 2001;2:11-20. 7. Lu B, Roegiers F, Jan LY, Jan YN: Adherens junctions inhibit asymmetric division in the Drosophila epithelium. Nature. 2001; 409:522-525. 8. Song X, Xie T: DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Drosophila ovary. Proc Natl Acad Sci. 2002;99:14813-14818. 9. Sommer L: Checkpoints of melanocyte stem cell development. Sci STKE. 2005; 298:pe42. 10. Nishimura EK, Granter SR, Fisher DE: Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science.2005;307:720-724. 11. Narisawa Y Hashimoto K, Kohda H: Epithelial skirt and bulge of human facial vellus hair follicles and associated Merkel cell–nerve complex. Arch Dermatol Res. 1983;285:269-277. 12. Moresi JM, Horn TD: Distribution of Langerhans cells in human hair follicle. J Cutan Pathol. 1997;24:636-640. 13. Ohyama M: Hair follicle bulge: a fascinating reservoir of epithelial stem cells. J Dermatol Sci. 2007;46(2):81-89. 14. Morrison SJ, Kimble J: Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006;441:10681074. 15. So AW, Langston N, Daniallinia JL, et al: Long-term establishment, characterization and manipulation of cell lines from mouse basal cell carcinoma tumors, Exp. Dermatol. 2006;15:742-750. 16. Massoumi R, Podda M, Fassler R, Paus R: Cylindroma as tumor of hair follicle origin, J. Invest. Dermatol. 2006;126:1182-1184. 17. Yu BD, Mukhopadhyay A, Wong C: Skin and hair: models for exploring organ regeneration. Hum Mol Genet. 2008;15; 17(R1):R54-R59.

APPENDEX 1 ■ STEM CELLS AND THE SKIN

By definition, SCs must be able to self-renew and produce differentiated progeny. Asymmetric cell division can accomplish both. However, many SCs also divide symmetrically, allowing the SC population to increase in number. This type of division may be vital to development and regeneration but may also confer a risk for the development of cancer.14 Another related problem is how one can best distinguish potential tumor SCs 15 from normal adult hair follicle–related SCs that can safely be used (eg, for regenerative medicine and gene therapy purposes). This is an important issue because several studies suggest that hair follicle SCs may not only give rise to a variety of benign skin appendage tumors such as pilomatricoma and cylindroma16 but also to basal cell carcinoma, the most prevalent human malignancy.15

Recent studies suggest the epidermis and hair may have an untapped potential to form other organs. Understanding the mechanisms that regulate adult SC proliferation is a major goal for regenerative medicine. In the hair follicle, pharmacologic agents, recombinant proteins, and artificial cell-permeable proteins have been developed to manipulate the proliferation of the quiescent bulge SCs. These advances illustrate a potential roadmap for regenerative medicine using molecular tools developed for skin biology to promote organ regeneration by manipulating adult SCs in situ.17 In summary, the hair follicle and its immediately adjacent tissue environment contain unipotent, multipotent, and possibly even pluripotent SC populations of different developmental origin, which can differentiate along neuroectodermal and mesodermal pathways. Under physiologic circumstances, SCs of the hair follicle bulge serve as a cell pool for the cyclic regeneration of the anagen hair bulb, and they can also regenerate the sebaceous gland and the epidermis after injury. As such, hair follicle SCs are uniquely interesting for regenerative medicine applications, but many important issues (eg, the identification and elimination of tumor SCs) remain unresolved. Hair follicle SCs also offer highly instructive model systems for the study of central issues in SC biology such as SC gene and protein profiling, SC plasticity, and SC niches.5

1023

APPENDEX 2 ■ LABORATORY METHODS

APPENDIX 2

Table A2-1 Common Special Stains in Dermatopathology

Laboratory Methods

STAIN

APPLICATION

RESULTS

H&E

Routine

Klaus J. Busam Raymond L. Barnhill

PAS/diastase

Masson’s trichrome

Fungi, parasites Glycogen (eg, in trichilemmoma) Basement membrane thickening (eg, LE) Cryoglobulinemia Adenocarcinomas, Cryptococcus Mast cells Mast cells Leishmania Fibrosis

Nuclei: blue; cytoplasm; red Collagen, muscles, nerves: red Wall of organisms: red Glycogen: red on PAS; clear after diastase digestion Basement membrane: pink/red

Van Gieson Van Kossa Congo red Fontana Prussian blue Gram stain

Infantile digital fibromatosis Arterial injury Calcium Amyloid Melanin Hemosiderin/iron Bacteria

The mainstay of dermatopathology is the examination of skin biopsies after fixation in formalin, embedding in paraffin, and staining with hematoxylin and eosin (H&E). This technique has been quite durable in the history of histopathology because it offers many advantages: it is relatively quick, inexpensive, suitable for most practical needs, and relatively easy to master. However, it cannot answer all the questions that a case may pose at the diagnostic level. Therefore, pathologists have always searched for additional methods to analyze their histologic material.

SPECIAL STAINS There is an extensive battery of “special” stains listed in texts discussing histologic techniques.1,2 Few of them are of practical value for diagnostic dermatopathologists. A synopsis of some of the stains that appear relevant for a modern dermatopathology laboratory is listed in Table A2-1.

Stains for Microorganisms Perhaps the most important of all the special stains in the practice of dermatopathology are stains that help to identify microorganisms. This includes the modifications of the Gram stain, such as by Brown and Hopp, for most bacterial organisms; the methenamine silver stain or periodic acid-Schiff (PAS) stain for fungi and parasites; and the Ziehl-Neelson or Fite stain for acid-fast bacilli. Silver stains, such as according to Dieterle, Warthin-Starry, and Steiner, are commonly used to identify spirochetes (syphilis, Lyme disease) and the organisms in cat-scratch disease and bacillary angiomatosis (Rochalimea). Leishmania is best identified by a Giemsa stain.

Mucicarmine Toluidine blue Giemsa

Methenamine-silver Dieterle/Steiner/ Warthin-Starry AFB/Fite

Fungi, parasites Spirochetes, Rochalimea

Cryoprecipitates: bright red Mucin: red Capsule: red Metachromatically purple Metachromatically purple Blue Collagen: green; nuclei, muscle: dark red Hyaline globules: red Elastic fibers: black Black Green under polarized light Black Black Depending on method used (gram positive: usually blue; gram negative: usually red) Black Black

Acid-fast bacilli

Red

digestion. The staining reaction yields a pink to red color. An intensely bright red homogeneous material within vessels suggests cryoglobulins. The PAS stain is also useful in highlighting most types of fungi and parasites.

Stain for Hemosiderin In the Prussian blue reaction, hydrochloric acid splits off the protein bond to the iron, allowing the potassium ferrocyanide to combine specifically with the ferric iron to form ferric ferrocyanide. The reaction leaves a blue color.

Giemsa Stain This technique is very useful for the demonstration of lymphoreticular cells, including mast cells. It is also used to highlight microorganisms such as Leishmania.

Mucicarmine Stain This technique has been recommended for epithelial mucins (ie, adenocarcinoma), and to stain the capsule of Cryptococcus. A positive reaction yields a reddish color.

Stains for Melanin In the Fontana-Masson method, an ammoniacal silver solution is used without a reducing bath. Only substances capable of reducing directly silver salts (ie, argentaffin material) such as melanin are demonstrated as grayish black pigment. This stain is not entirely specific for melanin. Some metabolic products of minocin, for example, also stain with this method.

Toluidine Blue Periodic Acid-Schiff Stain

1024

This stain demonstrates mucosubstances, basement membrane material, fibrinoid material, and glycogen in a specific fashion when combined with diastase

This stain is used to document metachromasia. Most acid mucosubstances show metachromasia at higher pH values. Toluidine blue is used most often to identify mast cells.

Von Kossa Stain for Calcium In this technique, silver is substituted for calcium in calcium salts; this silver is then reduced to yield a black metallic color.

Trichrome Stains In this stain, phosphotungstic or phosphomolybolic acid is used in combination with several anionic dyes. This stain is primarily used in the evaluation of extracellular material, in particular collagen such as in fibromatoses or connective tissue nevi. Its practical application includes also peculiar phenomena such as the identification of small globular structures in infantile digital fibromatosis.

Reticulin Stain

Elastic Fiber Stain In the Verhoeff-van Gieson stain, elastic fibers are outlined with a strong black color. Its main applications are in the demonstration of arterial injury and in connective tissue nevi.

Amyloid Stains A number of stains are available to demonstrate amyloid material. Most laboratories use the Congo red stain. This stain needs to be combined with polariscopic examination, which yields an apple-green birefringent appearance. However, one needs to be cautious in interpreting this stain because excess dye retained in the tissue may give a false-positive signal.

and then allowed to incubate with substrate tissue. Subsequently, the target tissue is labeled with fluorescent-tagged antibodies as described above for DIF. If the patient’s serum contains circulating antibodies to antigens present in the target tissue, a positive signal is obtained. With IF, semiquantitative analysis can be performed by determining titers of antibodies.5 Saline split-skin preparations are an addition to the methodology of indirect immunofluorescence (Table A2-3), and they are mainly used in the distinction between bullous pemphigoid (BP) and epidermolysis bullosa acquisita.6 This technique requires that biopsies of normal skin must be obtained from human volunteers. They are subsequently incubated with 1M sodium chloride at 4°C for 72 hours, and then the epidermis is separated from the dermis manually. The cleavage occurs between the lamina lucida and the remainder of the epidermal basement membrane, which allows localization of the BP antigen to the roof of the artificially induced blister, whereas the epidermolysis bullosa acquisita antigen is located in its base. Although a properly done saline split-skin procedure is very valuable methodology, it is tedious, which explains why it is routinely used only in a few laboratories.

APPENDEX 2 ■ LABORATORY METHODS

This method highlights reticulin fibers. It has traditionally been used to distinguish carcinoma (groups of cells surrounded by fibers) from sarcoma (single cells surrounded by fibers).

complex method with an enzyme antibody conjugate.3 This conjugate is typically an enzyme, such as horseradish peroxidase or alkaline phosphatase. Enhancing techniques using biotin and avidin are frequently used. A number of steps have been suggested to increase the sensitivity of these procedures. The aim is to expose the epitope that may otherwise be masked. Such “unmasking” techniques include digestion of the tissue with proteolytic enzymes or treatment with microwaves. In addition to labeling an antibody with an enzyme, a number of fluorescent probes are also available. Immunofluorescence can be performed either directly (DIF) with a probe such as fluorescane isothiocyanade (FITC) label or indirectly (IF). For DIF, a skin biopsy is submitted in saline (Table A2-2), or if immediate processing cannot be performed, in Michelle medium. Upon arrival of the specimen in the laboratory, frozen sections are prepared, and these are labeled in a one-step method with fluorescence probe tagged antibodies that are directed against human immunoglobulins, serum proteins, or complement fractions. A signal is then obtained by visualizing antibody binding by excitation of the fluorescent label by ultraviolet light using a fluorescence microscope.4 IF differs from DIF in that it does not probe the patient’s skin directly but rather analyzes the presence of circulating antibodies against cutaneous antigens in the patient’s serum. For this method, the patient's serum is obtained

Applications in Nonneoplastic Diseases BULLOUS DISEASES Immunofluorescent studies play an important role in the evaluation of primary bullous disorders

ENZYME HISTOCHEMISTRY Due to the complexity of the techniques involved in enzyme histochemistry, the need for fresh material, and the relative nonspecificity of most of the reactions, this technique has only very limited applications at present. In dermatopathology, the methods most commonly used are chloracetate esterase, also known as Leder stain, for the identification of mast cells or hematopoietic cells of the myeloid lineage, and the Dopa reaction to identify cells of the melanocytic lineage.2

IMMUNOHISTOCHEMISTRY

Table A2-2 Optimal Sites for Skin Biopsy for Direct Immunofluorescence SITE

Pemphigous Pemphigoid, bullous and cicatricial Epidermolysis bullousa acquisita Herpes gestationalis Dermatitis herpetiformis Linear immunoglobulin A (IgA) dermatosis Lupus erythematosus, bullous Porphyria cutanea tarda Lesional Erythema multiforme Lichen planus

Technical Aspects Several methods are applicable to the evaluation of skin biopsies. The most commonly used technique is an immune

DISEASE

Perilesional

Distant normal Leukocytoclastic vasculitis

1025

Table A2-3 Split-Skin Indirect Immunofluorescence Preparation for Selected Cutaneous Diseases Site of Autoantibody to NaCl-Separated Normal Human Skin at the Dermal–Epidermal Junctiona Epidermal portion only Bullous pemphigoid (usual) Cicatricial pemphigoid Chronic bullous dermatosis of childhood (IgA) class autoantibody Epidermis and dermis Bullous pemphigoid (rare) Dermal portion only

APPENDEX 2 ■ LABORATORY METHODS

Epidermolysis bullosa acquisita Lupus erythematosus, bullous Cicatricial pemphigoid a Use of 1.0 M NaCl-split human skin increases the likelihood of detecting basement membrane autoantibodies to an 85% positive rate.

because some of these disorders show a fairly specific reaction pattern (Tables A2-4 to A2-6). INTRAEPIDERMAL BLISTERS These include mainly variants of pemphigus. Immunohistologically, one typically observes a mosaic-like intercellular labeling of the acantholytic epidermis by DIF in virtually all forms of pemphigus (Fig. A2-1). IgG, in particular IgG1, is the most common immunoreactant. Other immuno-

globulins are rarely deposited. Deposition of C3 occurs but is seen infrequently.6 In pemphigus erythematosus, linear deposits of IgG, IgM, IgA, or C3 may be detectable at the epidermal basement membrane zone in addition to the intercellular labeling typical of the other variants of pemphigus.7 SUBEPIDERMAL BLISTERS Immunofluorescence plays a critical role in the distinction among a number of subepi-

dermal bullous disorders.8-11 This disease group includes BP, herpes gestationis (HG), dermatitis herpetiformis (DH), bullous disease of childhood, linear IgA dermatosis, bullous lupus erythematosus, and epidermolysis bullosa acquisita. In all of these diseases, a blister is formed by cleavage of the skin at the basement membrane zone, either in the lamina lucida or lamina densa. BP, HG, and epidermolysis bullosa acquisita all demonstrate linear continuous staining of the basement membrane zone by DIF, for IgG, and for C3 (Fig. A2-2). The distinction of these three entities from each other depends mainly on the clinical findings. If epidermolysis bullosa cannot reliably be separated from BP on clinical grounds alone, IF on saline splitskin preparations would be helpful (see above). It has also been suggested that if this technique is not available, one might also attempt to localize the site of immune complex deposition by staining the tissue sections for type IV collagen. This type of collagen is a major component of the lamina densa. It remains in the base of the blister in BP and HG but resides in the roof of the bulla in epidermolysis bullosa acquisita. Linear IgA dermatosis and chronic bullous dermatosis of childhood share the same immunofluorescence pattern:

Table A2-4 Findings of Direct Immunofluorescence in Bullous Diseases LOCATION/PATTERN OF DEPOSITION Intraepidermal Epidermal cell surface Dermal–epidermal junction Linear, nonhomogeneous Linear, homogeneous

IMMUNOREACTANT PRESENT

DISEASE

IgG, complement IgA

Pemphigus family Intraepidermal IgA dermatosis

Multiple Igs, complement or fibrin Multiple Igs, complement or fibrin

Lupus erythematosus Cicatricial pemphigoid EBA Lupus erythematosus Bullous pemphigoid Cicatricial pemphigoid EBA Herpes gestationalis Chronic bullous dermatosis of childhood Linear IgA dermatosis (adult)

IgG, complement

IgA Other upper dermis Cytoid bodies Interstitial perivascular or dermal–epidermal junction Intravascular Granular

1026

Multiple Igs, complement or fibrin Multiple Igs, complement or fibrin

IgM, complement or fibrin

Dermatitis herpetiformis Lichen planus Porphyria cutanea tarda

Erythema multiforme Vasculitis

Table A2-5 Immunofluorescence Patterns in Autoimmune Bullous Diseases LOCATION

IMMUNOREACTANT

REPRESENTATIVE DISEASE

FREQUENCY

Epidermal cell surface Dermal–epidermal junction

IgG intercellular IgG class

Pemphigus vulgaris Bullous pemphigoid Cicatricial pemphigoid EBA Chronic bullous dermatosis of childhood

Majority of cases >80% <10% >40% Majority of cases

IgA

Anti-bullous pemphigoid Antigen/anti-α6β4 integrin Antilaminin Anti-type IV collagen; anti-LDA-1

EB SIMPLEX

JUNCTIONAL EB

DYSTROPHIC EB

Dermal base

Dermal base

Epidermal roof

Dermal base Dermal base

Epidermal roof Dermal base

Epidermal roof Epidermal roof

linear deposits of IgA along the basement membrane zone. In DH, on the other hand, IgA deposits are found in a patchy granular distribution in the DP (Fig. A2-3). Complement C3 is also frequently deposited in each of these disorders. Occasionally, one may also find deposition of IgG or IgM. In bullous lupus erythematosus, usually a number of immunoglobulins and complements are deposited along the basement membrane in the blister base,

essentially showing the same patterns as in other lesion of lupus erythematosus.12 CONNECTIVE TISSUE DISEASE Immunofluorescence may also be helpful in the evaluation of connective tissue disease, in particular, for the diagnosis of lupus erythematosus. Immunoglobulins (IgG, IgM, IgA, IgE) and complements (C1q, C3, C4, C5) are commonly found along the basement membrane of lesional skin in discoid lupus erythematosus (DLE).12,13

 FIGURE A2-1 Immunofluorescence of pemphigus vulgaris. There is intercellular deposition of IgG in the epidermis.

APPENDEX 2 ■ LABORATORY METHODS

Table A2-6 Staining Patterns in Immunofluorescence Antigenic Mapping for Specific Antibodies to Inherited Epidermolysis Bullosa (EB)

The pattern of deposition is typically granular. In systemic lupus erythematosus (SLE), such granular deposits of immunoglobulins and complement are not only seen in lesional skin but also in clinically normal-appearing skin. The phenomenon that normal-appearing skin may show deposition of immunoglobulins and complements has been used diagnostically in the so-called lupus band test.14 This test may help in the distinction between SLE and DLE. In DLE, a lupus band test result should be negative. A positive test result is found in approximately 60% of patients with SLE. A positive test result in sunprotected normal skin in a patient with SLE has been suggested to also be of prognostic value, implying a worse prognosis. In patients with SLE, immunoglobulins and complements are not only found along the basement membrane zone but also around the vessels and diffusely between collagen bundles. Positive immunofluorescence findings are also commonly seen in a number of other examples of connective tissue disease, such as in mixed connective tissue disease, scleroderma, and dermatomyositis. In most cases, the immunofluorescence pattern is fairly nonspecific and usually adds little useful information. VASCULITIS Positive immunofluorescence findings are commonly seen in many cutaneous vasculitides.15 Many times, it is difficult to decide whether the deposition of immunoglobulins and complements in damaged vessels is primary or secondary. The diagnostically most useful application of immunofluorescence studies in vasculitides is in the evaluation of Henoch Schoenlein purpura.16

 FIGURE A2-2 Immunofluorescence of bullous pemphigoid. Note linear deposition of IgG in the basement membrane zone.

1027

APPENDEX 2 ■ LABORATORY METHODS

 FIGURE A2-3 Immunofluorescence of dermatitis herpetiformis. IgA is deposited in the dermal papillae in a delicate, speckled pattern.

In this clinical setting, the demonstration of IgA deposits by immunofluorescence is paramount for establishing the diagnosis (Fig. A2-4). LICHENOID DERMATITIS Positive immunofluorescence findings may also be seen in lichen planus or lichen planopilaris and some drug-induced dermatitides. Positive staining is often observed in socalled colloid bodies, which frequently represent immunoglobulin-encrusted keratinocytic material. Staining may be seen for IgM, IgG, IgA, C3, or fibrin. Drug-induced dermatitides may show a very broad spectrum of immunofluorescence patterns and lack specificity.17 IMMUNOHISTOLOGY OF INFECTIOUS DISEASES Direct antibodies have been developed for the detection of infectious agents. Most of them have been applied to formalin-fixed and paraffin-embedded tissue. The detection system usually relies on enzyme-conjugated antibodies (peroxidase or phosphatase) and not on immunofluorescence. One of the more frequently used antibodies in this context is antibodies to herpes simplex virus type I or II. A number of antibodies to other viral or bacterial organisms are available.

Applications in Neoplastic Skin Diseases

1028

CUTANEOUS LYMPHOID INFILTRATES Immunohistology plays an invaluable role in the characterization of lymphoid cells.18,19 A list of commonly used markers in the evaluation of lymphoid infiltrates is provided in Table A2-7. The application of these markers is guided

 FIGURE A2-4 Immunofluorescence of Henoch-Schoenlein purpura. Immunoreactants are deposited in the walls of microvessels.

by the differential diagnosis formulated based on the cytology and distribution of the infiltrate in routine H&E-stained sections. A thorough investigation of the cell phenotype requires the availability of fresh tissue for cryostat sections (Table A2-8). EPIDERMOTROPIC INFILTRATES These include cutaneous T-cell infiltrates, in particular, mycosis fungoides (MF), atypical T-cell reactions, such as lymphomatoid papulosis, lymphomatous drug reactions, lymphomatous lichenoid or spongiotic dermatitides, and actinic reticuloid. It has been said that the phenotype of the T-cell infiltrate in MF is different from other processes, such as

actinic reticuloid. MF, for example, typically has a predominant population of CD4-positive cells expressing other Tcell markers as well (CD2, CD3, CD5) and often some decrease in CD7.20,21 On the other hand, actinic reticuloid and some lymphomatoid dermatidities tend to retain pan T-cell markers and contain a larger proportion of CD8 cells.22 It is important not to put too much weight on these findings, however, because MF may have an uncharacteristic phenotype, and reactive lesions may mimic the immunophenotype of MF. CD30 is a useful antibody if lymphomatoid papulosis is suspected because the condition typically contains T-lymphocytes expressing this activation marker.23

Table A2-7 Lymphoid Markers

B-Cell Markers CD10 (CALLA): marks precursor B cells and granulocytes. Present in follicular center cell lymphomas (FCC), pre-all; absent in maltomas CD19: pan B-cell marker CD20 (L26): pan B-cell marker; best B-cell marker in paraffin sections CD22: pan B-cell marker CD45RA: pan B-cell marker Light chains: demonstration of monotypic plasma cells (cryostat or paraffin sections) T-Cell Markers CD1a (T6): Thymocytes and Langerhans’ cells CD2: pan T-cell marker CD3: pan T-cell marker CD4: T cells and macrophages, T-helper cells CD5: T cells and subsets of B cells CD7: precursor T, T subsets, and natural killer (NK) cells, one of the first markers lost in CTCL CD8: T subsets, NK cells, T suppressor cells CD43 (leu-22): T cells, macrophages, and granulocytes (e.g., chloromas) TdT: immature B and T cells UCHL-1: best pan T-cell marker in paraffin sections

Table A2-8 Lymphoma Panels

DEEP LYMPHOID INFILTRATES Bulky deep dermal lymphoid infiltrates generally suggest a B-cell phenotype. These infiltrates are readily identified as reactive if immunohistochemical studies demonstrate a mixture of B and T cells and the B cells lack light chain restriction. If frozen tissue is available, the demonstration of light chain restriction is perhaps the most useful test in diagnostic immunohistology of lymphoid infiltrates because it proves presence of a clonal neoplastic B cell population.24 Unfortunately, light chain immunostains are very difficult to perform technically, and many times they are difficult to interpret. Further light chains are not expressed in all B-cell lymphoproliferative disorders. If a deep T-cell infiltrate is present, CD30 may again be a useful marker if lymphomatoid papulosis or CD30-positive lymphoma is suspected.

Nonlymphoid Hematopoietic Infiltrates Immunohistochemical studies are also important in the evaluation of hematopoietic infiltrates other than lymphoid cells. These include Langerhans cell proliferations and leukemias.26,27 Langerhans cells are best recognized immunohistochemically by CD1a and a new marker langerin but also express S-100 protein, HLA-DR, and CD43. Most leukemic infiltrates of the skin are myeloid, which makes myeloperoxidase a very useful antibody in identifying a suspected leukemic population. Other less specific markers that are often positive in myelogenous leukemia are Leu-M1 (CD15) and KP-1 (CD68). EPITHELIOID NEOPLASMS Cytokeratins particularly cytokeratin 5/6 for cutaneous

Carcinoma Melanoma Lymphoma

CYTOKERATINS

S-100

HMB-45

LCA

+ − −

− + −

− + −

− − +

epidermoid carcinomas and epithelial membrane antigen (EMA) remain the most important markers of epithelial differentiation.28,29 Their application is usually needed for the evaluation of undifferentiated primary tumors or metastases. They need to be used in conjunction with the most likely mimics, such as melanoma or lymphoma (Table A2-9). Certain markers, such as thyroglobulin, GCDFG, calcitonin, and prostatespecific antigen, may be helpful in identifying possible primary sites.

Melanocytic Neoplasms A number of markers are available that aid in the identification of a lesion as melanocytic in origin (Table A2-10).29,30 This is most often needed in the evaluation of poorly differentiated (generally amelanotic) primary or metastatic tumors that suggest melanoma. Primary tumors that may mimic melanoma include spindle cell squamous cell carcinoma, atypical fibroxanthoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, and neuroendocrine carcinoma. Whenever a lesion is suspected to be melanocytic, it is important to apply a panel of antibodies, including antibodies positive for lesions that enter into the differential diagnosis. Three markers are used on a regular basis for the evaluation of melanocytic lesions: S-100 protein, Melan-A (Mart-1), and gp100 (HMB-45). Nonetheless, tyrosinase and MITF are used with increasing frequency, particularly in the

setting of a panel of antibodies. However, S-100 protein remains the gold standard and is the most sensitive marker for melanocytes; however, it is not specific. It is also expressed in Schwann cells, astrocytes, Langerhans cells, chondrocytes, and several other cell types. MelanA (Mart-1) and tyrosinase approach S 100 protein in sensitivity because they are expressed by virtually all melanocytic nevi and epithelioid melanomas. HMB-45 stains melanocytes in several nevi, notably blue nevi, Spitz nevi, and the intraepidermal components of atypical (dysplastic) nevi and some ordinary nevi, as well as many melanoma cells. It is not entirely specific for melanocytes. Positive staining for this maker has been observed in a variety of nonmelanocytic lesions, including angiomyolipoma, some breast cancers, and gliosarcomas. It should be noted that the vast majority of spindle cell and desmoplastic neurotropic melanomas are negative for most melanocytic markers, including Melan-A, HMB-45, MITF, and tyrosinase. Almost all of them, however express, S-100 protein and to a lesser degree p75 neurotrophin receptor.

APPENDEX 2 ■ LABORATORY METHODS

Fixed tissue: suspected T-cell lymphoma CD3: to confirm T-cell phenotype CD30 (Ki-1): in LYP or large cell lymphoma CD20, CD79a: to evaluate for presence of B cells Suspected B-cell lymphoma CD2, CD20, CD19, CD22, CD79a: to confirm B-cell phenotype CD2,CD3,CD4,CD5,CD7,CD43,CD1a,CD30: to evaluate for presence of T cells Light chains: demonstration of monotypic cells: kappa, lambda Frozen tissue: suspected B-cell lymphoma Light chains: lambda, kappa

Table A2-9 Poorly Differentiated Tumors

Soft Tissue Neoplasms Immunohistology is essential in the evaluation of poorly differentiated soft tissue neoplasms. The main role is to confirm suspected histogenesis or differentiation. A list of markers relevant in the workup of sarcomas is provided in Table A2-11.

Table A2-10 Commonly Used Melanocyte Differentiation Markers for Paraffin-Embedded Tissue ANTIBODY

ANTIGEN

SENSITIVITY

SPECIFICITY

Anti-S100P T311 A103/ M2-7C10 HMB-45 D5/C5

S100 protein Tyrosinase Melan-A/ Mart-1 gp100 MITF

>95% 70%-90% 70%-85%

Low High High

60%-80% 60%-80%

High Intermediate

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APPENDEX 2 ■ LABORATORY METHODS

Table A2-11 Soft Tissue Tumors S-100

AE1/AE3

HHF-35

SM-ACT

DESMIN

CD34

OTHER

+ ± −

− − − ⫿

− − − ⫿

− − − ⫿

− − − ±

− − − −

− − EMA + −

− − −

− − −

± ± ±

+ − +

+ + −

− − −

− − − −

− − − −

⫿ ⫿ − ⫿

⫿ ⫿ − ⫿

− − − −

+ ⫿

Neural origin: Schwannoma Neurofibroma Perineurioma MPNST Muscle origin: Smooth muscle Skeletal muscle Glomus tumor Fibrous tumors: DFSP FH Fibroma SFT

Small Cell Neoplasms Many different neoplasms can assume a small cell phenotype. These include metastatic small cell carcinoma, cutaneous neuroendocrine (Merkel cell) carcinomas, small cell sweat gland carcinoma, sarcomas (eg, Ewing sarcoma or primary neuroendocrine tumor), neuroblastoma or alveolar rhabdomyosarcoma, small cell lymphomas, and small cell melanomas. Immunophenotypic studies are paramount in the differential diagnosis of small cell neoplasms (Table A2-12).

CYTOGENETICS The main application of solid tumor cytogenetics in dermatopathology is in the evaluation of sarcomas because a surprising number of sarcomas have

characteristic karyotypic abnormalities and gene rearrangements.31 A list of diagnostically useful cytogenetic alterations in cutaneous sarcomas is provided in Table A2-13. If fresh tissue is available, conventional karyotypes may be obtained. The development of fluorescence in situ hybridization (FISH) also allows cytogenetic analysis on archival material.

Comparative Genomic Hybridization and Fluorescence in Situ Hybridization Over the past decade, comparative genomic hybridization (CGH) has contributed significantly to a better understanding of the developmental biology of melanocytic neoplasms, particularly melanoma. 31 Although CGH largely

+

remains in the research sphere, this technique has also been successfully applied to the diagnostic evaluation of many ambiguous or controversial melanocytic neoplasms because such lesions showing the chromosomal aberrations usually associated with melanoma provide support for a lesion likely to be melanoma. CGH evaluation of primary melanomas has demonstrated losses at 6q, 8p, 9p, and 10q and gains at 1q, 6p, chromosome 7, 8q, 17q, and 20q to be the most frequent DNA copy number changes in melanoma. Significant differences in regions of gain and loss were found among the major “histogenetic” variants. For example, acral melanomas had significantly more aberrations of chromosomes 5p, 11q, and 12q than socalled superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma. Furthermore,

Table A2-12 Small Cell Neoplasms

Small cell CA Merkel cell CA Small cell sweat gland CA Ewing/PNET Alveolar rhabdomyosarcoma Neuroblastoma Lymphoma Melanoma

1030

LCA

PAS

013

DES

CK

CK20

NSE

NF

S-100

− − −

− − −

− − −

− − −

+ + +

− + −

⫿ ⫿ ?

− − ?

− − +

− − − + −

+ ⫿ − − −

+ − − − −

− + − − −

⫿ − − − −

− − − − −

⫿ ⫿ + − ⫿

⫿ − + − −

− − − − +

LCA = leukocyte common antigen; PAS = periodic acid-Schiff stain; 013 = CD99; Des = desmin; CK = cytokeratin; CK20 = cytokeratin 20; NSE = neuronspecific enolase; NF = neurofilament; S-100 = S-100 protein.

Table A2-13 Cytogenetics of Cutaneous Neoplasms KARYOTYPIC ABNORMALITY

GENES

Melanoma

Heterogeneous abnormality, various deletions (eg, 1, 6, 9) Ring chromosome (17,22), trisomy 5 t(2;13)(p36;q14) t(1;13)(p36;q14) +2q, +8, +20, del 1

?

t(11;22)(q24;q12) t(11;22)( q13;q12) del (1p) +1 Rearrangements of 12q14−15, 6p, 13q Rearrangements of 16q, 13q +7, +5

FLI-1-EWS ATF-1-EWS ? ? HMGC-1 ? ?

DFSP Alveolar Rhabdomyosarcoma Embryonal rhabdomyosarcoma ES/PNET Clear cell sarcoma Neuroblastoma MPNST Lipoma (ordinary) Spindle cell lipoma Giant cell tumor of tendon sheath

LMM showed marked loss of chromosomes 17p and 13q. On the other hand, the general absence of chromosomal gains or losses considered characteristic of melanoma argues against melanoma but does not altogether exclude that entity. The FISH applications for melanocytic neoplasms are generally derivative from CGH results and involve a combination of particular probes likely to correlate with progression to melanoma: RREB1 (6p25), MYB (6q23), CCND1 (11q13), and CEP6 (6p11.1–q11.1) probes. For the time being, FISH techniques also remain investigational and should not be considered the “standard of care.” At present and for some time to come, the gold standard for difficult melanocytic lesions will continue to be histopathologic diagnosis and clinical correlation.

ELECTRON MICROSCOPY The main applications of electron microscopy to diagnostic dermatopathology is in the field of congenital bullous disorders, certain storage diseases, and tumor pathology. Ultrastructural studies are the gold standard for the localization of the cleavage site in the disease group of epidermolysis bullosa congenita. Electron microscopy is very helpful in identifying intracellularly stored or deposited material, such as intra-lysosomal electron dense lamellar bodies in Fabre disease and characteristic fibrils in amyloid. In the differential diagnosis of neoplastic disorders, ultrastructural studies play a role in the identification of Bierbeck granules in Langerhans cell proliferations. They may also reveal useful information

? PAX3-FKHR PAX7-FKHR ?

in a number of other neoplasms, such as melanosomes in melanoma, desmosomes and tonofilaments in epithelial tumors, myofibrils in myogenic tumors, electrondense core granules in neuroendocrine neoplasms, perinuclear bundles of intermediate filaments in epithelioid sarcoma, Weibel-Palade bodies in angiosarcoma, and rhomboid crystals in alveolar soft part sarcoma.

POLARISCOPIC EXAMINATION Polariscopic examination is useful in evaluating certain foreign material such as suture material, wood splinters, beryllium, sirconium, and silica. It is also helpful in highlighting some endogenous deposits, such as uric acid crystals in gout and oxalate crystals. It should routinely be used in the evaluation of granulomatous tissue reactions. It is also an ancillary technique in the Congo red stain to evaluate for amyloid.

REFERENCES 1. Bancroft JD, Cook HC: Manual of Histological Techniques and Their Diagnostic Application. Edinburgh: Churchill Livingston; 1994. 2. Johnson WC: Histochemistry of the skin, in Spicer S (ed). Histochemistry in Pathologic Diagnosis. New York: Marcel Dekker; 1984:665-694. 3. Rosai J: Special techniques in surgical pathology, in Rosai J (ed). Ackerman’s Surgical Pathology, 8th ed. St. Louis: Mosby; 1996:29-62. 4. Rodriguez HA, McGavran MH: A modified dopa reaction for the diagnosis and investiagtion of pigment cells. Am J Pathol. 1969;52:219-227.

APPENDEX 2 ■ LABORATORY METHODS

TUMOR

5. Beutner EH, Chorzelski TP, Kumar V: Imuunopathology of the Skin, 3rd ed. New York: John Wiley & Sons; 1987. 6. Ceballos P, Jimenez-Acosta F, Penneys NS : Immunohistochemical techniques in non-neoplastic conditions. Semin Dermatol. 1989;8:276-282. 7. Gammon WR, Fine JD, Forbers M, Briggaman RA: Immunofluorescence on split skin for the detection and differentiation of basement membrane zone autoantibodies. J Am Acad Dermatol. 1992; 27:79-87. 8. Beutner EH, Jordan RE, Chorzelski TP: The immunopathology of pemphigus and pemphigoid. J Invest Dermatol 1968; 51:63-80. 9. Farmer ER: Subepidermal bullous diseases. J Cutan Pathol. 1985;12:316-321. 10. Helm KF, Peters MS: Immunodermatology update: the immunogogically-mediated vesiculobullous diseases. Mayo Clin Proc. 1991;66:187-202. 11. Gately LE III, Nesbitt LT Jr: Update on immunofluorescent testing in bullous diseases and lupus erythematosus. Dermatol Clin. 1994;12:133-142. 12. Mutasim DF, Pelc NJ, Supapannachart N: Established methods in the investigation of bullous disease. Dermatol Clin. 1993;11: 399-418. 13. Pardo RJ, Pennesy NS: Location of basement membrane type IV collagen beneath subepidermal bullous diseases. J Cutan Pathol. 1990;17:336-341. 14. Braverman IM, Yen A: Demonstration of immune complexes in spontaneous and histamine-induced lesions and in normal skin of patients with leukocytoclastic vasculitis. J Invest Dermatol. 1975;64: 105-112. 15. Faile-Kuyper Eh dela, Kater L, Koviker CJ, et al: IgA-deposits in cutaneous blood vessel walls and mesangium in HenochSchoenlein syndrome. Lancet. 1973; 1:892. 16. Knowles DM: Immunophenotypic markers useful in the diagnosis and classivation of hematopoietic neoplasms, in Knowles DM (ed). Neoplastic Hematopathology, 2nd ed. Baltimore: Williams & Wilkins; 2001:93-226. 17. Burke J: Malignant lymphomas of the skin: their differentiation from lymphoid and non-lymphoid cutaneous infiltrates that simulate lymphoma. Semin Diagn Pathol. 1985;2:169-182. 18. Perksin SL, Kjeldsberg CR: Immuno-phenotyping of lymphomas and leukemias in paraffin-embedded tissues. Am J Clin Pathol. 1993;99:362-373. 19. Kaplan EH, Leslie WT: Cutaneous T-cell lymphomas. Curr Opin Oncol. 1993;5:812818. 20. Filippa DA, Ladanyi M, Wollner N, et al: CD30 (Ki-1) positive malignant lymphomas: clinical, immunophenotypic, histologic, and genetic characteristics and differences with Hodgkin’s disease. Blood. 1996;87:2905-2917. 21. Emile JF, Wechsler J, Brousse N, et al: Langerhans’ cell histiocytosis. Definitive diagnosis with the use of monoclonaal antibody 010 on routinely paraffinembedded samples. Am J Surg Pathol. 1995; 19:636-641. 22. Ratnam KV, Khor CJL, Su WPD: Leukemia cutis. Dermatol Clin. 1994;12: 419-431. 23. Battifora H: Diagnostic uses of antibodies to keratins. Prog Surg Pathol. 1988; 8:1-15.

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24. Thomas P, Battifora H: Keratins vs. epithelial membrane antigen in tumor diagnosis. An immunohistochemical comparison of five monoclonal antibodies. Hum Pathol. 1987;18:728-734. 25. Wick MR, Swanson PE, Ritter JH, et al: The immunohistology of cutaneous neoplasia: a practical perspective. J Cutan Pathol. 1993;20:481-497. 26. Busam KJ, Barnhill RL: Biopsies, tissue processing and special studies, in Barnhill RL, Piepkorn M, Busam KJ (eds). Pathology of

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Melanocytic Nevi and Malignant Melanoma, 2nd ed. New York: Springer Verlag;, 2004. 27. Prieto VG, Shea CR: The use of immunohistochemistry in the evaluation of melanocytic lesions. J Cutan Pathol. 2008; 35(suppl 2):1-10. 28. Miettinen M, Fernandez M, Franssila K, et al: Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma. Comparison with four other melanoma markers. Am J Surg Pathol. 2001;25:205-211.

29. Miettinen M: Immunohistochemistry of soft tissue tumors. Possibilities and limitations in surgical pathology. Ann Pathol. 1990;5:1-36. 30. Ladanyi M: The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol. 1995;4:162-173. 31. Bastian BC, Olshen AB, LeBoit PE, Pinkel D: Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol. 2003;163(5):1765-1770.

APPENDIX 3 Molecular Biologic Techniques for the Diagnosis of Cutaneous Lymphomas Gary S. Wood

ANTIGEN RECEPTOR GENES Immunoglobulin (Ig) molecules are the antigen-specific receptor of B cells.1,2 Each Ig molecule is a protein heterodimer consisting of two heavy chains and two light chains linked by disulfide bridges. Each B cell and its clonal progeny express Ig molecules containing only one of two possible types of Ig light chains (κ or λ). This is known as Ig light chain restriction. Tcell receptors (TCRs) are glycoproteins composed of two possible combinations of heterodimers usually linked by disulfide bridges in association with the CD3 complex.1,2 Four different protein chains of the human TCR are involved in antigen binding: α, β, γ, and δ. The TCR is expressed on the cell surface of lymphocytes as an αβ or γδ heterodimer and is responsible for antigen recognition. Each Ig and TCR protein chain consists of three to four distinct regions encoded by gene segments called variable (V), diversity (D), joining (J), and constant (C). Whereas V, J, and C segments are found in each gene, D segments are only present in the TCR β and δ genes. The V, D, and J genes are involved in forming the variable region of the Ig and TCR proteins. This region includes the antigen-recognition site. The C region is responsible for other functions such as signal transduction, oligomerization, secretion, passage across physiologic barriers, and interaction with other immune molecules such as complement and Fc receptors.

chain genes are rearranged. Because κ rearrangements are successful more often than not, there is usually a 2:1 ratio of B cells expressing κ versus λ light chains. As with T cells, if a B cell fails to rearrange its Ig genes successfully, then it is deleted via apoptosis. As B cells mature, they progress through a series of phenotypic and genetic alterations involving Ig genes.2 When a naive B cell migrates to the lymph node from the marrow, it is IgM+ IgD+ and has functional IgH gene rearrangements; however, the VH region within the rearranged Ig gene retains its germline sequence and has not yet undergone any of the VH somatic point mutations involved in the antigen selection phase of B-cell differentiation that results in a better fit between antibody and antigen. After the naive B cell is exposed to its corresponding antigen, it enters the germinal center, where it loses IgD expression and undergoes successive rounds of VH somatic point mutation and proliferation. After this process is completed, the B cell enters the post–germinal center memory B-cell phase in which it has stable VH point mutations and is either IgM+ or has switched to another Ig heavy chain isotype. These phenotypic and genetic alterations will allow us to determine the differentiation (or point of maturational arrest) exhibited by B-cell lymphoma tumor clones. In addition, the distribution of point mutations within antigen-relevant (eg, complementarily determining) versus antigen-irrelevant (eg, framework) regions of the VH gene allows us to determine the degree to which these B-cell clones have been antigen selected.

SOUTHERN BLOT ANALYSIS In this and the following sections, the most common molecular biologic assays for assessing B- and T-cell clonality are described. Key features of these assays are summarized in Table A3-1. Southern blot analysis is an assay that detects rearrangement of Ig and TCR genes from their germline configuration.2,3 As generally performed, however, it offers no information about clone-specific nucleotide sequence or the particular V, D, J, and C segments involved in the rearrangement. The sensitivity limit of this method is about 5% (ie, the percentage of clonal DNA in the DNA sample has to be at least 5%). In nonlymphatic tissues such as skin, in which a considerable amount of DNA is

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

This section focuses on the principal molecular biologic methods that have been developed to study cutaneous lymphoid infiltrates. It is presented as a review divided into six parts: antigen receptor genes, Southern blot analysis, gene amplification techniques, major findings, clinical applications, and conclusions.

During maturation of T cells and B cells from hematopoietic progenitor cells into functionally active lymphocytes, antigen receptor genes are assembled from one segment each of the V, D, J, and C gene sets through a series of DNA recombination events collectively referred to as gene rearrangement, followed by postranscriptional splicing and translation. The VDJ joining is mediated by specific enzymes collectively referred to as recombinases and is orchestrated by recombinase activation gene-1 (RAG-1) and RAG-2. These two genes are coexpressed at substantial levels only in primary lymphoid tissue and in cell lines that resemble precursor lymphocytes. The result is the creation of one intact continuous V, (D) J coding sequence at an antigen receptor gene locus. This is subsequently joined to a C-region coding segment by posttranscriptional splicing of mRNA. The diversity of Igs and TCRs is due to the many possible combinations among the different gene segments. In addition, the rearrangement itself creates diversity by small deletions or insertions of nucleotides at the V–D, D–J, and V–J junctions. The random nucleotide insertions are known as N regions. Consequently, the amino acid sequences at the junctions of V, D, and J segments demonstrate extreme hypervariability. During thymic development, T-lymphocytes are generated by several molecular events and by positive and negative selection. The present model of thymic T-cell development suggests that hematopoietic stem cells enter the thymus though the cortex with their TCR genes in the germline (unrearranged) configuration. In addition to the acquisition of T-cell differentiation antigens on their surface, many T-lymphocytes undergo rearrangement of the TCR β and δ chain genes. Some of these T cells then express the TCR γδ protein heterodimer throughout their lives. Others undergo subsequent rearrangement of their TCR α and β genes and replace their TCR γδ heterodimer with a TCR αβ heterodimer. TCR δ gene rearrangements are frequently deleted during TCR α gene rearrangement because the δ gene is embedded within the α gene. Although its expression is suppressed, the rearranged TCR γ chain remains intact within the genome. During their development, B cells also undergo a hierarchy of antigen receptor gene rearrangements. The heavy chain (IgH) genes are rearranged first. If a productive rearrangement occurs, then the κ light chain genes are rearranged. If these genes are abortive, then the λ light

1033

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

Table A3-1 Molecular Biologic Techniques for the Detection of Cutaneous T-Cell Lymphoma

1034

METHOD

SENSITIVITY

TIME

COMMENTS

Southern blot analysis

10−2

1-2 weeks

Non–tumor-specific PCR clonality assays

10−3 -10−4

A few days

Tumor-specific PCR clonality assays

10−5 -10−6

Initially, one to several weeks to obtain tumor-specific oligonucleotides; thereafter, a few days to analyze new specimens

Not optimal for small specimens or sparse CTCL infiltrates Reasonable compromise among sensitivity, specificity, simplicity, and rapidity of assays Requires diagnostic index specimen from which tumor-specific primers or probes are made; best suited for detailed case studies

contributed by various cell types, this limitation can be particularly problematic. Figure A3-1 summarizes the most important steps involved in this procedure, and Figure A3-2 illustrates representative results. Key factors in Southern blot analysis include restriction enzymes, hybridization probes, and the stringency of hybridization and wash conditions. Restriction enzymes are bacteria-derived endonucleases that cleave double-stranded DNA at or near a specific nucleotide sequence recognized by that enzyme.

At present, more than 100 different restriction enzymes are available. The incubation of genomic DNA with one of these enzymes results in DNA restriction fragments of many lengths. These fragments are

TISSUE

DNA EXTRACTION

DIGESTION

ELECTROPHORESIS (AGAROSE GEL)

TRANSFER TO NYLON MEMBRANE

HYBRIDIZATION WITH LABELED PROBE

AUTORADIOGRAPHY

 FIGURE A3-1 Southern blot analysis. The major steps involved in Southern blot analysis of T-cell receptor and Ig gene rearrangements in genomic DNA extracted from lesional tissues are summarized.

 FIGURE A3-2 Detection of clonal T-cell receptor β gene rearrangements by Southern blot analysis. Shown is an autoradiogram of genomic DNA digested with BglII restriction endonuclease and probed with a radiolabeled Jβ1/Jβ2 DNA probe. Germline bands are marked with dashes, and clonally rearranged bands are marked with an arrow. BL = blank lane; NC = negative control; MF = mycosis fungoides; LCL = CD30+ large cell lymphoma from the same patient showing an identical clonal band. This was confirmed by nucleotide sequencing.

separated according to their lengths using agarose gel electrophoresis. Separated DNA fragments are transferred by vacuum or capillary action onto a nylon membrane. The membrane is incubated with a DNA fragment (probe) that is known to hybridize with (be complementary to) the sequence of interest. Radiolabeled IgH and TCR β probes are the ones used most commonly to investigate the clonality of Ig and TCR gene rearrangements in lymphoproliferative disorders. Autoradiography is used to detect the band(s) where the radiolabeled probe has hybridized and to compare these bands with known germline and positive control bands. The number of bands varies depending on the restriction enzyme used. The positions of these bands reflect the difference in size of the rearranged DNA fragment(s) compared with the fragment(s) characteristically produced from DNA in the unrearranged or germline configuration of the relevant gene. There is no combination of a single restriction enzyme with a single probe that detects all corresponding gene rearrangements. Thus, more than one restriction enzyme digest is usually studied by Southern blot analysis (Table A3-2).

POLYMERASE CHAIN REACTION–BASED ASSAYS Polymerase chain reaction (PCR) is a procedure in which small regions of DNA can be amplified geometrically in vitro by means of a thermostable DNA polymerase purified from the bacterium Thermophilus aquaticus (so-called Taq polymerase).1-4 Short fragments of singlestranded DNA known as oligonucleotide primers are used in repeated cycles of heating and cooling. This allows denaturation of the double-stranded

Table A3-2 Cutaneous Lymphoproliferative Disorders: T-Cell and B-Cell Clonality as Determined by Southern Blot Analysis DISORDER

DOMINANT CLONALITY a

Mycosis fungoides/Sézary syndrome Other cutaneous lymphomas Regressing atypical histocytosis Granulomatous slack skin Lymphomatoid papulosis Pityriasis lichenoides and varioliformis acuta Angioimmunoblastic lymphadenopathy Malignant histiocytosis Cutaneous B-cell lymphomas Cutaneous lymphoid hyperplasia

T cellb T cell T cell T cell T cell > none T cell T cell > none T cell > B cell B cell None > B cell > T cell

Usually dominant clonality is monoclonal, but in some cases may be biclonal or oligoclonal. b Some early patch and thin-plaque lesions lack dominant clonality, by Southern blot analysis due to the limited sensitivity of this assay.

template DNA into single-stranded DNA, annealing of the primers to complementary sequences on the single-stranded template DNA, and synthesis of new copies of the template DNA by primer extension.

TCR-Based PCR Clonality Assays As a result of genetic events occurring during their thymic development, many T-lymphocytes expressing the αβ heterodimer also contain clonal TCR γ rearrangements.4,5 Therefore, molecular approaches for the analysis of clonality may focus on either TCR β or TCR γ rearrangements. In the TCR β gene, only the V and C genes contain consensus sequences that are highly conserved and thus the most suitable as templates for PCR consensus primers capable of detecting the vast majority of TCR β gene rearrangements. Because these V and C regions are separated by large introns within the rearranged gene, genomic DNA cannot be used for PCR amplification of the TCR β rearrangement. Instead, the target sequence must be transcribed from TCR β mRNA into TCR β cDNA. These extra steps are a relative disadvantage of methods involving TCR β amplification because handling RNA is much more complicated than handling DNA owing to its fast degradation by ubiquitous RNase. Attempts to circumvent this problem by using Vβ and Jβ consensus primers have been less than fully successful because of the sequence diversity of these regions. In contrast, conserved regions

in the Vγ and Jγ gene segments are close together (400-700 base pairs) in the rearranged TCR γ gene. This allows the use of genomic DNA for PCR amplification of TCR γ gene rearrangements. Furthermore, the relatively high degree of homology among various Vγ segments and among Jγ segments means that only a small number of different consensus primers are required to amplify most TCR γ gene rearrangements. Therefore, several PCR-based T-cell clonality assays focus on the rearranged TCR γ gene. After amplification using Vγ and Jγ primers, the TCR 1γ PCR products must be screened for dominant clonal TCR gene rearrangements. Several methods have been used to accomplish this.2-4 Fig. A3-3 shows the key steps of TCR γ PCR in combination with denaturing gradient gel electrophoresis (DGGE). Representative results are illustrated in Fig. A3-4. DGGE involves the electrophoresis of PCR products in a polyacrylamide gel that contains an increasing gradient of chemical denaturants, specifically formamide and urea. This type of electrophoresis separates the PCR products according to their nucleotide sequence as well as their size. The gradient in the gel causes local denaturation of domains within doublestranded DNA fragments, and the resulting formation of melted single-stranded DNA domains at various points along the gradient in the gel. This alteration reduces the mobility of the DNA fragment in the gel, causing all fragments of identical sequence to accumulate at the

DNA EXTRACTION

PCR AMPLIFICATION

DENATURING GRADIENT GEL ELECTROPHORESIS

ETHIDIUM BROMIDE STAINING

 FIGURE A3-3 Polymerase chain reaction/denaturing gradient gel electrophoresis. The major steps involved in the amplification and separation of T-cell receptor γ gene rearrangements in genomic DNA extracted from lesional tissues are summarized.

same position in the gel. Whereas polyclonal PCR products appear as a diffuse smear, bands are seen in the case of a dominant clone, constituting at least 0.1% to 1.0% of the total specimen DNA. The sensitivity threshold depends on the background content of polyclonal T cells in the specimen. Temperature gradient gel electrophoresis (TGGE) is similar in principle to DGGE except that a gradient of temperature rather than chemical denaturants provides the conditions for the sequence-dependent melting of PCR products. There are many additional methods for separating and analyzing TCR γ PCR products, including single-stranded DNA conformational polymorphism analysis (SSCP) and capillary gel electrophoresis. In addition to these TCR γ gene–based methods, non–tumor-specific PCR assays have been developed for the detection of clonal TCR β rearrangements. One of these methods involves reverse transcription of TCR β mRNA into cDNA followed by multiple separate PCRs, each specific for TCR β gene rearrangements involving one or two of the 24 known Vβ families. PCR products are then electrophoresed in a special agarose gel. The presence of a sharp band indicates a dominant clonal TCR β gene rearrangement. The sensitivity of this method ranges from 0.01% to 10% of the total cDNA depending on whether the clone is diluted by nonlymphoid or polyclonal T-cell cDNA, respectively.

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

a

TISSUE

1035

requires neither analysis of nucleotide sequences nor synthesis of tumor-clonespecific DNA primers or probes. It involves analysis of TCR γ gene rearrangements and has a sensitivity of 0.001% or 1 in 105 cells. 6,7

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

PCR Assays Other Than Clonality

1036

In addition to their use for detecting dominant clonality, genomic Southern blot and PCR assays can be used to study other tumor cell characteristics such as whether they contain the t(14;18) translocation (common among follicular B-cell lymphomas), the t(2;5) translocation (common among lymph node-based CD30+ anaplastic large cell lymphomas), or HTLV-1 retrovirus (a defining feature of adult T-cell leukemia/lymphoma).3

MOLECULAR BIOLOGIC FINDINGS

 FIGURE A3-4 Polymerase chain reaction (PCR)/denaturing gradient gel electrophoresis (DGGE). Detection of clonal Tcell receptor (TCR) γ gene rearrangements by PCR combined with DGGE. Shown is a photograph of an ethidium bromide–stained gel after DGGE of TCR γ PCR products that were amplified using consensus primers for Vγ 1-8 and Jγ 1-2. CO = carryover negative control; PC = positive control; LCL = CD30+ large cell lymphoma; LYP = lymphomatoid papulosis from the same patient showing a matching clonal band (upper arrow) indicating an identical nucleotide sequence. The lower arrow shows the position of the clonal band in the PC lane.

Ig-Based PCR Clonality Assays

Tumor-Specific PCR Clonality Assays

PCR assays involving IgH gene rearrangements have been used to assess the clonality of B-cell lymphoproliferative disorders.5 Strategies range from a single VH/JH consensus primer set to nested consensus primers to a single consensus JH primer combined with a set of VH consensus primers, each specific for a different VH family or subfamily (VH 1, 2, 3, 4a, 4b, 5, and 6). PCR products are then electrophoresed through gels designed to produce a discrete band when a dominant clonal IgH rearrangement is present and diffuse smears when it is not. As with TCR-based PCR assays, these Ig-based PCR methods are more sensitive than genomic Southern blot analysis of Ig gene rearrangements.

These techniques depend on the strategy of isolating and sequencing the monoclonal antigen receptor gene rearrangement from a diagnostic specimen and then using this tumor-specific dominant sequence to generate tumor-specific probes or PCR primers.3 These tools can be applied to detect tumor involvement in additional nondiagnostic tissue samples from the same patient; however, they are not useful for studying other patients because they are specific for only one unique tumor clone. These tumor-specific assays use several different technical approaches that target various antigen receptor genes. The PCR-RNase protection assay (PCR-RPA) has the advantage that although it is clone specific, it

Molecular biologic studies combined with immunophenotypic analyses have significantly advanced our understanding of cutaneous lymphoproliferative disorders in recent years. Cutaneous T-cell lymphoma (CTCL) has been shown to be a neoplasm of mature CD4+ memory T cells belonging to the skin-associated lymphoid tissue (SALT), which includes lymphocytes and antigenpresenting cells that traffic between the skin and peripheral lymph nodes.3,4,6,7 Using PCR-based methods, the monoclonality of many cases of early CTCL as well as advanced CTCL has been established. In fact, PCR techniques have allowed the recognition that some cases of chronic nonspecific dermatitis harbor occult dominant T-cell clones. These cases are referred to as clonal dermatitis.4 Some of these patients have progressed to overt CTCL, indicating that at least some cases of clonal dermatitis represent a precursor to CTCL. Molecular staging studies have shown that small numbers of CTCL cells can be found throughout the body in samples of morphologically normal lymph node, marrow, and blood even in early-stage IA disease.7 This suggests that tumor cells can traffic throughout the SALT system at low levels and that CTCL is a neoplasm of a T-cell circuit rather than a particular tissue. Studies of diseases associated with CTCL, such as large cell lymphoma, lymphomatoid papulosis, and Hodgkin disease, have shown that these diseases share a common clonal origin when they arise in the same patient.8 Taken together, these findings allow us

CLINICAL APPLICATIONS

Diagnosis The detection of dominant clonal lymphoid populations has been used to confirm a suspected diagnosis of lymphoma in patients whose clinicopathologic features were suggestive but not diagnostic. The rationale for this approach is based on two observations. First, well-developed lymphoma lesions are clearly monoclonal tumors. Second, with noted exceptions, such as some lymphomatoid drug reactions and collagen vascular diseases,13,14 dominant lymphoid clones are not found in unequivocally inflammatory infiltrates or in normal tissues.2-4,12 For example, the molecular biologic demonstration of dominant T-cell clonality has been used to establish or confirm a diagnosis of CTCL in patients with patch-type MF, large-plaque parapsoriasis, idiopathic erythroderma, and follicular mucinosis. In some instances, Southern blot analysis has been sufficient, but in other cases, PCR-based techniques have been required to detect the dominant T-cell clone. This has been especially true for very small specimens or for those in which the neoplastic

T-cell clone was diluted excessively by normal cell constituents, reactive T cells, or a combination of both cell types. The diagnostic sensitivity of PCR analysis has been enhanced even further by applying it to tissue samples enriched for tumor cells by laser-capture microscopy or other forms of microdissection.16,17 Although it is generally true that TCR gene rearrangements are indicative of T-cell lymphomas and Ig gene rearrangements are indicative of B-cell lymphomas, some lymphomas may exhibit both. 1-3,12 Therefore, it is helpful to supplement gene rearrangement studies with immunophenotypic data to achieve the clearest possible interpretation of lineage and clonality during immunodiagnostic workup of an unknown case. In addition, it is important to emphasize that the demonstration of a monoclonal lymphoid population per se cannot be equated with the diagnosis of lymphoma. Clinicopathologic correlation is essential. Several clinically benign lymphoproliferative disorders are known to contain dominant T- or B-cell clones in a variable proportion of cases. These include lymphomatoid papulosis, pityriasis lichenoides, atypical pigmentary purpura, indeterminate lymphocytic lobular panniculitis, parapsoriasis en plaques, and cutaneous lymphoid hyperplasia.2,12-14

Staging Because molecular biologic analysis of Ig and TCR gene rearrangements is significantly more sensitive than light microscopy for the detection of tumor cells, molecular biologic methods have increased the sensitivity of lymphoma staging. For example, among lymph nodes not diagnostic for CTCL by light microscopy, some were positive for CTCL by Southern blot analysis. 4,18 Southern blot analysis also has proven superior to light microscopy in detecting involvement of the peripheral blood in CTCL. 4,18 PCR-based techniques have further enhanced this sensitivity and have detected sites of involvement missed by Southern blot analysis. PCR techniques have detected CTCL involvement in microscopically uninvolved extracutaneous tissues and even in clinically normal-appearing skin containing only very sparse nonspecific lymphoid infiltrates histopathologically.7,15,19 The impressive sensitivity of molecular biologic analysis for detecting dominant Ig and TCR gene rearrangements (~10−2 for Southern blot analysis and 10−3-10−6 for various PCR techniques) raises important questions regarding

clinical relevance. For example, although we know that histopathologically detectable lymph node involvement is a poor prognostic sign in CTCL, the clinical relevance of histopathologically occult involvement detected solely by molecular biologic means remains to be determined fully.15,18 A key factor concerning assessment of blood involvement in CTCL is the recognition of apparently benign circulating T-cell clones in some elderly people.20 This phenomenon makes it essential to determine whether a circulating T-cell clone in the blood of a CTCL patient matches the one present in lesional skin before drawing any conclusions about blood involvement.18

Disease Monitoring In addition to their use in the initial diagnosis and staging of cutaneous lymphoma patients, molecular biologic techniques also have been used to monitor the response of the disease to treatment. For example, it has been shown that the skin can serve as a reservoir of clinically occult residual disease in CTCL.15

CONCLUSIONS It is apparent that in addition to their value for the early diagnosis and staging of cutaneous lymphomas, molecular biologic assays are proving valuable for monitoring the response to therapy, detecting early relapse, and enhancing our understanding of the compartmentalization and trafficking of tumor cells. To reap the full clinical benefit from this new information, however, it will be important to perform prospective longterm studies designed to determine the clinical significance of molecular biologic data. In addition, the complexity of cutaneous lymphoproliferative disorders dictates that molecular biologic clonality data should never be interpreted in a vacuum. In skin disease, dominant clonality does not always imply clinical malignancy. The proper diagnosis of CTCL and other cutaneous lymphoproliferative diseases requires the thoughtful integration of molecular biologic data with clinicopathologic and immunophenotypic findings.

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

to conceptualize CTCL and associated diseases as an array of lymphoproliferative disorders sharing a common clonal ancestry beginning with a single mature SALT T cell that undergoes one or more genetic alterations during the clonal dermatitis phase and its later progression to early CTCL, followed by additional somatic mutations responsible for creating subclones of the original tumor that manifest themselves clinically as advanced-stage CTCL and other CTCLassociated diseases. The early stages of this process (clonal dermatitis and early CTCL) may involve additional clones from which the dominant one emerges. Similarly, CBCL has been shown to be a monoclonal B-cell neoplasm of the skin that in some cases is preceded by cutaneous lymphoid hyperplasia (CLH), a clinicopathologically benign lymphoid infiltrate usually containing immunophenotypically polyclonal B cells.9-12 Molecular biologic studies have shown that up to one-third of CLH cases harbor occult dominant B-cell clones and that some may progress to overt CBCL containing the same dominant clone.12 In aggregate, these studies suggest that CLH, clonal CLH, and CBCL exist as clinicopathologically defined points along a continuum of cutaneous B-cell lymphoproliferative disease.

REFERENCES 1. Tamaru J, Hummel M, Marafioti T, et al: Burkitt’s lymphomas express VH genes with a moderate number of antigen-selected somatic mutations. Am J Pathol. 1995;147:1398-1407.

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2. Wood GS: The benign and malignant cutaneous lymphoproliferative disorders including mycosis fungoides, in Knowles DM (ed). Neoplastic Hematopathology, 2d ed. Baltimore: Williams & Wilkins; 2001: 1183-1233. 3. Wood GS: Cutaneous lymphoproliferative disorders: strategies for molecular biological analysis and their major findings. Springer Semin Immunopathol. 1992; 13:387-399. 4. Wood GS, Tung RM, Haeffner AC, et al: Detection of clonal T-cell receptor _gene rearrangements in early mycosis fungoides/Sézary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol. 1994;103:34-41. 5. Ramasamy I, Brisco M, Morley A: Improved PCR method for detecting monoclonal immunoglobulin heavy chain rearrangement in B cell neoplasms. J Clin Pathol. 1992;45:770-775. 6. Veelken H, Sklar JL, Wood GS: Detection of low-level tumor cell trafficking to allergic contact dermatitis induced by mechlorethamine in patients with mycosis fungoides. J Invest Dermatol. 1996;106: _685-688. 7. Veelken H, Wood GS, Sklar J: Molecular staging of cutaneous T cell lymphoma: evidence for systemic involvement in early disease. J Invest Dermatol. 1995;104: 889-894. 8. Wood GS, Crooks CF, Uluer AZ: Lymphomatoid papulosis and associated cutaneous lymphoproliferative disorders

9.

10.

11.

12.

13.

14.

15.

exhibit a common clonal origin. J Invest Dermatol. 1995;105:51-55. Wood GS, Ngan B-Y, Tung R, et al: Clonal rearrangements of immunoglobulin genes and progression to B-cell lymphoma in cutaneous lymphoid hyperplasia. Am J Pathol. 1989;135:13-19. Rijlaarsdam U, Bakels V, van Oostveen JW, et al: Demonstration of clonal immunoglobulin gene rearrangements in cutaneous B-cell lymphomas and pseudoB-cell lymphomas: differential diagnostic and pathogenetic aspects. J Invest Dermatol. 1992;99:749-754. Hammer E, Sangueza O, Suwanjindar P, et al: Immunophenotypic and genotypic analysis in cutaneous lymphoid hyperplasia. J Am Acad Dermatol. 1993; 28:426-433. Nihal M, Mikkola D, Horvath N, et al: Cutaneous lymphoid hyperplasia: a lymphoproliferative continuum with lymphomatous potential. Hum Pathol. 2003; 34:617-622. Magro CM, Nuovo GJ, Crowson AN: The utility of the in-situ detection of T-cell receptor beta rearrangements in cutaneous T-cell infiltrates. Diagn Mol Pathol. 2003;12: 133-141. Plaza JA, Morrison C, Magro CM: Assessment of TCR-beta clonality in a diverse group of cutaneous T-cell infiltrates. J Cutan Pathol. 2008;35(4):358-365. Lessin SR, Benoit BM, Jaworsky C, et al: Skin as a reservoir of minimal residual disease in cutaneous T cell lymphoma after complete clinical response to

16.

17.

18.

19.

20.

biological response modifier therapy. J Invest Dermatol. 1993;100:507. Ke M, Kamath NV, Nihal M, et al: Folliculotropic mycosis fungoides with central nervous system involvement: documentation of tumor clonality in intrafollicular T cells using laser capture microdissection. J Am Acad Dermatol. 2003;48: 238-243. Gellrich S, Lukowsky A, Schilling T, et al: Microanatomical compartments of clonal and reactive T cells in mycosis fungoides: molecular demonstration by single cell polymerase chain reaction of T cell receptor gene rearrangements. J Invest Dermatol. 2000;115:620-624. Olsen E, Vonderheid E, Pimpinelli N, et al: Revisions to the staging and classification of mycosis fungoides and Sezary 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. Volkenandt M, Soyer HP, Kerl H, et al: Development of a highly specific and sensitive molecular probe for detection of cutaneous lymphoma. J Invest Dermatol. 1991;97:137. Posnett DN, Sinha R, Kabak S, Russo C: Clonal populations of T cells in normal elderly humans: the T cell equivalent of “benign monoclonal gammopathy.” J Exp Med. 1994;179:609-618.

INDEX

Acanthosis nigricans, 320–321, 557–558 clinical features, 321, 557 differential diagnosis, 321, 557–558 histopathological features, 321, 557 Acanthotic seborrheic keratosis, 565 Accessory auricle, 408 Accessory digit. See Supernumerary digit Accessory mammary tissue ossification, 408t Accessory nipple, 409–410 clinical features, 409 differential diagnosis, 410 histopathological features, 409–410 Accessory tragus, 408–409 clinical features, 408 differential diagnosis, 409 histopathological features, 408–409 ACD, VH and, 838 AGEP. See Acute generalized exanthematous pustulosis Acid-fast bacillus (AFB), 421 Ackerman tumor, 596 Acne, 12 variants, 236 clinical features, 236 histopathological features, 236–237 Acne keloidalis, 230–231, 238f clinical features, 230 histopathological features, 230–231 Acne rosacea clinical features, 99 differential diagnosis, 99 histopathological features, 99 Acne vermiculata, 233 Acne vulgaris, 241t Acneiform folliculitis, 236 Acoustic neuroma. See Schwannoma Acquired dermal melanocytosis, 642 clinical features, 642 Acquired ichthyosis, 315 clinical features, 315 differential diagnosis, 315 histopathological features, 315 Acquired immunodeficiency syndrome (AIDS), 104. See also HIV BA and, 817 KS and, 810, 820, 831 Acquired lymphangiectases, 850

Acquired melanocytic nevi, 616, 662–663 clinical features, 618 common, 617–618, 618t histopathological features, 618 variants of, 619–627 Acquired perforating dermatosis, 333, 333t, 334f clinical features, 333 histopathological features, 333–334 Acquired progressive lymphangioma (APL), 843–844, 843f, 843t CAT and, 811 lymphangioma simplex and, 842 MLT and, 811 THH and, 810, 811 Acquired tufted angioma. See Tufted angioma Acral arteriovenous malformation (aAVM), 845–846, 845t, 846f Acral arteriovenous tumor. See Acral arteriovenous malformation; Arteriovenous malformations Acral fibrokeratoma, 768–769 clinical features, 768 differential diagnosis, 769 histopathologic features, 768 Acral melanoma, 657, 659, 662t, 664 Acral skin lentiginous intraepithelial component, 661–662 lentiginous melanoma of, 665f Acral skin melanocytic nevi, 623–624 clinical features, 623 compound, 624f differential diagnosis, 623–624 histopathological features, 623 Acremonium, 479, 487 histopathological features, 487 Acroangiodermatitis (AAD), 818–819, 818t, 819f. See also Stasis dermatitis clinical features, 818 differential diagnosis, 819 histopathological features, 818–819 KS and, 823 Acrochordon, 766–767 clinical features, 766 differential diagnosis, 787 histopathological features, 766–767

INDEX

A AAD. See Acroangiodermatitis aAVM. See Acral arteriovenous malformation ABCA12, 316 Abrikosoff tumor, 894–895 Acanthamebiasis, 502, 524–525 differential diagnosis, 524–525 Acanthamoeba, 267 Acanthamoeba astronyxis, 524 Acanthamoeba castellani, 524 Acanthamoeba culbertsoni, 524 Acanthamoeba lenticulata, 524 Acanthamoeba palestinensis, 524 Acanthamoeba polyphaga, 524 Acanthamoeba rhysodes, 524 Acantholysis, 137 spinous layer vesiculation due to, 327–332 Acantholytic acanthoma, 564 clinical features, 564 differential diagnosis, 564 histopathological features, 564 Acantholytic dermatitis, 138–150 Darier disease, 147–148, 148f differential diagnosis, 140t drug-induced pemphigus, 144–145 fogo selvagem, 143 generalized staphylococcal scalded skin syndrome, 147 Haley-Haley disease, 148–149 IgA pemphigus, 145 paraneoplastic pemphigus, 145–147 pemphigus erythematosus, 143–144 pemphigus foliaceus, 143 pemphigus vulgaris, 138–143 transient acantholytic dermatosis, 149–150 Acantholytic squamous cell carcinoma, 593–594, 595, 1018 Acanthomas, 562–569 acantholytic, 564 clear cell, 78, 568–569 epidermolytic, 562–563 large cell, 569 pilar sheath, 697–698 Acanthosis, 5f, 837 epidermal, 27f

1039

INDEX 1040

Acrodermatitis chronica atrophicans, 55, 396–307 clinical features, 396–397 histopathological features, 397 Acrodermatitis enteropathica, 77 clinical features, 77 histopathological features, 77 Acrogeria, 400 histopathological features, 400 Acrokeratoelastoidosis, 404–405 of Costa, 320 Acrokeratosis neoplastica, 76 clinical features, 76 histopathological features, 76 Acromelanosis, 347 Acropigmentation symmetrica, 347 Acrospiroma eccrine, 731–733, 733f, 737 malignant, 739–740 Acrosyringeal nevus, 730 Acrosyringeal-eccrine coil unit, 728 Acrosyringium, 588 ACTH. See Adrenocorticotropic hormone Actin, 582, 594, 973 myolipoma and, 862 Actinic amyloidosis, 376 Actinic cheilitis, 572–573 clinical features, 573 differential diagnosis, 573 histopathological features, 573 Actinic elastosis, 402 Actinic granuloma, 107, 404 clinical features, 107 differential diagnosis, 107 histopathological features, 107 Actinic keratosis, 570–572, 591 bowenoid, 572 epidermolytic, 571 histopathological features, 571 lichenoid, 571, 572f Actinic prurigo, 90, 306f Actinic prurigo cheilitis, 305 Actinic reticuloid, 306 Actinomyces, 430, 478 Actinomycetoma, 480t Actinomycosis, 459t, 481–482, 481t, 482f clinical features, 481 differential diagnosis, 482 histopathological features, 481–482 Active viral infections, 495 Acute febrile neutrophilic dermatosis, 188–190 clinical features, 188–190 Acute generalized exanthematous pustulosis (AGEP), 287 Acute graft-versus-host disease, 44–46 clinical features of, 44–45 cutaneous, 45t differential diagnosis, 46 histopathological features, 45–46 host reaction, 46t Acute infantile hemorrhagic edema (AHE), 184 Acute lobular panniculitis, 262f Acute monocytic leukemia, 943f, 944f, 945f Acute myelogenous leukemia, MVH and, 809

Acute myeloid leukemia, 941–942 clinical features, 941 histochemical findings, 943 histopathologic features, 941–942 immunohistochemical findings, 943 skin infiltrates of, 942t Acute promyelotic leukemia (APL), 941 Acute systemic lupus erythematosus, 49–51 differential diagnosis, 51 Adalimumab, 297 Adamantinoid basal cell carcinoma, 581 Addison disease, 346, 474 differential diagnosis, 346 histopathological features, 346 Adenocarcinoma. See also specific types ductal eccrine, 745, 746–747 metastatic, 966f papillary digital eccrine, 741–743, 742f, 743f primary signet ring cell, 752–753 pulmonary, 966 Adenoid basal cell carcinoma, 580, 588, 741 Adenoid cystic carcinoma, 741, 742f clinical features, 741 differential diagnosis, 741 histopathologic features, 741 Adenoidal seborrheic keratosis, 565 Adenoma aggressive papillary digital, 742 infundibular, 692 mixed-lineage adnexal, 737 nevus sebaceous, 690 papillary eccrine, 731, 732f papillary tubular, 731 sebaceous, 690–691, 691f sebocrine, 692 syringomatous, of nipple, 745 tubular apocrine, 731, 735, 737f Adenoma sebaceum. See Facial angiofibroma Adenosquamous carcinoma, 598, 744 clinical features, 598 differential diagnosis, 598 histopathological features, 598 primary cutaneous, 745 Adipocytes, 862 Adipose tissue, 857–868, 857t hypertrophy of, 858 Adjacent intraepithelial component, 662, 663t melanoma with, 662 Admixed adipose tissue, 890 Adnexal adenomas, mixed-lineage, 737 Adnexal carcinoma. See also Microcystic adnexal carcinoma with mixed differentiation, 717–718, 754–755, 755f Adnexal epithelium, 595 Spitz nevus, 635 Adnexal tumors, 689 Adrenal cortical carcinoma, pleomorphic liposarcoma and, 868 Adrenocorticotropic hormone (ACTH), 346 Adult nematodes, 530–531 Adult progeria, 399 Adult rhabdomyoma, 873–874, 873f, 873t adult rhabdomyoma and, 873

Adult T-cell lymphoma/leukemia (ATLL), 915, 952 clinical features, 915, 952 definition, 915 differential diagnosis, 915, 952 genotypic features, 915 histopathological features, 915, 952 immunohistochemical findings, 952 immunophenotypic features, 915 molecular biology, 952 Adult trematodes, 531, 532 AE13, 716 AE14, 716 AFB. See Acid-fast bacillus AFH. See Angiomatoid fibrous histiocytoma Afipia felis, 440 African histoplasmosis, 474 clinical features, 474 histopathological features, 474 AFXs. See Atypical fibroxanthomas Aggregations, 909 Aggressive papillary digital adenomas, 742 AHE. See Acute infantile hemorrhagic edema AIDS. See Acquired immunodeficiency syndrome Ainhum, 396 AITL. See Angioimmunoblastic T-cell lymphoma Albinism, 343t oculocutaneous, 341–342 Albright hereditary osteodystrophy, 383 histopathological features, 384 Alcoholic cirrhosis, unilateral nevoid telangiectasia and, 835 Algal infections, 517–527 ALK1, HHT and, 834 Alkaptonuria, 384–385 histopathological features, 384–385 Allergic contact dermatitis, 17, 27f clinical features of, 17 histopathological features of, 17 Alopecia, 13 algorithm for, 214f androgenetic, 215–216, 218f, 219f clinical features, 215 female, 218f histopathological features, 215–216 male, 219f areata, 218–219, 222f, 223t, 224f, 967 clinical features, 218 differential diagnosis, 219 histopathological features, 218 central centrifugal scarring, 227–229 common causes, 215t difficulty to classify, 232–233 diffuse, 216–217, 219t, 220t, 221f, 222f causes of, 219t differential diagnosis, 217 drugs causing, 220t histopathological features, 217 drug-associated, 291 end-stage scarring, 235 histopathological features of, 214f lipedematous, 232 mucinosa, 229–230 clinical features, 229 differential diagnosis, 229–230 histopathological features, 229

Amyloidosis (Cont.): systemic, 371–374 secondary, 372–374 systemic amyloid A, 372–374 systemic amyloid light chain, 371–372, 373f tumoral, 378 Amyopathic dermatomyositis, 93 Anagen, 213 effluvium, 216, 222f hairs, 215t postfebrile, 216 postpartum, 216 short cycle, 216 Anaplasma, 454 Anaplastic cells, 910 Anaplastic syringoma, 743 Anatomic site, 4 ANCA. See Antineutrophil cytoplasmic antibodies ANCA-associated vasculitis, 184, 195–196 types, 196t Anchoring filaments, subepidermal blistering diseases, 156 Ancient schwannomas, 890, 891 Androgenetic alopecia, 215–216 clinical features, 215 female, 218f histopathological features, 215–216 male, 219f Anetoderma, 402 Aneuploidy, 578 Aneurysmal fibrous histiocytoma, 777f Angioblastoma. See Tufted angioma Angiodermatitis. See Acroangiodermatitis Angioedema, 83 Angioendothelioma. See Acquired progressive lymphangioma Angioendotheliomatosis, 817 Angiofibromas, 797 facial, 797 Angioimmunoblastic lymphadenopathy, 925f Angioimmunoblastic T-cell lymphoma (AITL), 924 Angiokeratoma, 836, 836t, 837f VH and, 838 Angiokeratoma of Mibelli, VH and, 838 Angioleiomyoma, 869–870, 870f, 870t Angioleiomyomas, 890 Angiolipoma, 858–859, 859f, 859t Angiolymphoid hyperplasia with eosinophilia. See Epithelioid hemangioma Angioma cherry, 849–850, 849f microcapillary, 808 Angioma serpiginosum, 835–836 VH and, 838 Angiomatoid fibrous histiocytoma (AFH), 777, 789–790, 789t, 790f clinical features, 790 differential diagnosis, 790 histopathologic features, 790 Angiomatoid Spitz nevus, 639 Angiomatosis of soft tissue (AST), 844, 844t, 845f CH and, 827 Angiomyolipoma, 862–863, 863f Angiomyoma, 869–870

Angiomyxoma, superficial, 795–796 Angiopathy, hyaline, 380 Angiosarcoma, 596, 829–831, 829t, 830f, 831f APL and, 844 capillary hemangioma and, 830 cavernous hemangioma and, 830 CD 31, 830 CD34 and, 830 D2-40 antibody, 830 epithelioid, 829, 831 foreign objects and, 829 intravascular disseminated, 817 KS and, 823, 831 laminin and, 830 LYVE and, 830 mastectomy and, 829 Milroy disease, 829 morbid obesity and, 829 PILA and, 826 radiation and, 829 RH and, 826 SCH and, 807, 830 spindle cell hemangioma and, 807, 830 TA and, 806 VEGFR and, 830 vimentin and, 830 von Willebrand factor and, 830 Angiotropic large cell lymphoma. See Angioendotheliomatosis Angiotropic melanoma, 669–670, 669f clinical, 670 Angiotropism, 669 Angiotumoral complex, 670 Animal poxviruses, 512 Anoplastic lymphoid cells, 906 Anorexia nervosa, 88 ANOTHER syndrome, 347 Anthrax, 433–435, 440f differential diagnosis, 435 histopathological features, 434 Antibody production, 495 Antibody-mediated reactions, 281 Anticytokeratin antibodies, 593 Anti-DNA antibodies, 92 Antigenic targets, in CP, 163t Antimalarials, 356 Antineutrophil cytoplasmic antibodies (ANCA), 12 Antiphospholipid syndrome, RAE and, 817 Antiretroviral therapy, PG and, 813 Anti-Ro antibodies, 284 Antistreptolysin O (ASO), 425 APL. See Acquired progressive lymphangioma; Acute promyelotic leukemia Aplasia cutis congenita, 395 clinical features, 395 histopathological features, 395 Apocrine adenoma, 696 Apocrine carcinoma ductal, 752, 753f ductopapillary, 749–750, 751f simulating metastasis, 752 Apocrine carcinomas, 749–750 primary, 749

INDEX

Alopecia (Cont.): neoplastica, 961 nonscarring, 13, 215–223 causes of, 221–223 clinical features, 221 differential diagnosis, 223 histopathological features, 222–223 differential diagnosis, 216 histopathological features, 217t, 222–223 scarring v., 215 pressure, 220–221, 226 primary scarring lymphocyte-associated, 225, 231t pustulofollicular, neutrophil-associated primary scarring, 230 scarring, 13, 215, 223–232, 238t central centrifugal, 227–229 end-stage, 235 nonscarring v., 215 primary, 224–225 lymphocyte-associated, 225, 231t pustulofollicular, neutrophil-associated primary, 230, 236t secondary, 224–225, 232, 238t syringolymphoid hyperplasia with, 911–912 traction, 220–221, 226, 227f, 228f Alpha-1 antitrypsin deficiency, 263, 263t clinical features, 263 histopathological features, 263 ALT. See Atypical lipomatous tumor Alternaria, 478 Alternariosis, 478 clinical features, 478 differential diagnosis, 478 histopathological features, 478 Aluminum chloride solution reaction, 124 clinical features, 124 Alveolar rhabdomyosarcomas (ARMs), 875, 875f Amalgam tattoo, 1015 clinical features, 1015 differential diagnosis, 1015 histopathologic features, 1015 AMART-1, 780 Amebiasis, 525–526 clinical features, 525 differential diagnosis, 525–526 histopathological features, 525 American Rheumatism Association, 68, 92t, 168 Amiodarone, 356 Amyloid deposition, 586 Amyloid elastosis, 372 Amyloid-hyaline-colloid deposition, 371t Amyloidosis, 191 actinic, 375 biphasic, 374–375 differential diagnosis, 375 histopathologic features, 374–375 epithelioma-associated keratin, 375–376 insulin, 376 lichen, 61, 375, 375f colloid milium, 374t nodular, 376–377, 377f secondary systemic, 372–374 skin-limited, 373t, 374–379

1041

INDEX 1042

Apocrine hidrocystomas, 756–757 clinical features, 756 differential diagnosis, 757 histopathological features, 756–757 Apocrine neoplasms, 733–735 Apocrine nevi, 755 Apocrine type Paget disease, differential diagnosis, 751–752 Apolipoprotein D, 777 Apophysomyces, 483 Apoptosis, 36, 587, 908 Arachnid reactions, 308 clinical features, 308 differential diagnosis, 308 Arachnidism, 308 Arao-Perkins bodies, 216 Architectural disorder, 630 compound nevus with, 653f, 654f junctional nevus with, 654f Argyria, 355 ARMs. See Alveolar rhabdomyosarcomas Arsenic, 355 histopathological features, 355 Arsenical keratosis, 573 clinical features, 573 differential diagnosis, 573 histopathological features, 573 Arterial spider, 832, 848–849, 849f Arteriovenous fistulas, RAE and, 817 Arteriovenous hemangioma, 834f Arteriovenous malformations (AVMs), 813, 844–847, 847f AAD and, 818, 819 Cobb syndrome, 833 HHT and, 834 Parkes Weber syndrome, 832–833 PWSs and, 832 VM and, 839 Arteriovenous shunt. See Arteriovenous malformations Arthritis, reactive clinical features, 68 differential diagnosis, 68 histopathological features, 68 Arthroderma, 458 Arthropod bite reactions, 167 Aschoff nodules, 109 Ascomycota, 458, 467 Ash leaf spots of tuberous sclerosis, 343 differential diagnosis, 343 histopathological features, 343 Ashkenazi Jews, KS and, 820 ASO. See Antistreptolysin O Aspergillosis, 459t, 486–487, 487f clinical features, 486 differential diagnosis, 486–487 histopathological features, 486 Aspergillus, 463, 484 AST. See Angiomatosis of soft tissue Asteatotic eczema, 23 Asteroid bodies, 101 Ataxia telangiectasia, 835 HHT and, 834 ATLL. See Adult T-cell lymphoma/leukemia Atopic dermatitis, 18–19, 28f, 29t clinical features of, 19 histopathological features of, 19 ATP2A2, 330

ATPases, 315 Atrichia, 321 Atrophic collagenoses, 395–397 Atrophic connective tissue panniculitis, 274 Atrophie blanche, 192, 206, 207f clinical features, 206 histopathological features, 206 Atrophoderma of Pasini and Pierini, 396 clinical features, 396 differential diagnosis, 396 histopathological features, 396 Atrophy, epidermal, 90 Attenuated yaws, 450 Atypical cellular blue nevus, 647 Atypical decubital fibroplasia, 772 Atypical dermal nodular melanocytic proliferation, 631f Atypical fibrous histiocytoma, 776–777, 778f Atypical fibroxanthomas (AFXs), 593, 778–780, 779t clinical features, 778 differential diagnosis, 779–780 histopathological features, 778–779 Atypical halo nevus, 663 Atypical lipomatous tumor (ALT), 858, 865–866, 865f, 865t lipoblastoma and, 864 Atypical lymphocytic hyperplasia, 908 Atypical melanocytic nevi, 651 cytologic features, 654 epithelioid cell variant, 655 grading of, 656 halo nevus variant, 655 histological features of, 655–656 junctional, 652 as melanoma precursors, 652 host response, 654 melanoma v., 655t severely, 655t significance of, 651–654 Atypical melanocytic proliferation, 997–998 clinical features, 997 differential diagnosis, 998 histopathologic features, 997–998 Atypical mycobacteria, 432, 434f, 435f clinical features, 432 histopathological features, 432 Atypical mycobacterial folliculitis, 235–236 Atypical Spitz nevus, 636 assessment of, 637t Atypical Sweet syndrome, 128 Atypical vascular proliferation with inflammation. See Epithelioid hemangioma Autoimmune diseases, diagnosis, 186 Autoimmune subepidermal blistering diseases, 157–160 bullous pemphigoid, 157–160 Autosomal recessive lamellar ichthyosis, 318t AVMs. See Arteriovenous malformations B B. afzelii, 55 B. burgdorferi, 55 B lymphocytes, marginal zone, 930 BA. See Bacillary angiomatosis

Bacillary angiomatosis (BA), 441–442, 442f, 817 cherry angioma and, 850 clinical features, 441 differential diagnosis, 441–442 histopathological features, 441, 502 in HIV, 501 KS and, 823 Bacillary peliosis, 441 Bacillus anthracis, 433 Backhart impetigo, 234 Bacterial folliculitis, 234, 239f clinical features, 234 Bacterial infections, 421–443. See also specific types differential diagnosis, 422t histological features, 422t Bacteroides, 427 Baker itch, 308 Balamuthia mandrillaris, 524 Balanitis circinata, 68, 464 Balloon cell melanoma (BCM), 620, 676–677 clinical features, 677 histopathological features, 677 Balloon cell nevus, 620 clinical features, 620 differential diagnosis, 620 histopathological features, 620 Bancroftian filariasis, 530 Bandlike growth pattern, 907f Bandlike infiltrates, 906 Bart syndrome, 170, 171t Bartonella, 439, 441, 501 Bartonella quintana, 817 Bartonellosis, 442 Basal cell carcinoma, 578–590, 729, 733, 961 aAVM and, 845t adamantinoid, 581 adenoid, 580, 588, 741 basosquamous, 583–584 clear cell, 581 clinical features, 579–580 derivation of, 579 differential diagnosis of, 587–588 with eccrine differentiation, 585f follicular, 585 granular, 581 halo, 580 histopathological features, 580 in HIV, 579 immune system in, 579 infiltrative, 583, 584f, 588, 706 inflammation in, 586 infundibulocystic, 584–585, 586 keratotic, 584–585 matrical, 585 metastatic, 580 metatypical, 583, 585 micronodular, 582, 583f with mixed histology, 582 morpheaform, 588, 706, 727 multicentric, 580 with myoepithelial differentiation, 585–586 necrosis in, 588 nevoid, 589–590 nodular, 580–582, 580f

Bednar tumor, 787 Behçet disease, 127, 186, 187t, 498 clinical features, 127, 186 histopathological features, 127, 186–187 Bejel, 451 Benign acquired vascular lesions, with radiation, 850 Benign adipocytic tumors, 858, 858t Benign adnexal neoplasm, 692 Benign cephalic histiocytosis, 119–120 clinical features, 119–120 differential diagnosis, 120 histopathological features, 120 Benign fibrohistiocytic tumors, 775–781 Benign fibrous tumors, 766–776 Benign hair follicle tumors, 697–714 Benign keratosis, 5f Benign lymphangioendothelioma. See Acquired progressive lymphangioma Benign lymphangiomatous papule, 850 Benign migratory glossitis, 1008–1009 clinical features, 1009 different diagnosis, 1009 histopathological features, 1009 Benign neoplasms distinguishing malignant from, 5f features of, 5 of umbilicus, 415t Benign proliferating pilar tumor (BPPT), 701–702 clinical features, 701 cytologic features of, 701–702 differential diagnosis, 702 histopathologic features, 701–702 Benign sebaceous proliferations, 689–692 Benign spiradenoma, 746 Benign sweat gland tumors, 725–733 Benign T-cell lymphoproliferations, 908–926 Benign tertiary syphilis, 446 Benign vascular tumors, 802–811 Benzene, 353 Bharma forest, 503 B-immunoblasts, 906, 929–930 BIOMED2, 908 Biphasic amyloidosis, 374–375 differential diagnosis, 375 histopathologic features, 374–375 Biphasic tumors, 797 Bipolaris spicifera, 477 Bird’s-eye cells, 509 Birt-Hogg-Dubé syndrome, 713 Bismuth, 355 Black piedra, 459t, 467 Blaschko lines, 835 Blastocladiomycota, 458 Blastomycosis-like pyoderma, 111, 113t, 428–429 clinical features, 111 differential diagnosis, 111 histopathological features, 111 Bleomycin, 390 Blistering distal dactylitis, 426 clinical features, 426 histopathological features, 426 Blistering drug eruptions, 288

Blisters, 136. See also Subepidermal blistering diseases coma, 174–175 friction, 150 intraepidermal, 136f, 137f, 139t suprabasal, 141f Bloch-Sulzberger syndrome, 349–350 Bloom syndrome, 59 ataxia telangiectasia and, 835 Blue nevi, 641, 642–643 atypical cellular, 647 cellular, 645, 646f lymph node involvement in, 647 common, 643, 644f compound, 645 epithelioid, 643, 644f hypopigmented, 645 malignant melanoma arising in, 675 clinical features, 675 differential diagnosis, 675 histopathological features, 675 patchlike, 647 plaque-type, 647–648 sclerosing, 645 target, 648 Blue rubber bleb nevus syndrome (BRBNS), 838 GVM and, 840 Blueberry muffin baby syndrome, 497 B-lymphoblastic lymphoma, 938 clinical features, 938 differential diagnosis, 938 histopathologic features, 938 immunology, 938 BM. See Basement membrane BMZ. See Basement membrane zone Bone, 381–383, 877–879 Bone deposits, 382t dystrophic type, 382 idiopathic type, 382–383 Borderline melanoma, 680 Borderline sebaceous tumors, 692–693 Borrelia burgdorferi, 110, 387, 451, 927, 928, 933, 948 Borst-Jadassohn phenomenon, 729 Bortezomib, 297 Botryoid embryonal rhabdomyosarcoma, 873 Botryomycoma. See Pyogenic granuloma Botryomycosis, 459t, 482–483 clinical features, 482 differential diagnosis, 483 histopathological features, 482–483 Bowel-associated dermatosis-arthritis syndrome, 127, 189f, 191 clinical features, 127, 191 differential diagnosis, 127 histopathological features, 127, 191 Bowen disease, 78, 509, 573–575, 591, 992, 996 clinical features, 574 differential diagnosis, 574–575 histopathological features, 78, 574 Bowenoid actinic keratosis, 572 Bowenoid papulosis, 508, 510f, 511f BPAC1. See Bullous pemphigoid antigen 1 BPAC2. See Bullous pemphigoid antigen 2 BPPT. See Benign proliferating pilar tumor BRAF mutations, 657

INDEX

Basal cell carcinoma (Cont.): occurrence of, 579 ossification within, 586 pigmented, 581f pilar, 584–585 pleomorphic, 582 polypoid, 580 prevalence of, 579 risk factors for, 579 sclerosing, 583 with sebaceous differentiation, 581f superficial, 582–583, 583f superficial multicentric, 582 tumors associated with, 579 Basal cell epithelioma, with monster cells, 582 Basal layer disorders, 326–327 Basal vacuolization, 36 Basaloid eccrine carcinoma, 749 clinical features, 749 differential diagnosis, 749 histopathologic features, 749 Basaloid follicular hamartomas, 588, 708–709, 709f clinical features, 708 differential diagnosis, 709 histopathologic features, 708–709 Basaloid sebaceous carcinomas, 694 Basement membrane (BM), 156 protein constituents of, 158f Basement membrane zone (BMZ) epidermolysis bullosa, junctional, 326 epidermolysis bullosa simplex, 326 mutations, 169–171 subepidermal blistering diseases and, 169–171 thickening, 90 Basidiobolus, 484–485 clinical features, 484–486 differential diagnosis, 486 histopathological features, 486 Basidiomycota, 458, 467 Basilar melanocytes, lesions composed of, 615–616 Basiomycota, 465 Basomelanocytic tumor, malignant, 581 Basophil degranulation, 82 Basosquamous basal cell carcinoma, 583–584 Bazex syndrome, 76 clinical features, 76 histopathological features, 76 B-cell lymphomas, large, in immunocompromised patients, 937–938 B-cell series, 929–932 B-chain gene (PDFGB), 785 bcl-2 protein, 705 BCM. See Balloon cell melanoma Beanbag cells, 264 Becker nevus, 719 clinical features, 719 congenital smooth muscle hamartoma and, 868 differential diagnosis, 719 histopathologic features, 719 Becker pigmented hairy nevus, 351–352 clinical features, 351 differential diagnosis, 351–352 histopathologic features, 351

1043

INDEX 1044

Branchial cleft cysts, 550, 551f differential diagnosis, 550 histopathological features, 550 BRBNS. See Blue rubber bleb nevus syndrome Breast carcinoma, 960, 963–965 clinical features, 963 differential diagnosis, 964 histopathologic features, 963–964 immunohistochemistry, 964–965 metastatic mucinous, 965f special stains, 964–965 Breast melanocytic nevi, 625 Breslow thickness, 661 Brevibacterium epidermidis, 462 Broders classification, 591 Bronchogenic cysts, 549–550, 551f differential diagnosis, 550 histopathological features, 550 Bronze baby syndrome, 355 Brooke-Fordyce syndrome, 703, 704 Brooke-Spiegler syndrome, 599 Brown recluse spider bite, 308f Brucella abortus, 435 Brucella canis, 435 Brucella melitensis, 435 Brucella suis, 435 Brucellosis, 435–436 clinical features of, 435–436 differential diagnosis, 436 histopathological features, 436 Brugia malayi, 533, 534 Brugia pahangi, 533 Brugia timori, 533 BSCL2, 274 Buerger disease, 201 clinical features, 201 differential diagnosis, 201 histopathological features, 201 Bullae, 136 Bullosis diabeticorum, 175 clinical features, 175 diagnosis, 175 differential diagnosis, 175 histopathological features, 175 Bullous congenital ichthyosiform erythroderma, 328–329, 328t Bullous ichthyosis, epidermolytic hyperkeratosis and, 328–329 Bullous impetigo, 152 clinical features, 152 histopathological features, 152 Bullous lichen planus, 39f Bullous lupus erythematosus, 167 Bullous pemphigoid, 157–160, 288 cell-poor, 159f clinical features, 158 diagnosis, 159 differential diagnosis, 159–160 direct immunofluorescence, 159 histopathological features, 158 indirect immunofluorescence, 159 urticarial lesion of, 160f Bullous pemphigoid antigen 1 (BPAC1), 156 Bullous pemphigoid antigen 2 (BPAC2), 156 Bullous systemic lupus erythematosus, 168–169 clinical features, 168–169

Bullous systemic lupus erythematosus (Cont.): diagnostic features, 169 differential diagnosis, 169 histopathological features, 169 Bunyaviruses, 503 Burns, thermal, 150–152 Buruli ulcers, 591 Buschke-Loewenstein tumor, 596, 597 clinical features, 597 differential diagnosis, 598 histopathological features, 597–598 C C5b-9, 93 CA-125 glycoprotein, 748, 970 CAFCA. See Cryopyrin-associated familial cold autoinflammatory syndrome Cafe-au-lait spots, 350–351, 886 differential diagnosis, 351 histopathological features, 350–351 Calcareous bodies, 537 Calcific uremic arteriopathy. See Calciphylaxis Calcifying aponeurotic fibroma, 774–775 clinical features, 774 differential diagnosis, 774–775 histopathologic features, 774 Calcinosis iatrogenic, 383 milia-like, 383 tumoral, 383f Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST), 847 Calcinosis cutis, 381 metastatic, 381–382 Calciphylaxis, 207–208, 208t, 209f, 258t, 381 clinical features, 207, 258 differential diagnosis, 207–208, 259 histopathological features, 207, 258 Calcium, 381–383, 382t dystrophic type, 382 idiopathic type, 382–383 Callitroga, 309 Callus, 602 clinical features, 602 differential diagnosis, 602 histopathological features, 602 Calymmatobacterium, 436 Candida, 77 Candida albicans, 152, 990 Candidal granuloma, 464 Candidiasis, 152–153, 459t, 463–465 chronic, 74 clinical features, 152 differential diagnosis, 464–465 disseminated, 464 histopathological features, 152, 464 mucocutaneous, 463t systemic, 464 Cantu syndrome, 348 Capillary aneurysm, 848 Capillary hemangioma, angiosarcoma and, 830 Capillary malformation-Arteriovenous Malformation (CM-AVM), 833 Capillary malformations (CMs), 813, 831–832, 833t VM and, 839

Carcinoembryonic antigen (CEA), 575, 739, 751, 962, 969, 970, 971 Carcinoma. See also specific types adenoid cystic, 741, 742f adenosquamous, 598, 744 adnexal, 717 apocrine, 749, 752, 753f, 754f basal cell, 578–590, 706, 727, 729, 733, 845t, 961 breast, 960, 963–965, 965f clear cell eccrine, 694, 739, 747–748 colloid, 963 cuniculatum, 598 ductal apocrine, 752, 753f, 754f ductopapillary apocrine, 749–750, 751f eccrine, 694, 738–755, 750t ex mixed tumors, 748 gastrointestinal, 967–968 intraepidermal, 573–576 lung, 965–967 lymphoepithelioma-like, 599–600, 753–754 Merkel cell, 515 microcystic adnexal, 699, 727, 728, 743–745, 744f mucinous, 740–741 mucinous eccrine, 740t mucoepidermoid, 598–599, 745 mucoid, 963 neuroendocrine, 673, 897t oral, 968 pilomatrix, 717, 718t primary cutaneous adenosquamous, 745 primary mucoepidermoid, 745 primary neuroendocrine, 896–897, 898f sclerosing sweat duct, 743 sebaceous, 690, 693–695, 694f, 695f sinonasal, 968 spindle cell, 962 squamous cell, 544, 590–596, 596t, 693, 961, 996, 1017–1018 sweat gland, 738, 753 syringoid, 743 thyroid, 961, 963 trichilemmal, 694, 715–716 verrucous, 596–598 Carcinoma ex dermal cylindroma, 745–746 histopathological features, 746 Carcinosarcoma, 599, 599t, 748–749 clinical features, 599 differential diagnosis, 599 histopathological features, 599 Carmustine, 356 Carney complex, 796 Carney syndrome, 348–349 Carotinoids, 356 Carrion disease, 442 Cartilage, 381–383, 876–877 Cartilage-like matrix, 736 Casal necklace, 77 Cast immobilization, PG and, 813 Castleman disease, 815 CAT. See Cutaneovisceral angiomatosis with thrombocytopenia Catagen, 213 Catagen hairs, 218 Caterpillar bodies, 380 Cathepsin C, 320

CD81, 670 CD87, 257 CD99, 780 CD206, KS and, 822 CD208c, 83 CD445R0, 711 CD681, 447 CDK4 gene, 865 dedifferentiated liposarcoma and, 867 CDX2, 970 CEA. See Carcinoembryonic antigen Cell-poor bullous pemphigoid, 159f Cell-poor interface dermatitis, 90 Cellular angiolipomas, 859 Cellular blue nevus, 645, 646f atypical, 647 clinical features, 645 histopathologic features, 645–646 lymph nodes in, 647 occasional, 646–647 Cellular dermatofibroma, 779f Cellular neurothekeoma, 894f extraskeletal myxoid chondrosarcoma and, 877 Cellular neurothekeomas, 892 Cellular schwannoma, 890, 892f Cellulitis, 426–427 infectious, 426t Center for Disease Control and Prevention, 421, 433, 500 Central centrifugal scarring alopecia, 227–229 clinical features, 228 differential diagnosis, 229 histopathological features, 228–229 Central nervous system (CNS), 468 Centroblasts, 929, 932 Centrocyte-like cells, 933 Centrocytes, 929, 932 Centrofacial neurodystrophic lentiginosis, 348 Cephalothoracobrachial lipodystrophy, 274 Cerebellar degeneration, 590 Cerebral angioendotheliomatosis. See Angioendotheliomatosis Cerebrospinal fluid (CSF), 447, 521 Cestodes, 530, 536–538 CGH. See Comparative genomic hybridization CH. See Composite hemangioendothelioma; Congenital hemangioma Chagas disease, 520, 521, 522f Chagoma, 522 Chalazion, 102–103 clinical features, 102 differential diagnosis, 102 histopathological features, 102 Chancroid, 437–438, 440t clinical features, 437 differential diagnosis, 437 histopathological features, 437 Charcot-Leyden crystals, 534 Chédiak-Higashi syndrome, 343 clinical features, 343 histopathological features, 343 Cheilitis actinic prurigo, 305 follicular, 305

Cheilitis glandularis, 1011–1012 differential diagnosis, 1011–1012 histopathological features, 1011 Cheilitis granulomatosa, 100, 101t Chemical panniculitis, 271 clinical features, 271 differential diagnosis, 272 histopathological features, 271 Chemokine, 93 Chemotherapeutic agents, 291–293, 356–357 clinical features, 291–292 differential diagnosis, 292 histopathological features, 292 Cherry angioma, 849–850, 849f Cheyletiella, 308 Chickenpox. See Varicella Chiggers, 308 Chikungunya, 503 Chilblains. See Perniosis Childhood melanoma, 627–632 Chlamydia, 438, 443 Chloasma, 350 differential diagnosis, 350 histopathologic features, 350 Chloramphenicol, 281 Chlorella, 526 Chlorellosis, 526, 526t clinical features, 526 differential diagnosis, 527 histopathological features, 526–527 Chlorhexidine, 421 Chlorpromazine, 289 Cholesterol emboli, RAE and, 817 Chondrodermatitis nodularis chronic helicis, 397 clinical features, 397 differential diagnosis, 397 histopathological features, 397 Chondrodysplasia punctata, X-linked dominant ichthyosis with, 316 Chondroid lipoma, 861, 862f Chondroid syringoma, 733, 735–737, 737t, 738f clinical features, 735–736 differential diagnosis, 736–737 extraskeletal myxoid chondrosarcoma and, 877 malignant, 588 Chondromas, cutaneous, 736 Chondrosarcomas, 972 Chordoma, extraskeletal myxoid chondrosarcoma and, 877 Choriocarcinomas, 960, 970 CHP. See Cytophagic histiocytic panniculitis Chromatin, 438 Chromhidrosis, 244 clinical features, 244 differential diagnosis, 244 histopathological features, 244 Chromoblastomycosis, 459t, 475–477 clinical features, 476 differential diagnosis, 476–477 histopathological features, 476 Chromogranin, 590, 901, 963 Chronic bite injury, 1007 clinical features, 1007 differential diagnosis, 1007 histopathologic features, 1007

INDEX

Cat-scratch disease, 439–441 clinical features, 440 differential diagnosis, 441 histopathological features, 441 Cave disease. See Classic histoplasmosis Cavernous angioleiomyomas, 870 Cavernous hemangioma, 802. See also Venous malformation angiosarcoma and, 830 Cavernous lymphangioma, 842, 842f Cavernous malformation. See Venous malformation CCA. See Clear cell acanthoma CCDPP-15, 751 CCND1, 657 CCS. See Clear cell sarcoma CD 5/6, 965 CD 31 alveolar rhabdomyosarcoma and, 875 angiosarcoma and, 830 APL and, 844 extraskeletal chondroma and, 876 KS and, 822 RAE and, 818 CD 34 alveolar rhabdomyosarcoma and, 875 APL and, 844 extraskeletal chondroma and, 876 KHE and, 824 KS and, 822 leiomyoma and, 869 leiomyosarcoma and, 871, 872 RAE and, 818 spindle cell lipoma and, 860 WDL/ALT and, 866 CD 45, alveolar rhabdomyosarcoma and, 875 CD 68 adult rhabdomyoma and, 874 chondroid lipoma and, 861 GH and, 816 CD 99 embryonal rhabdomyosarcoma and, 874 extraskeletal osteosarcoma and, 879 CD1a, 316 CD4, 218 CD4+, CD56+ hematodermic neoplasm, 926 clinical features, 926 definition, 926 differential diagnosis, 926 genotypic features, 926 histopathological features, 926 immunophenotypic features, 926 CD5, 711 CD8, 43, 306, 495, 711 CD10, 780 CD31, 802, 815 EH and, 812 GH and, 816 SCH and, 808 CD34, 802, 815 angiosarcoma and, 830 EH and, 812 SCH and, 808 CD48, 711 CD56, 907 CD57, 887, 893, 894, 896 CD68, 83, 116

1045

INDEX 1046

Chronic candidiasis, 74 clinical features, 74 histopathological features, 74 Chronic dermatophytosis, 74 clinical features, 74 histopathological features, 74 Chronic graft-versus-host disease, 46–48 clinical features, 46 differential diagnosis, 47 histopathological features, 46 Chronic lymphocytic leukemia, 146, 949f, 950f B-cell type, 948–949 clinical features, 948 histopathological features, 948–949 immunohistochemical findings, 949 molecular biology, 949 infiltrates in, 948t Chronic myeloid leukemia (CML), 944–946 clinical features, 944 histochemical findings, 946 histopathologic features, 944–945 immunohistochemical findings, 946 infiltrates of, 947t Chronic pulmonary histoplasmosis, 473 Chronic spongiotic dermatitides, 72–73 clinical features, 73 differential diagnosis, 73 histopathologic, 73 Chronic urticaria, 81 common forms of, 82t Chrysiasis, 355 Chrysomyia, 309 Churg-Strauss granuloma, 109, 184 clinical features, 197 histopathological features, 197 Churg-Strauss syndrome, 196–197 Chytridiomycota, 458 Cicatricial pemphigoid (CP), 162–163 antigenic targets in, 163t clinical features, 162 differential diagnosis, 163 histopathological features, 162 Ciliated cysts of vulva, 551–552 differential diagnosis, 552 histopathological features, 552 Circumscribed hypermelanosis, 347–348, 348t Cirsoid aneurysm. See Arteriovenous malformations Civatte body, 36 CK7, 966, 967, 969, 970 CK20, 966, 969, 970, 971 CL. See Cutaneous lymphadenoma Cladophialophora bantiana, 477 Cladophialophora carrionii, 476 Cladosporium werneckii, 477 Classic histoplasmosis, 473–474 clinical features, 473–474 differential diagnosis, 474 histopathological features, 474 HIV and, 473 Classic Sweet syndrome, 188–190 Clavus, 601–602 clinical features, 601 differential diagnosis, 601–602 histopathological features, 601

Clear cell acanthoma (CCA), 78, 568–569 clinical features, 568 differential diagnosis, 569 histopathological features, 78, 568–569 Clear cell basal cell carcinoma, 581 Clear cell cutaneous tumors, 716t Clear cell dermatofibroma, 777, 779f Clear cell eccrine carcinoma, 694, 739, 747–748 clinical features, 748 differential diagnosis, 748 histopathologic features, 748 Clear cell hidradenoma, 732 Clear cell sarcoma (CCS), 676 differential diagnosis, 676 histopathological features, 676 Clefts, 136 suprabasal, 141f Clofazamine, 356 Clofazimine-induced hyperpigmentation, 123 Clomeromycota, 458 Clonal seborrheic keratosis, 565 Clostridium, 427 CM, AVMs, 847 CM-AVM. See Capillary malformationarteriovenous malformation CML. See Chronic myeloid leukemia CMs. See Capillary malformations CMTC. See Cutis marmorata telangiectatica congenita CMV. See Cytomegalovirus CNS. See Central nervous system Coagulopathies, 203 clinical features, 203 histopathological features, 203 Cobb syndrome, 833 VH and, 838 Coccidioides immitis, 527 Coccidiomycosis, 459t, 471 clinical features, 471 differential diagnosis, 471–472 histopathological features, 471 Coccobacilli, 437 Coenuriasis, 537 COL7A1, 327 Cold panniculitis, 270 clinical features, 270 histopathological features, 270 Cold reactions, 303–304 clinical features, 303–304 differential diagnosis, 304 histopathological features, 304 Collagen, 291, 387–405 alterations of, 387 type IV, 889 Collagen bodies, 897 Collagenosis nuchae, 394 clinical features, 394 histopathological features, 394 Collagenous crystalloids, 586 Collagenous plaques, 392 Collagenous plaques of hands, 402 Collarette, 678 Collections, 909 Colloid body, 36

Colloid carcinoma, 963 Colloid milium, 374t, 378 of adult, 378–379, 379f juvenile, 376f Coma blisters, 174–175 clinical features, 174 histopathological features, 174–175 Combined nevus, 648 Comedo patterns, 693 Comedone, 242f Comel-Netherton syndrome, 318, 323 clinical features, 323 differential diagnosis, 323 histopathological features, 323 Common blue nevus, 643, 644f clinical features, 643 differential diagnosis, 643 histopathologic features, 643 Comparative genomic hybridization (CGH), 680 Complement, 274 membrane attack complex of, 92–93 Complex aphthosis, 1006 Composite hemangioendothelioma (CH), 827 Compound blue nevus, 645 Compound nevus, 618 of acral skin, 624f with architectural disorder, 653f, 654f and cytologic atypia, 653f, 654f of vulva, 626f Compound Spitz nevus, 637f Concurrent cutaneous B-cell lymphomas, 931 Condyloma acuminatum, 506, 507t, 508f, 509f, 598 Confluent and reticulate papillomatosis of Gougerot and Carteaud, 558 clinical features, 558 differential diagnosis, 558 histopathological features, 558 Congenital dysplasia angiopathies, 832 Congenital generalized phlebectasia. See Cutis marmorata telangiectatica congenita Congenital hemangioma (CH), 803, 803t, 804–805, 805f Congenital hemidysplasia, 322, 447 Congenital hypotrichosis, 228f Congenital lymphedema, 807 KHE and, 823 Congenital melanocytic nevi, 627–632 with atypical features, 630 architectural disorder, 630 cytologic atypia, 630 dermal nodular proliferations, 630 intraepidermal pagetoid spread, 630 giant, 632 histological features, 628 incidence, 628–630 clinical features, 628 histopathological features, 628 large, 632 melanoma in, 630–631 risk factors, 628–630 clinical features, 628 histopathological features, 628 small, histopathological features, 628–630

Cryopyrin-associated familial cold autoinflammatory syndrome (CAFCA), 190 Cryptococcosis, 459t, 468 clinical features, 468 differential diagnosis, 469 histopathological features, 469 Cryptococcus, 468, 527 Crystalline lamellae, in endothelial cells, 806 Crystal-related panniculitis, 265–266, 266t Crystal-storing histiocytosis, adult rhabdomyoma and, 873 CSF. See Cerebrospinal fluid CTCL. See Cutaneous T-cell lymphomas Ctenocephalides felis, 441 Cuniculatum, 596 Cunninghamella bertholletiae, 483 Curettage specimen, 3 Cutaneous adnexal polyp, 758–759 Cutaneous appendage disorders, 213–245 miscellaneous, 243–245 transverse section techniques, 213–215 vertical section techniques, 213–215 Cutaneous B-cell lymphoid hyperplasia, 926–940 clinical features, 927 differential diagnosis, 928–929 histopathologic features, 927–928 immunohistological features, 930–931 immunology, 928 Cutaneous B-cell lymphomas, 929–932 classification, 931–932 clinical features, 929 cytomorphological features, 929 histopathologic features, 929 molecular genetic analysis, 931 primary, 931 Cutaneous BM zone, 156 Cutaneous cholesterol embolism, 204 histopathological features, 204 Cutaneous chondromas, 736 Cutaneous ciliated cysts, 551 histopathological features, 551 Cutaneous Crohn disease, 100–101 clinical features, 100 differential diagnosis, 100–101 histopathological features, 100 Cutaneous cysticercosis, 536–537 clinical features, 536 differential diagnosis, 537 histopathological features, 536–537 Cutaneous cysts, 543–554 algorithm for, 543f branchial cleft, 550, 551f bronchogenic, 549–550, 551f ciliated, of vulva, 551–552 cutaneous ciliated, 551 dermoid, 548–549 digital mucous, 552–553 epidermoid, 543–544 with epithelial lining, 543–548 without epithelial lining, 552–554 eruptive vellus hair, 547 follicular hybrid, 548 histopathological features, 553 hybrid epidermoid and apocrine, 554 lined by mixed ciliated epithelium, 546t

Cutaneous cysts (Cont.): lined by stratified squamous epithelium, 534, 545t median raphe, 552 metaplastic synovial, 553–554 not lined by epithelium, 547t pigmented follicular, 548 pilar, 544 pilonidal, 553 proliferating epithelial, 554 proliferating pilar, 544 pseudostratified columnar epithelium, 552 thymic, 549 thyroglossal duct, 550–551, 551f vellus hair, 544–547 Cutaneous deciduosis, 412 Cutaneous dirofilariasis, 534–535 clinical features, 534 differential diagnosis, 535 histopathological features, 534–535 Cutaneous drug eruptions, 281–297 antibody-mediated reactions, 281 blistering drug eruptions, 288 clinical forms of, 282–296, 282t cytokines, 295–296 delayed-type hypersensitivity reactions, 281–282 dilantin hypersensitivity syndrome, 295 drug-associated ichthyosiform dermatoses, 293 drug-associated vasculitis, 292–293 drug-induced linear IgA disease, 288–289 drug-induced lupus erythematosus, 289 drug-induced pemphigoid, 288 drug-induced pemphigus, 288 drug-induced pseudoporphyria cutanea tarda, 288 eczematous, 287–288 erythema multiform, 293–294 erythroderma, 294–295 exanthematous, 282 fixed, 284–285, 285f halogenoderma, 294 histopathological features, 282–296 HIV and, 281 immediate hypersensitivity reactions, 281 immune-complex-mediated reactions, 281 immunologic drug reactions, 281 interstitial granulomatous drug reaction, 295 lichenoid, 283–284, 283t, 284t lymphomatoid, 290–291 photosensitivity, 285–287 pityriasiform eruptions, 293 psoriasiform, 293 pustular, 287 sclerodermatoid tissue reactions, 291 Stevens-Johnson syndrome, 293–294 toxic epidermal necrolysis, 293–294 Cutaneous epithelioid angiomatous nodules, 813 Cutaneous extravascular necrotizing granuloma, 109, 198 Cutaneous focal mucinosis, 368 differential diagnosis, 368 histopathological features, 368

INDEX

Congenital melanoma, 627–632 Congenital self-healing Langerhans histiocytosis, 117 clinical features, 117 differential diagnosis, 117 histopathological features, 117 Congenital smooth muscle hamartoma, 868, 869f Congenital telangiectatic erythema, 59 Conidiobolus, 484 clinical features, 484 histopathological features, 484 Conjunctival Lisch nodules, 886 Connective tissue diseases, 90 diagnosis, 186 seropositivity by, 91t vasculopathies and, 209 Connective tissue nevi, 391–392 clinical features, 392 differential diagnosis, 392 histopathological features, 392 Connective tissue panniculitis, 274 atrophic, 274 Conradi-Hunermann syndrome, 316 clinical features, 316 differential diagnosis, 316 histopathological features, 316 Contact dermatitis, 15–34 allergic, 26t clinical features of, 17 histopathological features of, 17 dermal/protein, 18, 28f irritant, 17 clinical features of, 17 histopathological features of, 17 Conventional melanoma, 663t Conventional spongiosis, 6f Copra itch, 308 Coral reef granuloma, 428 Cordylobia, 309 Corp grains, 147 Corp ronds, 147 Corticosteroids, 271, 274 atrophy, 396 injection sites, 381 Corynebacterium minutissimum, 429, 430, 989 Corynebacterium tenuis, 429 Cowden syndrome, 699, 703, 715 Cowpox, 512, 513 CP. See Cicatricial pemphigoid Crab yaws, 450 Cray-patch ringworm, 460 CREST. See Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia CREST syndrome, 382, 389 Crohn disease, 197 TA and, 805–806 Crow-Fukase syndrome, 347 Cryoglobulinemias, 185, 203–204 clinical features, 204 clinical-pathological associations of, 205t histopathological features, 204 mixed, 185 type I, 185, 204t type II, 185 type III, 185

1047

INDEX 1048

Cutaneous gamma/delta T-cell lymphoma, 922 clinical features, 922 definition, 922 differential diagnosis, 922 genotypic features, 922 histopathological features, 922 Cutaneous Hodgkin lymphoma, 939–940 clinical features, 939 differential diagnosis, 939 histopathologic features, 939 immunology, 939 Cutaneous horn, 600–601, 600f clinical features, 600 differential diagnosis, 601 histopathological features, 600–601 Cutaneous larva migrans, 535–536 differential diagnosis, 535–536 histopathological features, 535 Cutaneous leukemic infiltrates, 940–952 Cutaneous lupus mucinosis, 367 Cutaneous lymphadenoma (CL), 710–711, 712f clinical features, 710–711 differential diagnosis, 711 histopathological features, 711 Cutaneous lymphomas, clinical aspects of, 905–906 Cutaneous mastocytosis, 130–131 clinical features, 130 differential diagnosis, 131 histopathological features, 130 major, 130 minor, 130 Cutaneous melanoma anatomic levels of, 659t classification, 656–665 clinical features, 657–659 differential diagnosis, 662–665 histopathological features, 659–662 intraepithelial component, 659–660 invasive, 660 lentiginous, 656 metastatic, 678, 679t nested, 656 pagetoid, 656, 658f primary, 678, 679t Cutaneous meningioma, 898 differential diagnosis, 898 histopathological features, 898 Cutaneous metastases, 960–973 clinical features, 960–961 general approach to, 961–962 morphological features, 960–961 sites of origin, 960t, 963–965 Cutaneous mucinoses, 362–363, 363t follicular degenerative primary, 369 hamartomatous, 370–371 neoplastic, 370–371 primary, dermal degenerative, 363–369 Cutaneous myxoma, 370–371, 795–796 differential diagnosis, 370–371 histopathological features, 370 Cutaneous necrosis syndrome, 258 Cutaneous neural neoplasms, histopathological features, 885t

Cutaneous neutrophilic small vessel vasculitis, 182t Cutaneous ossification, 383–384 primary, 384 secondary, 384 Cutaneous paragonimiasis, 538 Cutaneous satellites, 677 Cutaneous strongyloidiasis, 536 Cutaneous T-cell lymphomas (CTCL), 7, 71, 74–75, 229, 276, 291 classifications of, 905t clinical features, 74–75 cytogenetic findings in, 908 cytomorphologic basis, 906–907 diagnosis of, 907–809 differential diagnosis, 75 etiopathogenesis of, 908 growth patterns, 906–907 histomorphologic basis, 906–907 histopathological features, 75 juvenile granulomatous, 912 reproduction of morphologic criteria in, 907 special features, 907 staging, 906 Cutaneovisceral angiomatosis with thrombocytopenia (CAT), 811 Cutis hyperelastica, 397–399 Cutis laxa, 403, 404f clinical features, 403 histopathological features, 403 Cutis marmorata telangiectatica congenita (CMTC), 835 Cyclooxgenase-2, 593 Cyclophosphamide, 276 Cyclops, 535 Cyclosporine, 264 CYLD gene, 704f Cylindroma, eccrine, 725 Cystadenoma, 756 Cystic hygromas, 842 IPEH and, 816 Cysticercosis, 530 cutaneous, 536–537 Cysts, 992–993. See also specific types Cytokeratin, 575, 588, 593, 901, 962 extraskeletal chondroma and, 876 Cytokine receptor blockers, 296–297 Cytokines, 295–296 Cytologic atypia, 630 in neurofibromas, 887 Cytologic features, atypical melanocytic nevi, 654 Cytolysis of keratinocytes, 137 spinous layer vesiculation due to, 327–332 Cytolytic dermatitis, 150–152 epidermolytic hyperkeratosis, 150 friction blisters, 150 thermal burns, 150–151 Cytomegalovirus (CMV), 87, 281, 495, 511–512, 511t, 524 acute exanthem of, 496t clinical features, 511 differential diagnosis, 512 histopathological features, 511–512 in HIV, 511

Cytophagic histiocytic panniculitis (CHP), 263–265 clinical features, 264 differential diagnosis, 265 histopathological features, 264 Cytotoxic cutaneous lymphomas, 919 Cytotrophoblasts, 970 D D2-40, 965, 969 D2-40 antibody, 802, 806 angiosarcoma and, 830 KHE and, 824 KS and, 822 LM and, 843 PILA and, 826 THH and, 809 DAA. See Ductal apocrine adenocarcinoma Dabska tumor. See Papillary intralymphatic angioendothelioma Darier disease, 76, 147–148, 148f, 328, 330–331 clinical features, 147, 330 differential diagnosis, 147–148, 330–331 histopathological features, 147, 330 Darier sign, 130 Darling disease. See Classic histoplasmosis Daughter yaws, 450 DCs. See Dendritic cells DDIT3 gene, 867 DEA. See Ductal eccrine adenocarcinoma Deafness syndromes, 319 clinical features, 319 differential diagnosis, 319 DEB. See Dystrophic epidermolysis bullosa Dedifferentiated liposarcoma, 866–867, 866f extraskeletal osteosarcoma and, 879 Deep granuloma annulare, 106–107 clinical features, 106 differential diagnosis, 106–107 histopathological features, 106 Deep penetrating nevus (DPN), 648, 649–650, 650t clinical features, 649–650 histopathologic features, 649–650 Deep perivascular dermatitis, 81–94 Degos lesion, 208f Degos syndrome, 206, 207t clinical features, 206 histopathological features, 206 DEJ. See Dermo-epidermal junction Delayed-type hypersensitivity reactions, 281–282 Dematiaceous fungi, 474–477 Demodex folliculitis, 234–235, 241t clinical features, 234–235 histopathological features, 235 Denaturing, 908 Dendritic cells (DCs), 500, 907 Dendritic reticulum cells, 930 Dengue fever, 499 clinical features, 499 histopathological features, 499 Deposition disorders, 362–385 calcium, bone, and cartilage, 381–383 corticosteroid injection sites, 381 cutaneous mucinoses, 362–363 cutaneous ossification, 383–384

Dermatitis (Cont.): follicular atopic, 19–20 infectious palisaded granulomatous, 110–111 interface, 9, 36–61 cell-poor, 90 of HIV infection, 44 leukocyte infiltration, 36 miscellaneous diseases with features of, 59–61 vacuolar alteration, 36–37 intraepidermal vesicular and pustular, 10t lichenoid interface, 37–40 histopathological features of, 38–39 major psoriasiform, 64–66 nummular, 21, 29f clinical features of, 21 histopathological features of, 21 palisaded granulomatous, 107t palisaded neutrophilic and granulomatous, 109–111 perioral, 99–100, 237–240 perivascular, 81–94 deep, 81–94 superficial, 81–94 photoallergic, 17–18, 28f clinical features of, 18 histopathological features of, 18 photosensitivity, 286 phototoxic, 18 clinical features of, 18 histopathological features of, 18 pityriasiform, 10 psoriasiform, 9, 64–78 radiation, 301–303, 302f, 303f, 394–395 rheumatoid neutrophilic, 126 seborrheic, 22, 31f, 73 clinical features, 22 histopathological features, 22 spongiotic, 7f, 8–9, 8t, 15–34, 138, 306 acute changes in, 7f, 15 algorithm for, 16f chronic changes in, 7f, 15 clinical features in, 17t differential diagnosis for, 16t histopathological features in, 17t secondary changes in, 24t skin diseases with, 16t subacute, 7f, 19f stasis, 25 subepidermal bullous, 10f subepidermal vesicular, 10t superficial perivascular, 11 vacuolar interface, 40–48 vesicular and bullous, 9–10 Dermatitis herpetiformis (DH), 163–165, 164f, 164t, 165f diagnostic tests, 164–165 differential diagnosis, 165 histopathological features, 164 Dermatitis-arthritis syndrome, 431 Dermatobia, 309 Dermatofibroma, 122–124, 775–778, 776t. See also Fibrous histiocytoma cellular, 779f characterizing, 776t clear cell, 777, 779f clinical features, 775

Dermatofibroma (Cont.): differential diagnosis, 777 histopathologic features, 775–777 leiomyoma and, 869 MVH and, 809 variants of, 775t Dermatofibrosarcoma protuberans (DFSP), 770, 786–788, 787f, 866, 972 clinical features, 786–787 dedifferentiated liposarcoma and, 867 differential diagnosis, 787–788 histopathological features, 787 leiomyoma and, 869 leiomyosarcoma and, 871 pigmented, 787, 788f Dermatomycoses, 463 Dermatomyofibroma, 770–771, 771f clinical features, 770 differential diagnosis, 770–771 histopathological features, 770 Dermatomyositis, 51f, 52f, 53, 90, 93–94, 523 amyopathic, 93 clinical features, 53, 93–94 differential diagnosis, 53, 94 histopathological features, 53, 94 immunofluorescence, 94 myopathic, 93t panniculitis in, 273–274 clinical features, 273–274 histopathological features, 273–274 poikiloderma accompanying, 59 Dermatopathia pigmentosa reticularis, 348 Dermatophilus congolensis, 430 Dermatophytosis, 458, 460t chronic, 74 Dermatosis acquired perforating, 333, 333t, 334f drug-associated ichthyosiform, 293 erosive pustular, 232 neutrophilic, 188–190 pigmented purpuric, 88, 193–194 reticulated pigmented, 348 subcorneal pustular, of SneddonWilkinson, 67 transient acantholytic, 149–150, 331–332 Dermatosis papulosa nigra, 567 clinical features, 567 differential diagnosis, 567 histopathological features, 567 Dermis inflammatory process in, 10–14 absence of vascular injury, 10–11 granulomatous reaction patterns, 12 hair follicle, 12–13 panniculitis, 13 presence of vascular injury, 12 skin appendages, 12 sweat apparatus, 13 papillary, alterations of, 14 reticular, alterations of, 14 Dermocystidium, 489 Dermo-epidermal junction (DEJ), 156 Dermoid cysts, 548–549 differential diagnosis, 549 histopathological features, 549

INDEX

Deposition disorders (Cont.): dermal degenerative and inflammatory primary cutaneous mucinoses, 363–369 endogenous pigment deposits, 384–385 follicular degenerative and inflammatory primary cutaneous mucinoses, 369 gout, 380–381 hamartomatous and neoplastic cutaneous mucinoses, 370–371 hyaline angiopathy, 380 hyaline depositions, 371 mucopolysaccharidoses, 384–385 porphyria, 379–380 skin-limited amyloidoses, 374–379 systemic amyloidoses, 371–734 Waldenstrom macroglobulinemia, 379 Dermacentor, 454 Dermal amyloid angiopathy, RAE and, 817 Dermal atrophying and sclerosing lesions, 452–453 Dermal component, Spitz nevus, 637–638 differential diagnosis, 638 Dermal cylindroma, carcinoma ex, 745–746 Dermal degenerative primary cutaneous mucinoses, 363–369 Dermal duct tumor, 730f Dermal inflammatory infiltrates, 11t Dermal leishmanoid, 518 Dermal melanocyte hamartoma, 642 in adipose tissue, 858 clinical features, 642 differential diagnosis, 642 histopathologic features, 642 Dermal melanocytosis, 641 acquired, 642 differential diagnosis of, 642t Dermal nevus, 619f melanoma in, 674–675 clinical features, 674–675 differential diagnosis, 675 histopathological features, 674–675 papillomatous, 672 Dermal nodular proliferations, 630 Dermal processes, 3 Dermal/protein contact dermatitis, 18, 28f Dermatitides, 72–73. See also specific types chronic spongiotic, 72–73 clinical features, 73 differential diagnosis, 73 histopathological features, 73 neutrophilic dermatitides, 275–276 subacute spongiotic, 72–73 clinical features, 73 differential diagnosis, 73 histopathological features, 73 Dermatitis. See also specific types acantholytic, 138–150 differential diagnosis of, 140t atopic, 18–19, 28f, 29t clinical features of, 19 histopathological features of, 19 contact, 15–34 allergic, 17 irritant, 17 dermal/protein contact, 18, 28f eczematous, 72 exfoliative, 24–25, 73

1049

INDEX 1050

Desert rheumatism, 471 Desmin, 962, 973 embryonal rhabdomyosarcoma and, 874 myolipoma and, 862 Desmoglein 1, 143, 288, 421 Desmoplasia, pathogenesis of, 666 Desmoplastic melanoma (DM), 639, 665–668 clinical features, 666 desmoplastic Spitz nevus v., 640t diagnosis of, 667 histopathologic features, 666–668 mixed, 668 mucin in, 669 with neurotropism, 665, 666t without neurotropism, 665 prognosis of, 668 pure, 668 Desmoplastic Spitz nevus, 638–639, 639t clinical features, 638 differential diagnosis, 639 DM v., 640t histopathologic features, 638–639 Desmoplastic trichoepithelioma (DTE), 705–706, 727 clinical features, 705 differential diagnosis, 706 histopathologic features, 705–706 Desmosomes, 587 Desquamative gingivitis (DG), 1007 DFSP. See Dermatofibrosarcoma protuberans DG. See Desquamative gingivitis Diagnosis algorithmic approach to, 3f ANCA-associated, 184 ancillary techniques in, 680 autoimmune diseases, 186 of borderline melanoma, 680 bullosis diabeticorum, 175 bullous pemphigoid, 159 bullous systemic lupus erythematosus, 169 connective tissue diseases, 186 CP, 162 cutaneous T-cell lymphoma, 907–809 DEB, 170 of desmoplastic melanoma, 667 DH, 164–165 drug-induced vasculitis, 186 epidermal changes in, 5f epidermolysis bullosa acquisita, 168 herpes gestationis, 161 HSP, 184 infectious vasculitis, 183–184 JEB, 170 Kindler syndrome, 171 linear IgA disease, 166–167 LPP, 162 of melanoma, 679–680 panniculitis, 251f–252f paraneoplastic vasculitis, 186 protozoal infections, 517 pseudoporphyria, 174 reaction patterns in, 5f serum sickness, 185–186 small-vessel neutrophilic vasculitis, 183–186 urticarial vasculitis, 184–185

DIC. See Disseminated intravascular coagulation Diethylcarbamazine, 532 Diffuse acromelanosis, 347 Diffuse alopecia, 216–217, 221f, 222f causes of, 219t differential diagnosis, 217 drugs causing, 220t histopathological features, 217 Diffuse dermal infiltrates, 11f, 98–133 Diffuse histiocytic infiltrates, 113–122 infectious causes of, 114t xanthomas, 113–114 Diffuse hyperpigmentation disorders, 346 Diffuse lymphocytic-plasma cellular infiltrates, infectious causes of, 128t Diffuse neurofibroma, WDL/ALT and, 866 Diffuse normolipemic plane xanthoma, 114 clinical features, 114 differential diagnosis, 114 histopathological features, 114 Diffuse panniculitis, 269 Digital mucous cyst, 368–369, 552–553 differential diagnosis, 552–553 histopathological features, 368, 552–553 Digital myxoid pseudocyst, 994 clinical features, 994 differential diagnosis, 994 histopathologic features, 994 Digital tumors, 797 DIL. See Drug-induced lupus erythematosus Dilantin hypersensitivity syndrome, 295 clinical features, 295 differential diagnosis, 295 Dilated pore of Winer (DPW), 698, 699f clinical features, 698 differential diagnosis, 698 histopathological features, 698 Diphtheria, 429 clinical features, 429 differential diagnosis, 429 histopathological features, 429 Direct immunofluorescence, 91–93, 165 bullous pemphigoid, 159 Dirofilaria immitis, 534 Dirofilaria repens, 534 Dirofilaria tenuis, 534, 535f Dirofilaria ursi, 534 Discoid lupus erythematosus, 48, 50f, 51–53, 225–226 clinical features, 225 differential diagnosis, 53, 226 histopathological features, 225–226 Dissecting cellulitis, 230, 237f clinical features, 230 differential diagnosis, 230 histopathological features, 230 Disseminated candidiasis, 464, 503 Disseminated cutaneous leishmaniasis, 518 Disseminated histoplasmosis, 473–474 Disseminated intravascular coagulation (DIC), 430, 455 Distal lateral subungual onychomycosis (DLSO), 462 Diuretics, 281 DLSO. See Distal lateral subungual onychomycosis DM. See Desmoplastic melanoma

Donovan bodies, 436, 438 Donovania, 436 DOPA stain, 338, 339 Dorfman syndrome, 318–319 Dorfman-Chanarin syndrome, 318–319 Dowling-Degos disease, 348, 556–557 clinical features, 557 histopathological features, 557 Down syndrome, 383 Downgrading reaction, 432 DPN. See Deep penetrating nevus DPW. See Dilated pore of Winer DQ7, 218 DR4, 218 DR11, 218 Dracontiasis, 535 clinical features, 535 histopathological features, 535 Dracunculus medinensis, 535 Drug deposits, 355 Drug eruptions blistering, 288 cutaneous, 281–297 antibody-mediated reactions, 281 blistering drug eruptions, 288 clinical forms of, 282–296, 282t cytokines, 295–296 delayed-type hypersensitivity reactions, 281–282 dilantin hypersensitivity syndrome, 295 drug-associated ichthyosiform dermatoses, 293 drug-associated vasculitis, 292–293 drug-induced linear IgA disease, 288–289 drug-induced lupus erythematosus, 289 drug-induced pemphigoid, 288 drug-induced pemphigus, 288 drug-induced pseudoporphyria cutanea tarda, 288 eczematous, 287–288 erythema multiform, 293–294 erythroderma, 294–295 exanthematous, 282 fixed, 43–44, 283–285, 285f halogenoderma, 294 histopathological features, 282–296 HIV and, 281 immediate hypersensitivity reactions, 281 immune-complex-mediated reactions, 281 immunologic drug reactions, 281 interstitial granulomatous drug reaction, 295 lichenoid, 283–284, 283t, 284t lymphomatoid, 290–291 photosensitivity, 285–287 pityriasiform eruptions, 293 psoriasiform, 293 pustular, 287 sclerodermatoid tissue reactions, 291 Stevens-Johnson syndrome, 293–294 toxic epidermal necrolysis, 293–294 exanthematous, 282 clinical features, 282 differential diagnosis, 282 histopathological features, 282

Dysplasia epithelioid cell, 654 lichenoid, 1017 Dysplastic conditions, 1016–1018 Dysplastic melanocytic nevi, 651 grading of, 656 Dystrophic epidermolysis bullosa (DEB), 170 abopapulidea, 171t clinical features, 170 Cockayne-Touraine, 171t diagnosis, 170 differential diagnosis, 170 Hallopeau-Siemens, 171t, 327 histopathological features, 170 non-Hallopeau-Siemens, 171t transient, 171t variants of, 171t Dystrophic type deposits, 382 Dystrophy, 988 E EAC. See Erythema annulate centrifugum EAH. See Eccrine angiomatous hamartoma Early-onset varicose veins, SCH and, 807 Ears, elastotic nodules of, 402 Ebola, 503 EBV. See Epstein-Barr virus E-cadherin, 570 Ecchymoses, 179 Eccrine acrospiroma, 731–733, 733f, 737 clinical features, 731–732 differential diagnosis, 733 histopathological features, 732–733 Eccrine angiomatous hamartoma (EAH), 755 Eccrine carcinomas, 738 basaloid, 749 clear cell, 694, 739, 747–748 mucinous, 740t primary tumors, 738–755 simulating metastatic tumors, 746 small cell, 749, 750t Eccrine cylindroma, 725, 727f clinical features, 725 differential diagnosis, 725 histopathologic features, 725 Eccrine differentiation, 585f Eccrine epithelioma, 584, 588 Eccrine glands, TA and, 806 Eccrine hidrocystomas, 756–757 clinical features, 756 differential diagnosis, 757 Eccrine nevi, 755 Eccrine porocarcinoma, 738–739, 739f clinical features, 738 differential diagnosis, 739 histopathologic features, 738–739 Eccrine poroma gap, 728–730, 729t clinical features, 729 differential diagnosis, 729 histopathologic features, 729 Eccrine spiradenoma, 725–726, 727t, 728t, 745–746 differential diagnosis, 726 histopathologic features, 726 Eccrine squamous syringometaplasia, 244

Eccrine syringofibroadenoma, 730–731 clinical features, 730 differential diagnosis, 730–731 histopathologic features, 730 Eccrine tumors, 725 Eclabium, 78 ECs. See Epidermoid cysts Ecthyma, 423 clinical features, 423 differential diagnosis, 423 histopathological features, 423 Ecthyma gangrenosum, 423–424 clinical features, 423 differential diagnosis, 424 histopathological features, 423 Ectomesenchymal chondromyxoid tumor, 1018 clinical features, 1018 different diagnosis, 1018 histopathologic features, 1018 Ectopic cutaneous endosalpingiosis, 413 clinical features, 413 differential diagnosis, 413 histopathological features, 413 Ectopic salivary glands, 414, 415f Ectopic thyroid tissue, 415 histopathological features, 415 Ectopic tissue, 408–417 Ectothrix, 231 Ectropion, 78 Eczema, 72 asteatotic, 23 dyshidrotic, 67 follicular, 19–20 differential diagnosis, 19–20 histopathological features, 19 pompholyx clinical features, 21–22 histopathological features, 21–22 Eczematid-like purpura of Doucas and Kapetanakis, 193 Eczematous dermatitis, 72 Eczematous drug reactions, 287–288 clinical features, 287–288 differential diagnosis, 288 histopathological features, 288 Eczematous onychitis, 989–990 clinical features, 989 differential diagnosis, 989–990 histopathological features, 989 Eddies, 700 Edema, malignant, 434 EGFR. See Epidermal growth factor receptor EH. See Epithelioid hemangioma EHE. See Epithelioid hemangioendothelioma Ehlers-Danlos syndrome, 397–399 clinical features, 397 histopathological features, 397–398 Ehrlichia, 454 Ehrlichia chaffeensis, 451 Elastic globes, 401 Elastic tissue changes, variable, 405 Elastic tissue decreases, 402–405 Elastic tissue increases, 400–401 Elastin, 387–405, 712 alterations of, 400 Elastofibroma, 400 Elastolysis, generalized, 403

INDEX

Drug eruptions (Cont.): fixed, 43–44, 284–285, 285f clinical features of, 43–44, 283 differential diagnosis, 44, 285 histopathological features, 44, 284–285 lichenoid, 39, 283–284, 283t causes of, 284t clinical features, 40, 283 differential diagnosis, 40, 283 histopathological features, 40, 283 lymphomatoid, 290–291 clinical features, 290 differential diagnosis, 291 histopathological features, 290–291 morbilliform, 61 photosensitivity, 285–287 differential diagnosis, 286–287 histopathological features, 286 spongiotic, 27–28 clinical features, 27–28 histopathological features, 27–28 Drug reactions. See Drug eruptions Drug-associated alopecia, 291 Drug-associated ichthyosiform dermatoses, 293 clinical features, 293 differential diagnosis, 293 histopathological features, 293 Drug-associated vasculitis, 292–293 Drug-induced linear IgA disease, 288–289 Drug-induced lupus erythematosus (DIL), 284, 289 clinical features, 289 histopathological features, 289–290 Drug-induced pemphigoid, 288 clinical features, 288 histopathological features, 288 Drug-induced pemphigus, 144–145, 288 clinical findings, 144–145 differential diagnosis, 145 histopathological features, 145 Drug-induced pseudoporphyria cutanea tarda, 288 Drug-induced vasculitis diagnosis, 186 examples of, 186t DTE. See Desmoplastic trichoepithelioma Ductal apocrine adenocarcinoma (DAA), 752 Ductal apocrine carcinoma, 752, 753f, 754f Ductal eccrine adenocarcinoma (DEA), 745, 746–747 clinical features, 746 differential diagnosis, 747 with fibromyxoid stroma, 747 histopathologic features, 746–747 Ductopapillary apocrine carcinoma, 749–750, 751f differential diagnosis, 750 histopathological features, 750 Dupuytren contracture, 773 Dusty melanin, 654, 660 Dwarfism, 385 Dyschromatosis symmetrica, 347 Dyschromatosis universalis hereditaria, 347 Dyskeratosis, 36, 148, 302, 588 Dyskeratosis congenita, 59, 350 histopathological features, 350

1051

INDEX 1052

Elastoma, 400 Elastophagocytosis, 105, 107 Elastosis perforans serpiginosa (EPS), 240, 334–335, 334t, 400–401 clinical features, 334, 400 differential diagnosis, 335, 401 histopathological features, 334–335, 400–401 Elastotic nodules of ears, 402 Elastotic plaques of hands, 402 Elephant skin, 532 Elephantiasis, 533 ELISA. See Enzyme-linked immunosorbent assay EMA. See Epithelial membrane antigen Embryonal rhabdomyosarcoma, 873, 874–875, 874f Enbrel, 297 Encapsulated fat necrosis, 270 Encapsulated lipoma, 270 mobile, 271 Encapsulated neuromas, 886t Encephalitozoon intestinalis, 527 Encephalotrigeminal angiomatosis. See Sturge-Weber syndrome Endemic syphilis, 451 histopathological features, 451 Endometrioma, 412 Endometriosis, 411–413 clinical features, 412 differential diagnosis, 413 histopathological features, 412–413 Endoneurium, 883 Endothelial cells crystalline lamellae in, 806 EH and, 813 IH and, 802 pericytes and, 802 PILA and, 826 Endothrix, 231 Endovascular papillary angioendothelioma, 827 CH and, 827 End-stage scarring alopecia, 235 ENL. See Erythema nodosum leprosum Entamebiasis, 525t Entamoeba histolytica, 517 Enterobacter, 234 Entomophthoromycoses, 484 Entomophthoromycotina, 458, 483 Enzyme-linked immunosorbent assay (ELISA), 533 Eosinophilia-myalgia syndrome, 260 Eosinophilic fasciitis, 259–261, 260t, 261f, 276, 390 clinical features, 260, 390 differential diagnosis, 261 histopathological features, 260–261, 390 Eosinophilic folliculitis, 241–242, 243t, 244f clinical features, 241–242 differential diagnosis, 242 histopathological features, 242 HIV-associated, 242 Eosinophilic infiltrates, 131–133 parasitic causes of, 131t Eosinophilic panniculitis, 275t clinical features, 275 histopathological features, 275

Eosinophilic spongiosis, 6f, 15, 25f Eosinophils, 592, 907 EPD. See Extramammary Paget disease Ephelides, 350 differential diagnosis, 350 histopathological features, 350 Epidermal acanthosis, 27f Epidermal atrophy, 90 Epidermal growth factor inhibition, 296–297 clinical features, 296–297 histopathological features, 297 Epidermal growth factor receptor (EGFR), 296 Epidermal hyperplasia, Spitz nevus, 635 Epidermal inclusion cysts, 992 Epidermal nevi, 556–561 differential diagnosis, 556 histopathological features, 556 Epidermal processes, 3 in diagnosis, 5f Epidermal stem cells, 1022 Epidermis, 1022 alterations of, 14, 313–335 inflammatory conditions without, 6f inflammatory reaction patterns of, 8–10 overlapping, 10 tumors of, 556–602 Epidermodysplasia verruciformis, 508, 591 Epidermoid cysts (ECs), 543–544 histopathological features, 543–544 Epidermolysis bullosa, junctional, 326–327 clinical features, 326–327 Epidermolysis bullosa acquisita, 167–168 classical lesions of, 168f clinical features, 167 diagnostic tests, 168 differential diagnosis, 168 inflammatory, 167 variants, 167 Epidermolysis bullosa dystrophica, 327 clinical features, 327 differential diagnosis, 327 histopathological features, 327 Epidermolysis bullosa simplex, 326 clinical features, 326 differential diagnosis, 326 histopathological features, 326 Epidermolytic acanthoma, 562–563 clinical features, 562 differential diagnosis, 563 histopathological features, 562–563 Epidermolytic actinic keratoses, 571 Epidermolytic disorders, 324–326 Epidermolytic hyperkeratosis, 150, 151f bullous ichthyosis and, 328–329 clinical features, 150 differential diagnosis, 150 histopathological features, 150 Epidermotropic metastatic melanoma, 679f Epidermotropism, 678, 910, 911 Epithelial membrane antigen (EMA), 410, 962 leiomyosarcoma and, 872 Epithelioid angiomatosis. See Bacillary angiomatosis Epithelioid angiosarcoma EHE and, 829 KS and, 831

Epithelioid blue nevus, 643, 644f clinical features, 643 histopathologic features, 643 Epithelioid cell atypical melanocytic nevi, 655 Epithelioid cell dysplasia, 654 Epithelioid cells, 634 Epithelioid fibrous histiocytoma, 777 Epithelioid hemangioendothelioma (EHE), 827–829, 828f, 828t angiosarcoma and, 830 CH and, 827 EH and, 813 extraskeletal chondroma and, 876 SCH and, 808 Epithelioid hemangioma (EH), 811–813, 812f, 812t, 850 aAVM and, 845t BA and, 817 EHE and, 829 MVH and, 809 PILA and, 826 Epithelioid nevus cells, 671 Epithelioid sarcoma, 795, 972 clinical features, 795 differential diagnosis, 795 EHE and, 829 histopathologic features, 795 leiomyosarcoma and, 872 Epithelioid schwannoma, 890 Epithelioma basal cell, 579, 582 cuniculatum, 596 eccrine, 584 superficial, 691–692 Epithelioma-associated keratin amyloidosis, 375–376 EPS. See Elastosis perforans serpiginosa Epstein-Barr virus (EBV), 83, 264, 500, 511, 591, 599, 754 KS and, 819 Epulis fissuratum, 1012 clinical features, 1012 differential diagnosis, 1012 histopathologic features, 1012 Erdheim-Chester disease, 120 Erosive adenomatosis of nipple, 757–758 clinical features, 757 differential diagnosis, 758 histopathologic features, 757 Erosive adenosis, 409 Erosive pustular dermatosis of scalp, 232 Eruptive vellus hair cysts (EVHCs), 547 Erysipelas, 425–426 clinical features, 425 differential diagnosis, 425–426 histopathological features, 425 Erysipeloid, 426 clinical features, 426 histopathological features, 426 Erythema, toxic, of pregnancy, 84 Erythema ab igne, 402 histopathological features, 402 Erythema annulate centrifugum (EAC), 85 trigger factors, 86 Erythema chronicum migrans, 86, 451–452, 453f

EVHCs. See Eruptive vellus hair cysts EVMM. See Extravascular migratory metastasis Ewing sarcoma, 874 alveolar rhabdomyosarcoma and, 875 extraskeletal osteosarcoma and, 879 Ewing sarcoma family, 900, 971 Ewing sarcoma oncogene (EWS), 676 EWS. See Ewing sarcoma oncogene extraskeletal myxoid chondrosarcoma and, 877 EWSR1 gene, 867 Exanthematous drug eruptions, 282 clinical features, 282 differential diagnosis, 282 histopathological features, 282 Excisional specimen, 3 Exfoliative dermatitis, 24–25, 73 Exocytosis, 36 Exogenous agents, 301–310 arachnid reactions, 308 cold reactions, 303–304 heat reactions, 303–304 insect reactions, 308–310 irritation reactions, 301 marine agent reactions, 307–308 radiation reactions, 301–303 trauma reactions, 301 Exogenous pigment deposits, 384–385 Exophiala, 477 Extramammary Paget disease (EPD), 693, 729, 750, 752t, 961 Extraneural growth patterns, 887 Extranodal NK/T-cell lymphoma, 919–921, 920f clinical features, 919 differential diagnosis, 921 genotypic features, 919 histopathologic features, 919 immunophenotypic features, 919 Extraskeletal chondroma, 876 Extraskeletal mesenchymal chondrosarcoma, hemangiopericytoma and, 825 Extraskeletal myxoid chondrosarcoma, 861, 876–877, 877f Extraskeletal osteosarcoma, 878–879, 879f Extravascular migratory metastasis (EVMM), 669 F Fab portion, 517 Facial angiofibroma, 767 clinical features, 767 Factitial panniculitis, 271 clinical features, 271 differential diagnosis, 272 histopathological features, 271 Factor VIII, 595 Factor VIII- related antigen. See von Willebrand factor Factor XIIIa, 889 Familial amyloidotic polyneuropathy, 374 Familial dyskeratotic comedones, 560–561 clinical features, 560 differential diagnosis, 560–561 histopathological features, 560 Familial Hibernian fever, 191 Familial Mediterranean fever (FMF), 190 skin lesions of, 191

Fas/CD95, 43 Fasciitis, 46, 250–276, 276 eosinophilic, 259–261, 260t, 261f, 276, 390 necrotizing, 426, 427–428 nodular, 771–773, 972 proliferative, 772f tryptophan and, 260 Fasciitis ossificans, 878 Fasciitis panniculitis syndrome (FPS), 260, 276 Fasciola hepatica, 538 Fascioliasis, 538–539 clinical features, 538 differential diagnosis, 539 histopathological features, 539 Fat necrosis manifestations of, 250t WDL/ALT and, 866 Favre-Racouchot syndrome, 236 Favus, 231–232 clinical features, 231 differential diagnosis, 231–232 histopathological features, 231 FCH. See Folliculosebaceous cystic hamartoma Festooning, 380 Fetal rhabdomyoma (F-RM), 872–873, 873f Fibrin thrombi, 179 Fibrinoid degeneration, 179f, 182 Fibroblastic rheumatism, 394 clinical features, 394 differential diagnosis, 394 histopathological features, 394 Fibroblastoma, giant cell, 785–786, 786f Fibroblasts, 618 Fibroepithelial polyp, 766–767 clinical features, 766 differential diagnosis, 767 histopathologic features, 766–767 Fibroepithelioma of Pinkus, 585, 587f, 588, 730 Fibrofolliculoma, 712t, 713–714, 714f Fibrohistiocytic tumors, 766–797 benign, 775–781 of childhood, 781–786, 797 intermediate, 775–781 of intermediate malignancy, 786–791 malignant, 791–795 plexiform, 788–789 Fibrolipomas, 536 Fibroma, 993–994, 1012 clinical features, 994, 1012 differential diagnosis, 994, 1012 histopathologic features, 994, 1012 Fibroma of tendon sheath, 769–770 clinical features, 769 differential diagnosis, 770 histopathologic features, 769–770 Fibromatosis inclusion body, 781 infantile digital, 781–782 juvenile hyaline, 784 leiomyoma and, 869 palmar, 773–774 plantar, 773–774 Fibromyxoid proliferative responses, 700 Fibromyxoid stroma, 747

INDEX

Erythema elevatum diutinum, 187–188 clinical features, 187 differential diagnosis, 187–188 GCSF and, 127–128 histopathological features, 187 Erythema gyratum repens, 85–86 Erythema induratum of Bazin, 255, 268–269 histopathological features, 268–269 Erythema induratum of Whitfield, 268 Erythema infectiosum, 498 Erythema marginatum, 86 Erythema multiform, 40–42, 293–294 clinical manifestations of, 40–41 differential diagnosis, 42 histopathological features, 40–41 toxic epidermal necrolysis v., 42t Erythema nodosum, 252–255, 254f, 255t clinical features, 252–253 differential diagnosis, 255 histopathological features, 253–254 reaction pattern, 256f Erythema nodosum leprosum (ENL), 184, 269–270, 433 clinical features, 269–270 histopathological features, 270 HIV and, 270 Erythema toxicum neonatorum (ETN), 31–32, 154t clinical features, 154 differential diagnosis, 154 histopathological features, 154 Erythematous papules, 200f Erythrasma, 429 clinical features, 429 differential diagnosis, 429 histopathological features, 429 Erythroderma, 24–25, 32f, 72, 294–295 bullous congenital ichthyosiform, 328–329, 328t clinical features, 73, 294–295 histopathological features, 73 ichthyosiform, 322–323 ichthyotic, 318–319 Erythrodermatoderma variabilis, 320 clinical features, 320 differential diagnosis, 320 histopathological features, 320 Erythrokeratoderma variabilis, 320 clinical features, 320 differential diagnosis, 320 histopathological features, 320 Erythroleukoplakia, 1016 Erythroplakia, 1017 Erythroplasia of Queyrat, 575, 591 clinical features, 575 differential diagnosis, 575 histopathological features, 575 Escherichia coli, 123, 234, 482 Estrogen, unilateral nevoid telangiectasia and, 835 ETN. See Erythema toxicum neonatorum Etretinate, PG from, 813 Eumeces fasciatus, 451 Eumycetoma, 479–480 clinical features, 479 differential diagnosis, 480 histopathological features, 479–480

1053

INDEX 1054

Fibroosseous pseudotumor, 877–878, 878f extraskeletal chondroma and, 876 Fibroplasia, atypical decubital, 772 Fibrosarcoma, 793–794, 866 clinical features, 793 differential diagnosis, 793–794 histopathologic features, 793 Fibrosis, 392–393 differential diagnosis, 393 histopathological features, 393 Fibrous hamartoma of infancy, 784–785, 785f clinical features, 784 differential diagnosis, 785 histopathologic features, 784–785 Fibrous histiocytoma, 122–124, 669. See also Dermatofibroma aneurysmal, 777f angiomatoid, 777, 789–790 atypical, 776–777, 778f epithelioid, 777 Fibrous papule, 767 Fibrous tissue, 797 Fibrous tract, 213 Fibrous tumors, 766–797. See also specific types benign, 766–776 of childhood, 781–786, 797 of intermediate malignancy, 786–791 malignant, 791–795 solitary, 790–791 Fibroxanthomas, atypical, 778–780 Fifth disease, 496t, 498 Filoviruses, 503 Filterable agent, 495 Fite-Faraco acid-fast stain, 520 Fixed cutaneous disease, 475 Fixed drug eruption, 43–44, 284–285, 285f clinical features of, 43–44, 283 differential diagnosis, 44, 285 histopathological features, 44, 284–285 Flesh-eating bacteria, 427 Flexural skin melanocytic nevi, 625 Floret cells, 861 Florid intraepidermal melanoma, 667 Florid reactive periostitis. See Fibroosseous pseudotumor Flower cells, 952 Fluorouracil, 320 Fluoxetine, 304 FMF. See Familial Mediterranean fever Focal atypical epithelioid cell component, melanocytic nevi with, 649 differential diagnosis, 649 Focal dermal deposition, 364f Focal dermal hypoplasia, 395, 857 clinical features, 395 differential diagnosis, 395 nevus lipomatous superficialis and, 858 Focal epithelial hyperplasia, 1005–1006 clinical features, 1006 differential diagnosis, 1006 histopathologic features, 1006 Focal facial dermal dysplasia, 396 Focal melanocytic aggregates in lymph nodes, 632 in placenta, 632 in skin, 632

Focal panniculitis, 269 Focal parakeratosis, 74 Fogo selvagem, 143 Follicle center lymphoma, 932–933, 932t clinical features, 932 differential diagnosis, 933 immunology, 933 primary cutaneous, 934f Follicle-related mesenchyme, 711 pseudoneoplastic proliferations of, 718–720 Follicular atopic dermatitis, 19–20 Follicular basal cell carcinoma, 585 Follicular cheilitis, 305 Follicular cysts and sinuses, 111–113 clinical features, 112 histopathological features, 112 Follicular degeneration syndrome, 227–229 clinical features, 228 differential diagnosis, 229 histopathological features, 228–229 Follicular degenerative primary cutaneous mucinoses, 369 Follicular eczema, 19–20 differential diagnosis, 19–20 histopathological features, 19 Follicular hybrid cysts, 548 differential diagnosis, 548 histopathological features, 548 Follicular hyperkeratosis, 232–233 clinical features, 233 histopathological features, 233 Follicular infundibulum tumor, 697, 729 clinical features, 697 differential diagnosis, 697 Follicular mucinosis, 12, 910, 911f Follicular myxoma, 714 clinical features, 714 histopathologic features, 714 Follicular occlusion triad, 111, 230 clinical features, 111 differential diagnosis, 111 histopathological features, 111 Follicular spongiosis, 6f with lymphocyte exocytosis, 29f Follicular units, 213 description of, 215t Folliculitis, 233–242. See also specific types acneiform, 236 atypical mycobacterial, 235–236 bacterial, 234, 239f Demodex, 234–235, 241t eosinophlic, 241–242, 243t, 244f fungal, 234 herpes, 505 infectious, 234 Malassezia, 465–467 perforating, 240–241 subtypes, 239t ulerythematosa reticulata, 233 viral, 235 Folliculitis decalvans, 230, 237f clinical features, 230 differential diagnosis, 230 histopathological features, 230

Folliculosebaceous cystic hamartoma (FCH), 703 clinical features, 703 differential diagnosis, 703 histopathologic features, 703 Folliculotropic mycosis fungoides, 910, 911f Fonsecaea pedrosoi, 476 Fontana-Masson, 985 Forchheimer sign, 497 Fordyce granules, 1002 clinical features, 1002 differential diagnosis, 1002 histopathologic features, 1002 Foreign objects, angiosarcoma and, 829 Foreign-body granulomas, 103–104, 416–417 clinical features, 417 differential diagnosis, 103–104, 417 histopathological features, 417 Fowler solution, 573 Fox-Fordyce disease, 20–21, 243–244 clinical features, 243 differential diagnosis, 244 histopathological features, 243 FPS. See Fasciitis panniculitis syndrome Fragile X syndrome, 404 histopathological features, 404 Frambesia tropica, 449 Francisella tularensis, 435, 439 Freckles. See Ephelides French-American-British classification, 941t Friction blisters, 150 clinical features, 150 differential diagnosis, 150 histopathological features, 150 Friction melanosis, 352 histopathological features, 352 F-RM. See Fetal rhabdomyoma Frostbite, 303f, 591 Fungal folliculitis, 234 clinical features, 234 histopathological features, 234 Fungal infections, 458–490. See also specific types dematiaceous fungi, 474–477 histopathological features, 459t morphology, 987t nail plate biopsy, 983–985 systemic, 468–474 Fungal morphology, 984 Fusarium, 463, 484, 487 clinical features, 487 histopathological features, 487 G Ganglion cell choristomas, 900 Ganglioneuroblastoma, 901 Ganglioneuroma, 900, 901 Ganglions, 552 Gangosa, 450 GAP. See Granulomatous angiopanniculitis Gargoylism, 385 GAS. See Group A-beta hemolytic streptococci Gastroenteritis, 197

Giant cells, 618 Giant solitary sebaceous hyperplasia, 690 Giardiasis, 527 Giemsa, 438, 455, 521 Gingival cyst, 1003–1004 clinical features, 1004 differential diagnosis, 1004 histopathologic features, 1004 Gingival epulides, 1013–1014 Gingival nodules, 1014 Glandular lumina, 729 Glenosporella loboi, 488 Glenosporopsis, 488 Glial fibrillary acidic protein (GFAP), 962 Glial heterotopia, 415 Glomangioma. See Glomuvenous malformations Glomangiomatosis, 840–841 Glomangiomyomas, 840 Glomangiopericytoma, 841 hemangiopericytoma and, 825 SFTS and, 825 Glomangiosarcoma, 840–841 Glomeromycota, 483 Glomeruloid hemangioma (GH), 805, 806, 815–816, 816f Glomerulonephritis, 197 Glomus tumor, 839–841, 840f, 840t, 841f, 996 clinical features, 996 differential diagnosis, 996 histopathologic features, 996 Glomuvenous malformations (GVMs), 839–841, 840t VM and, 839 Glossina palpalis, 520 Glucagonoma syndrome, 77–78 clinical features, 77 histopathological features, 77–78 Glucose transporter molecule isoform 1 (GLUT-1), 803 KHE and, 824 NICH and, 805 RICH and, 805 VH and, 809 GLUT-1. See Glucose transporter molecule isoform 1 Glut-1, 261, 889 Glycosaminoglycans, 385, 581 GMCSF. See Granulocyte-macrophage colony-stimulating factor GMS. See Gomori methenamine silver Gnathostoma, 133, 275, 535 Gnathostoma spinigerum, 537f Gnathostomiasis, 536 Golberger, Joseph, 76 Gold deposition, 355 histopathological features, 355 Goldenhar syndrome, 408 Gomori methenamine silver (GMS), 429, 524 Gonococcal infections, 431 clinical features, 431 differential diagnosis, 431 histopathological features, 431 Good patterns, 5 Gorlin syndrome, 589 Gottran syndrome, 400 Gottron papule, 93

Gougerot-Blum disease, 193 Gout, 380–381 histopathological features, 381 Graft-versus-host disease, 285, 315 Graham-Little syndrome, 226 Gram stain, 455 Granular basal cell carcinoma, 581 adult rhabdomyoma and, 873 Granular cell tumor, 894–895, 895t clinical features, 894, 1018 different diagnosis, 1018 differential diagnosis, 895 histopathologic features, 894–895, 1018 Granular lumina, 412f Granular parakeratosis, 317, 592 clinical features, 322 differential diagnosis, 322 histopathological features, 322 Granulocyte colony-stimulating factor (GCSF), 295, 296 erythema elevatum diutinum and, 127–128 Granulocyte-macrophage colony-stimulating factor (GMCSF), 123 Granulocytic sarcoma, 946–947 clinical features, 946 differential diagnosis, 947 histochemical findings, 946–947 histopathologic features, 946 immunohistochemical findings, 946–947 Granuloma. See also specific types actinic, 107, 404 annulare, 104–105 clinical features, 104–105 deep, 106–107 interstitial form, 105–106 candidal, 464 Churg-Strauss, 109 coral reef, 428 cutaneous extravascular necrotizing, 109, 198 foreign-body, 103–104, 416–417 differential diagnosis, 103–104 lethal midline, 99 lipophagic, 257 Majocchi, 240f palisading, 261 pyogenic, 803t, 813–815, 814f, 814t, 823t, 1013f traumatic ulcerative, 1006 Granuloma faciale, 127–128, 187, 188, 189t clinical features, 188 differential diagnosis, 188 histopathological features, 188 Granuloma fissuratum, 561 clinical features, 561 differential diagnosis, 561 histopathological features, 561 Granuloma gravidarum. See Pyogenic granuloma Granuloma inguinale, 436–437, 440t clinical features, 436 differential diagnosis, 437 histopathological features, 436 Granuloma pyogenicum. See Pyogenic granuloma

INDEX

Gastrointestinal carcinoma, 967–968 clinical features, 967 differential diagnosis, 967–968 histopathologic features, 967 immunohistochemistry, 968 special stains, 968 GCDFP. See Gross cystic disease fluid protein GCSF. See Granulocyte colony-stimulating factor Generalized elastolysis, 403 Generalized eruptive histiocytosis, 120 clinical features, 120 differential diagnosis, 120 histopathological features, 120 Generalized essential telangiectasia, 832, 847, 848f HHT and, 834 Generalized exanthematous pustulosis, 153 Generalized hyperpigmentation disorders, 346 Generalized lentiginosis, 349 Generalized melanosis in metastatic melanoma, 352 Generalized myxedema, 363–364 histopathological features, 364 Generalized staphylococcal scalded skin syndrome, 147 clinical features, 147 histopathological features, 147 Genital rhabdomyoma, 873 Genital skin melanocytic nevi, 624–625 clinical features, 625 differential diagnosis, 625 histopathological features, 625 Genital tract tumors clinical features, 970 differential diagnosis, 970 histopathologic features, 970 immunohistochemistry, 970 special stains, 970 Genotyping, 907 Geographic tongue, 68 Germinal center cells, 929 Germinative follicular epithelium tumors, 702 GFAP. See Glial fibrillary acidic protein GH. See Glomeruloid hemangioma Gherkin-Goltz syndrome, 589 Ghost cells, 702 Gianotti-Crosti syndrome, 28–29, 34f, 498 clinical features of, 28–29 histopathological features of, 28–29 Giant cell arteritis, 203 Giant cell fibroblastoma, 785–786, 786f APL and, 844 clinical features, 785 differential diagnosis, 786 histopathologic features, 785–786 Giant cell tumor, 780–781 clinical features, 780–781 extraskeletal chondroma and, 876 Giant cell tumor of tendon sheath, 780–781 clinical features, 780 histopathological features, 781 Giant cell variant malignant fibrous histiocytoma, 791–792

1055

INDEX 1056

Granulomatosis orofacial, 1009–1010 vasculitis with, 194–195 Wegener, 109, 184, 197–199, 198t Granulomatous angiopanniculitis (GAP), 275 Granulomatous black skin, 404, 912 Granulomatous dermatitis infectious palisaded, 110–111 palisaded neutrophilic, 109–111 Granulomatous diseases, 404 Granulomatous infiltrates, 98–104 Granulomatous inflammation, inflammatory conditions with, 6f Granulomatous mycosis fungoides, 911–912, 912f Granulomatous reaction patterns, 12 Granulomatous rosacea, 243f Granulomatous slack skin, 913f Granulomatous vasculitis, 196f differential diagnosis, 196f Graphite, 354f Graves disease, 364 Grenz zone, 778 Grocer’s itch, 308 Groove sign, 443 Gross cystic disease fluid protein (GCDFP), 963 Group A-beta hemolytic streptococci (GAS), 276 Grover disease, 328, 331–332, 332f. See also Transient acantholytic dermatosis clinical features, 332 differential diagnosis, 332 histopathological features, 332 Guttate psoriasis, 66f, 67f GVMs. See Glomuvenous malformations Gyrate erythemas, 85–86 clinical features, 85–86 differential diagnosis, 86 histopathological features, 86 H HAART. See Highly active antiretroviral therapy Haber syndrome, 556 Haemophilus, 437 Haemophilus ducreyi, 437, 446 Hailey-Hailey disease, 331 clinical features, 331 differential diagnosis, 331 histopathological features, 331 Hair follicle, 1022 disorders, 12–13 pseudoneoplastic proliferations of, 718–720 Hair follicle hamartoma, 718 differential diagnosis, 718 Hair follicle nevus, 719 clinical features, 719 differential diagnosis, 719 histopathologic features, 719 Hair follicle tumors, 689–720 Hairs anagen, 215t catagen, 218 telogen, 215t terminal, 213, 215t vellus, 213, 215t vellus-like, 213

Hairy cell leukemia, 951–952 clinical features, 951 histochemical features, 951–952 histopathologic features, 951 immunohistochemical features, 951–952 Haley-Haley disease, 148–149 clinical features, 148 differential diagnosis, 148–149 histopathological features, 148 Hallermann-Streiff syndrome, 222 Hallopeau-Siemens syndrome, 171t, 327 Halo atypical melanocytic nevi, 655 Halo basal cell carcinoma, 580 Halo nevus, 620–621, 663 atypical, 663 clinical features, 620 differential diagnosis, 621 histopathological features, 620–621 Halo Spitz nevus, 639 Halogenodermas, 111, 113t, 294 clinical features, 111, 294 differential diagnosis, 111 histopathological features, 111, 294 Hamartomas, 857 basaloid follicular, 588, 708–709, 709f dermal melanocyte, 642 eccrine angiomatous, 755 fibrous, of infancy, 784–785, 785f hair follicle, 718 neurofollicular and pilar neurocristic, 719–720 of peripheral nerve, 883–884 pilar neurocristic, 648 Hamartomatous cutaneous mucinoses, 370–371 Hamazaki-Wasserman bodies, 101 Hand, foot, and mouth disease, 496t, 499 clinical features, 499 differential diagnosis, 499 histopathological features, 499 Hands collagenous plaques of, 402 elastotic plaques of, 402 Hanger-Rose test, 440 Hanging groin, 532 Hansen disease. See Leprosy Hantaviruses, 503 Harlequin ichthyosis, 316–317 clinical features, 316–317 differential diagnosis, 317 histopathological features, 317 Hartnup disease, 77 Hashimoto-Pritzker disease. See Congenital self-healing Langerhans histiocytosis Hat bulb, 215t HBID. See Hereditary benign intraepithelial dyskeratosis hCG. See Human chorionic gonadotropin HDs. See Hemidesmosomes Heat reactions, 303–304 clinical features, 303–304 differential diagnosis, 304 histopathological features, 304 Helicobacter pylori, 83, 1006 Helminthic diseases, 530–540. See also specific diseases

Helper T cells, 218 Hemangioma, 589 angiolipoma and, 859 epithelioid, 809, 811–813, 812f, 812t, 817, 826, 829, 850 aAVM and, 845t BA and, 817 EHE and, 829 MVH and, 809 PILA and, 826 glomeruloid, 805, 806, 815–816, 816f hobnail APL and, 844 PILA and, 826 RH, 826 infantile, 802–805, 803f, 804f clinical features of, 803t endothelial cells and, 802 KMS and, 824 platelets and, 802 lobular capillary AAD and, 819 BA and, 817 cherry angioma and, 850 IPEH and, 816 KS and, 821 MVH and, 809 PWSs and, 832 TA and, 805 microvenular, 808–809, 809f, 809t acute myelogenous leukemia and, 809 dermatofibroma and, 809 Epithelioid hemangioma (EH) and, 809 HHV and, 809 histologic features of, 823t KS and, 809 PG and, 809 POEMS and, 809 sclerosing hemangioma and, 809 TA and, 809 THH and, 809 Wiskott-Aldrich syndrome and, 809 papillary, 807, 807f GH and, 807 hyaline globules and, 807 NICH and, 807 POEMS and, 807 rapidly involuting congenital, 804–805 sclerosing, 776, 809, 811 sinusoidal, 838 spindle cell, 807–808, 807t, 808f angiosarcoma and, 807, 830 CD31 and, 808 CD34 and, 808 CH and, 827 early-onset varicose veins and, 807 epithelioid hemangioendothelioma and, 808 human herpes virus and, 808 Klippel-Trenaunay syndrome and, 807 KS and, 808, 823 Maffucci syndrome and, 807–808, 838 Milroy disease and, 807 phlebolith and, 808 Ulex europaeus lectin-1 and, 808 VM and, 839 von Willebrand factor and, 808

Herpes gestationis, 160, 161–162 clinical features, 161 diagnostic tests, 161 differential diagnosis, 161–162 histopathological features, 161 Herpes simplex virus, 504–515, 505f clinical features, 504 histopathological features, 504 Herpes zoster, 496t, 504–506 clinical features, 505–506 differential diagnosis, 506 histopathological features, 506 Herring-bone fascicles, 797 Herring-bone pattern, 896 Heterotopic meningeal tissue, 897–898 clinical features, 897 differential diagnosis, 897–898 histopathologic features, 897 Heterotopic neuroblastic tissue, 900–901 clinical features, 900–901 differential diagnosis, 901 histopathological features, 901 Heterotopic neuroglial tissue, 898–899 clinical features, 899 differential diagnosis, 900 histopathologic features, 899–900 HHF35, 116 HHT. See Hereditary hemorrhagic telangiectasia HHV. See Human herpes virus Hibernoma, 863–864, 863f, 863t adult rhabdomyoma and, 873 Hidradenitis, 13 neutrophilic eccrine, 244 palmoplantar eccrine, 245 Hidradenitis suppurativa, 114f, 238, 241t, 242f clinical features, 238 histopathological features, 238 Hidradenocarcinomas, 732, 748 Hidradenoma clear cell, 732 poroid, 729 solid and cystic, 732 tubulopapillary, 731 Hidradenoma papilliferum (HP), 731, 734–735, 736f clinical features, 734 differential diagnosis, 734–735 histopathological features, 734 Hidradenomas, nodular, 588 Hidroa vacciniforme-like lymphoma, 921 Hidrocystomas apocrine, 756–757 eccrine, 756–757 Hidrotic ectodermal dysplasia, 320 High magnification, 4 High-grade pleomorphic sarcoma, 791 Highly active antiretroviral therapy (HAART), 468, 473 Hirsutism, 385 Histamine, 81–82 Histiocytoid hemangioma. See Epithelioid hemangioendothelioma; Epithelioid hemangioma Histiocytoma aneurysmal fibrous, 777f angiomatoid fibrous, 777, 789–790, 789t, 790f

Histiocytoma (Cont.): atypical fibrous, 776–777, 778f epithelioid fibrous, 777 fibrous, 122–124, 669 hemosiderotic, 776 malignant fibrous, 791–792 giant cell variant, 791–792 hemangiopericytoma and, 825 pleomorphic, 791–792 progressive nodular, 122 Histiocytosis, 113 benign cephalic, 119–120 congenital self-healing Langerhans, 117 generalized eruptive, 120 hereditary progressive mucinous, 122 indeterminate cell, 118 Langerhans cell, 116–117 Histoid leprosy, 432 Histoplasma capsulatum, 465, 520 Histoplasmosis, 459t African, 474 chronic pulmonary, 473 classic, 473–474 disseminated, 473–474 HIV, 468. See also Acquired immunodeficiency syndrome acute exanthem of, 496t, 499–502 clinical features, 500 cutaneous manifestations of, 500–502 differential diagnosis of, 502 histopathological features, 500 bacillary angiomatosis in, 501 basal cell carcinoma in, 579 in classic histoplasmosis, 473 cutaneous drug eruptions and, 281 cutaneous manifestations of, 500t cytomegalovirus in, 511 in ENL, 270 eosinophilic folliculitis associated with, 242 interface dermatitis of, 44 clinical features, 44 differential diagnosis, 44 histopathological features of, 44 KHE and, 824 KS and, 819, 820 leishmaniasis in, 518 lipoatrophy and, 274 lipodystrophy and, 274 Pneumocystis carinii and, 501 in scabies, 75 spread of, 500 syphilis in, 501 HLA associations, 306 HLA-B6, 557 HLA-B51, 186 HLA-DR antigens, 587 HMB45, 669, 780, 962, 965 angiomyolipoma and, 862 leiomyosarcoma and, 872 HMGA2 gene, 858 Hobnail hemangioma. See also Targetoid hemosiderotic hemangioma APL and, 844 PILA and, 826 RH, 826 Hodgkin disease, 146 Homer-Wright rosettes, 901

INDEX

Hemangioma (Cont.): targetoid hemosiderotic, 809–811, 810f, 810t APL and, 810, 811 D2-40 antibody and, 809 HHV and, 810 histologic features of, 823t KS and, 810–811, 823 MVH and, 809 Retiform hemangioendothelioma and, 810 RH and, 811, 827 sclerosing hemangioma and, 811 Ulex europaeus lectin-1 and, 810 Vascular endothelial growth factor and, 809 von Willebrand factor and, 810 verrucous, 809, 836–838, 837f, 837t Hemangioma with Kaposi sarcoma-like features. See Kaposiform hemangioendothelioma Hemangiopericytoma, 824–825, 825f dedifferentiated liposarcoma and, 866 myolipoma and, 862 SFTS and, 825 Hematopoiesis, 384 Hematopoietic malignancies, 961 Hematoxylin, 105, 213, 341 Heme synthase, 380 Hemidesmosomes (HDs), 156, 587 Hemochromatosis, idiopathic, 354 Hemolymphatic malformation, 842 Hemosiderin, 354–355 KS and, 821 VH and, 837 Hemosiderotic histiocytoma, 776 Hendersonula toruloidea, 462, 463 Henoch-Schönlein purpura (HSP), 191, 196, 281, 498 angioma serpiginosum and, 836 diagnosis, 184 Heparin, 383 Hepatitis A virus, 503 Hepatitis B antibodies, 183 Hepatitis B virus, 503 Hepatitis C, 37, 183, 185, 365 unilateral nevoid telangiectasia and, 835 Hepatomegaly, 319 Hepatosplenomegaly, 385, 924 Herald patch, 73 Hereditary benign intraepithelial dyskeratosis (HBID), 1002 Hereditary benign telangiectasia, 832, 833 HHT and, 834 Hereditary hemorrhagic telangiectasia (HHT), 832, 833–834, 834t, 835f Hereditary progressive mucinous histiocytosis, 122 clinical features, 122 differential diagnosis, 122 histopathological features, 122 Hermansky-Pudlak syndrome, 342–343 clinical features, 342 histopathological features, 342–343 Herpes folliculitis, 505

1057

INDEX 1058

Horizontal growth phase, 657 Hortaea werneckii, 477 Host response, 654 HP. See Hidradenoma papilliferum HPV. See Human papillomavirus HRAS gene, 636 HSP. See Henoch-Schönlein purpura HTLV-1. See Human T-lymphotropic virus 1 Human chorionic gonadotropin (hCG), 963 Human growth hormone, 274 Human herpes virus (HHV), 73, 281, 498, 510, 850 APL and, 844 BA and, 817 KHE and, 824 KS and, 819, 823, 831 MVH and, 809 RH and, 827 SCH and, 808 THH and, 810 Human papillomavirus (HPV), 495, 506–510, 507t, 508f, 562, 567, 570, 590, 591, 1005 clinical features, 506–508 differential diagnosis, 509–510 infection with, 508–509 Human T-lymphotropic virus 1(HTLV-1), 908 Humira, 297 Hutchinson melanotic freckle, 655 Hutchinson sign, 659 Hutchinson-Gilford syndrome, 399–400 Hyaline angiopathy, 380 Hyaline depositions, 371 Hyaline globules KS and, 821 PH and, 807 Hyalinizing spindle cell tumor, 794 Hyalinizing Spitz nevus, 639 Hyalinosis cutis et mucosae, 378 differential diagnosis, 378 histopathological features, 378 Hyalohyphomycosis, 477, 487 Hyaluronic acid, 595, 792 Hybrid epidermoid and apocrine cyst, 554 differential diagnosis, 554 histopathological features, 554 Hydralazine, 289 Hydroa vacciniforme, 90, 305, 306 Hydrocephalus, 632 Hydroquinone, 353 Hyperchromatism, 671 Hypereosinophilic syndrome, 133 clinical features, 133 differential diagnosis, 133 histopathological features, 133 Hyperimmunoglobulinemia D, 190 Hyperkeratosis, 5f, 90, 314t, 837 epidermolytic, 150, 151f without epidermolytic change, 313, 313f follicular, 232–233 subungual, 983 Hyperkeratotic seborrheic keratosis, 565 Hyperorthokeratosis, 313–317, 314t clinical features, 314 histopathological features, 314–315 prominent stratum granulosum, 317–322 and prominent stratum granulosum, 317–322

Hyperoxaluria, 259 Hyperparakeratosis, 322–324 granular parakeratosis, 322 Hyperpigmentation disorders, 339f, 346–357 acromelanosis, 347 Addison disease, 346 clofazimine-induced, 123 Crow-Fukase syndrome, 347 diffuse, 346 generalized, 346 Nelson syndrome, 346 POEMS, 347 postinflammatory, 352 differential diagnosis, 352 histopathological features, 352 zosteriform, 352 Hyperplasia atypical lymphocytic, 908 cutaneous B-cell lymphoid, 926–929 focal epithelial, 1005–1006 inflammatory papillary, 1012–1013 lymphoid, 905 sebaceous, 689–691 syringolymphoid, 911–912 verrucous, 1017 Hypertensive portal gastropathy, RAE and, 817 Hypertrichosis, 380 Hypertriglyceridemia, 265 Hypertrophic collagenoses, 391–394 Hypertrophic keloid, 766 clinical features, 766 differential diagnosis, 766 histopathological features, 766 Hypertrophic lichen planus, 39f Hypertrophic lupus erythematosus, 48 Hypertrophic scars, 392–393, 766 clinical features, 766 differential diagnosis, 393, 766 histopathologic features, 766 histopathological features, 393 Hypervitaminosis D, 258 Hyphae, 458 Hypogranulosis, 67 Hypomelanosis of Ito, 344 differential diagnosis, 344 histopathological features, 344 Hypopigmentation disorders, 338–346, 342t Ash leaf spots, 343 Chédiak-Higashi syndrome, 343 Hermansky-Pudlak syndrome, 342–343 hypomelanosis, 345 hypomelanosis of Ito, 344 idiopathic guttate hypomelanosis, 344 incontinentia pigmenti achromians, 344 nevus anemicus, 345–346 nevus depigmentosus, 344–345 oculocutaneous albinism, 341–342 piebaldism, 338–339 pityriasis alba, 345 postinflammatory leukoderma, 345 vitiligo, 340–341 Vogt-Koyanagi-Harada syndrome, 340–341 Hypopigmented blue nevus, 645 Hypospadia, CMTC and, 835 Hypotrichosis, congenital, 228f

I Iatrogenic calcinosis, 383 histopathological features, 383 ICAM-1. See Intercellular adhesion molecule 1 Ichthyophorus, 489 Ichthyosiform erythroderma, 322 Ichthyosis, bullous, 328–329 Ichthyosis bullosa of Siemens, 329 clinical features, 329 differential diagnosis, 329 histopathological features, 329 Ichthyosis follicularis, 321 clinical features, 321 differential diagnosis, 321 histopathological features, 321 Ichthyosis hystrix of Curth and Macklin, 329 clinical features, 329 differential diagnosis, 329 histopathological features, 329 Ichthyosis vulgaris, 313–315 Ichthyotic erythroderma, neutral lipid storage disease, 318–319 Idiopathic guttate hypomelanosis, 344 clinical features, 344 histopathological features, 344 Idiopathic hemochromatosis, 354 differential diagnosis, 354 histopathological features, 354 Idiopathic lobular panniculitis, 261 Idiopathic type deposits, 382–383 IEE. See Intraepidermal epithelioma IFN. See Interferons IgA. See Immunoglobulin A IgA pemphigus, 145 clinical features, 145 differential diagnosis, 145 histopathological features, 145 IgC. See Immunoglobulin C IgE. See Immunoglobulin E IgG. See Immunoglobulin G IgM. See Immunoglobulin M IH. See Infantile hemangioma IL-1. See Interleukin 1 IL-5. See Interleukin 5 ILVEN. See Inflammatory linear verrucous epidermal nevus Immature nerve sheath myxomas, 892 Immediate hypersensitivity reactions, 281 Immune-complex-mediated reactions, 281 Immune-mediated conditions, 1006–1014 Immunoblasts, 910 Immunocytochemistry, 313 Immunofluorescence dermatomyositis, 94 direct, 91–93, 159, 165 IgG, 144 indirect, 92–93, 159 lupus erythematosus, 91t mixed connective tissue disease, 94 Immunoglobulin A (IgA), 183 Immunoglobulin C (IgC), 167 Immunoglobulin E (IgE), EH and, 813 Immunoglobulin G (IgG), 138, 140, 185, 340, 534 immunofluorescence, 144 Immunoglobulin M (IgM), 185, 523

Infectious cellulitis, 426t Infectious folliculitis, 234 Infectious mononucleosis, 496t, 502–503 clinical features, 502–503 Infectious palisaded granulomatous dermatitis, 110–111 clinical features, 111 differential diagnosis, 111 histopathological features, 111 Infectious vasculitis, diagnosis, 183–184 Infiltrates. See also specific types acute myeloid leukemia, 942t bandlike, 906 chronic lymphocytic leukemia, 948t of chronic myeloid leukemia, 947t cutaneous leukemic, 940–952 dermal inflammatory, 11t diffuse dermal, 11f, 98–133 diffuse histiocytic, 113–122 diffuse lymphocytic-plasma cellular, 128t eosinophilic, 131–133 parasitic causes of, 131t granulomatous, 98–104 interstitial lymphocytic, 160f Jessner lymphocytic, 86 leukemic, 905–952 lymphocytic-plasma cellular, 128–129 lymphoid, 905–952 mast cell, 130–131 neutrophilic, 124–127 infectious causes of, 125t nodular dermal, 11f, 98–133 palisaded granulomatous, 104–111 peribulbar lymphocytic, 219 perivascular inflammatory cell, 81t, 160f, 635 suppurative granulomatous, 111–113 Infiltrative basal cell carcinoma, 583, 584f, 588, 706 Inflammatory angiomatous nodules with abnormal blood vessels. See Epithelioid hemangioma Inflammatory conditions without epidermal alterations, 6f with granulomas, 6f with granulomatous inflammation, 6f without vascular injury, 6f Inflammatory lesions, features of, 5–8 Inflammatory linear verrucous epidermal nevus (ILVEN), 60, 76, 114, 558–559 clinical features, 76, 558 differential diagnosis, 76, 559 histopathological features, 76, 558–559 Inflammatory morphea, 387 Inflammatory papillary hyperplasia, 1012–1013 clinical features, 1012–1013 differential diagnosis, 1013 histopathologic features, 1013 Inflammatory primary cutaneous mucinoses, 363–369, 369 Inflammatory reaction patterns of dermis, 10–14 absence of vascular injury, 10–11 granulomatous reaction patterns, 12 hair follicle, 12–13 panniculitis, 13 presence of vascular injury, 12 skin appendages, 12 sweat apparatus, 13

Inflammatory reaction patterns (Cont.): of epidermis, 8–10 interface dermatitis, 9 overlapping, 10 psoriasiform dermatitis, 9 spongiotic dermatitis, 8–9 vesicular and bullous dermatitis, 9–10 major, 8–14 Inflammatory vascular reaction, 180f Infliximab, 297 Infrabasilar, 6f Infundibular adenoma, 692 Infundibular cysts, 543 Infundibulocystic basal cell carcinoma, 584–585, 586 Inherited autoinflammatory syndromes, 190–199 ANCA-associated systemic vasculitides, 195–196 bowel-associated dermatosis-arthritis syndrome, 191 Churg-Strauss syndrome, 196–197 lymphocytic vasculitides and vascular reactions, 192 lymphomatoid vascular reactions, 194 lymphomatoid vasculitis, 194 microscopic polyarteritis nodosum, 199 perniosis, 192–193 pigmented purpuric dermatitis, 193–194 pyoderma gangrenosum, 191–192 vasculitis with granulomatosis, 194–195 Wegener granulomatosis, 197–199 Inherited patterned lentiginosis, 347 Inherited pityriasis rubra pilaris, 321–322 clinical features, 321 differential diagnosis, 321–322 histopathological features, 321 Inhibin, pleomorphic liposarcoma and, 868 Insect reactions, 308–310 clinical features, 309 differential diagnosis, 310 Insulin, 274 Insulin amyloidosis, 376 α6β4 integrin, 156 Intercellular adhesion molecule 1 (ICAM-1), 39, 587 PILA and, 826 Interface dermatitis, 9, 36–61. See also specific types algorithm, 36 cell-poor, 90 of HIV infection, 44 clinical features, 44 differential diagnosis, 44 histopathologic features, 44 leukocyte infiltration, 36 miscellaneous diseases with features of, 59–61 vacuolar alteration, 36–37 Interferons (IFN), 295, 296 Interleukin 1 (IL-1), 81–82, 296, 425 Interleukin 5 (IL-5), 471 Intermediate lesions, 576–578 Intermediate magnification, 4 International Society for the Study of Vascular anomalies (ISSVA), 802, 802t, 831

INDEX

Immunohistochemical findings acute myeloid leukemia, 943 adult T-cell lymphoma/leukemia, 952 breast carcinoma, 964–965 chronic lymphocytic leukemia B-cell type, 949 chronic myeloid leukemia, 946 EHE and, 829 extraskeletal osteosarcoma and, 879 gastrointestinal carcinoma, 968 genital tract tumors, 970 granulocytic sarcoma, 946–947 hairy cell leukemia, 951–952 KS and, 831 leiomyosarcoma and, 871 lung carcinoma, 966–967 myelodysplastic syndrome, 948 myelomonocytic leukemia, 944 neuroendocrine carcinoma, 971 oral carcinomas, 968 sarcoma, 972–973 schwannoma, 890 sinonasal carcinomas, 968 sweat gland tumors, 758t, 759 T-cell prolymphocytic leukemia, 950–951 thyroid tumors, 970–971 urinary tract tumors, 969 Immunologic drug reactions, 281 Immunoperoxidase, 455 Immunophenotyping, 907, 912 Immunoreactants, 48 Impetigo, 152, 421–423 bullous, 152 clinical features, 152, 422 differential diagnosis, 152, 422–423 histopathological features, 152, 422 Implantation epidermoid cysts, 992 In situ hybridization (ISH), 517 Inclusion body fibromatosis, 781 Incontinentia pigmenti, 30–32, 34f, 349–350 clinical features of, 31 differential diagnosis, 31–32, 349–350 histopathological features of, 31, 349 Indeterminate cell histiocytosis, 118 Indirect immunofluorescence, 92–93 bullous pemphigoid, 159 Infantile acropustulosis clinical features, 154 differential diagnosis, 154 histopathological features, 154 Infantile digital fibromatosis, 781–782 clinical features, 781–782 differential diagnosis, 782 histopathological features, 782 Infantile hemangioma (IH), 802–805, 803f, 804f clinical features of, 803t endothelial cells and, 802 KMS and, 824 platelets and, 802 Infantile hemangiopericytoma, 783 Infantile myofibromatosis, 782–784, 783t clinical features, 782 differential diagnosis, 783 histopathologic features, 782–783 Infection-related panniculitis, 267–268, 269f clinical features, 267–268 differential diagnosis, 268 histopathological features, 268

1059

INDEX 1060

Interstitial granuloma annulare, 105–106 differential diagnosis, 105–106 histopathological features, 105 Interstitial granulomatous drug reaction, 295 clinical features, 295 histopathological features, 295 Interstitial lymphocytic infiltrates, 160f Intracellular edema, 137 Intracytoplastic lumina, 963 Intradermal poroma, 730f Intraepidermal blistering, 136f, 137f, 139t Intraepidermal carcinomas, 573–576 Intraepidermal component, 636 lentiginous, 660–662 pagetoid, 660 Intraepidermal epithelioma (IEE), 575 Intraepidermal melanoma, florid, 667 Intraepidermal pagetoid spread of melanocytes, 630 Intraepidermal vesicular and pustular dermatitis, 10t Intraepidermal vesiculopustular diseases, 136–154. See also specific disorders definitions, 136–138 Intraepithelial component adjacent, 662 in cutaneous melanoma, 659–660 Intraepithelial epithelioma, 575–576 of Borst-Jadassolm, 575 clinical features, 576 differential diagnosis, 576 histopathological features, 576 Intralaminar melanin, 986 Intramuscular myxoma, extraskeletal myxoid chondrosarcoma and, 877 Intraneural growth patterns, 887 Intrastratum spinosum, 6f Intravascular bronchioloalveolar tumor. See Epithelioid hemangioendothelioma Intravascular disseminated angiosarcoma, angioendotheliomatosis and, 817 Intravascular large B-cell lymphoma, 937 clinical features, 937 differential diagnosis, 937 histopathological features, 937 immunology, 937 Intravascular papillary endothelial hyperplasia (IPEH), 807, 816–817, 816t, 817f GH and, 816 PILA and, 826 Intravenous atypical vascular proliferation. See Epithelioid hemangioma Intravenous immunoglobulin (IVIG), 43, 93, 294 Invasive component, 665–669 Invasive melanoma, 660 Invasive pilomatricoma, 717, 718t clinical features, 717 differential diagnosis, 717 histopathologic features, 717 IPEH. See Intravascular papillary endothelial hyperplasia Irritant contact dermatitis, 17 clinical features of, 17 histopathologic features of, 17 Irritant contact vulvitis, 26f Irritated seborrheic keratosis, 566

Irritation reactions, 301 clinical features, 301 differential diagnosis, 301 histopathological features, 301 Ischemic necrosis, subcutaneous fat, 255 ISH. See In situ hybridization Islet amyloid polypeptide, 376 Isotretinoin, PG from, 813 ISSVA. See International Society for the Study of Vascular anomalies IVIG. See Intravenous immunoglobulin J JEB. See Junctional epidermolysis bullosa Jellyfish, 307 Jessner lymphocytic infiltrate, 86 Jones, Wilson, 805 Junctional atypical melanocytic nevi, 652 Junctional cleavage, Spitz nevus, 635 Junctional epidermolysis bullosa (JEB), 169–170 clinical features, 169 diagnostic measures, 170 differential diagnosis, 170 of Herlitz type, 170t of non-Herlitz type, 170t with pyloric, 170t variants, 170t Junctional nevus, 618 architectural disorder with, 654f Junin, 503 Juvenile granulomatous cutaneous T-cell lymphomas, 912 Juvenile hyaline fibromatosis, 784 clinical features, 784 differential diagnosis, 784 histopathologic features, 784 Juvenile xanthogranuloma, 893 Juxtaarticular nodes, 452 K K7 EH and, 812 EHE and, 828 K18, EHE and, 828 K19, EH and, 812 Kala-azar, 518 Kamino bodies, Spitz nevus, 635 Kaposi sarcoma (KS), 510–511, 804, 819–823, 820t, 821f, 822f, 850 AAD and, 819 AIDS and, 810, 820, 831 angiolipoma and, 859 APL and, 844 BA and, 817 histologic features of, 823t KHE and, 824 MVH and, 809 promontory sign and, 821 SCH and, 808 TA and, 806 THH and, 810–811 Kaposiform hemangioendothelioma (KHE), 803t, 804, 823–824 TA and, 805 Kaposi-like infantile hemangioendothelioma. See Kaposiform hemangioendothelioma

Kasabach-Merritt syndrome (KMS), 802 IH and, 824 KHE and, 823–824, 824 TA and, 805, 824 Kawasaki syndrome, 202 clinical features, 202 histopathological features, 202 Keloidal blastomycosis, 488–489 clinical features, 488 differential diagnosis, 488 histopathological features, 488–489 Keloids, 392–393 differential diagnosis, 393 histopathological features, 393 Keratin 9, 320 alveolar rhabdomyosarcoma and, 875 Keratin pseudocyst, 5f Keratinization, 983 Keratinocyte-keratinocyte adhesion, 137 Keratinocytes, 67, 302 cytolysis of, 137 fluorescence, 93 Keratinocytic dysplasia, 570–573 Keratoacanthoma, 330, 512, 556, 576–578, 996–997 clinical features, 577, 996 differential diagnosis, 578, 997 histopathological features, 577–578, 996 subungual, 577 Keratoacanthoma centrifugum, 577 Keratoderma blenorrhagicum, 68 Keratoderma climactericum, 320 Keratohyalin, 314 Keratolysis, pitted, 430 Keratomycosis, 478 Keratosis, 239f, 562–569, 570–572 arsenical, 573 benign, 5f lichenoid, 616 psoriasiform, 566 scarring follicular, 233 seborrheic, 5f stucco, 601 Keratosis follicularis, 76 Keratosis pilaris. See Follicular hyperkeratosis Keratosis pilaris atrophicans (KPA), 233, 396 differential diagnosis, 396 histopathological features, 396 Keratosis pilaris spinulosa decalvans (KPSD), 233 Keratotic basal cell carcinoma, 584–585 Kerion, 231–232 clinical features, 231 differential diagnosis, 231–232 histopathological features, 231 KHE. See Kaposiform hemangioendothelioma Ki-67, 575, 585 Kickxellomycotina, 458, 483 Kikuchi disease, 50 Kimura disease, EH and, 811–813 Kindler syndrome, 170–171, 172t clinical features, 170–171 diagnosis, 171 differential diagnosis, 171 histopathological features, 171 KIT gene, 338

L Lacazia loboi, 473 LAD-1. See Ladinin Ladinin (LAD-1), 289 Lagochilascariasis, 536 Lahore sore, 518 LAM. See Lymphangioleiomyomatosis LAMB3, 326 Lamellar bone, 384 Lamellar ichthyosis (LI), 78, 318 autosomal recessive, 318t clinical features, 318 differential diagnosis, 318 histopathological features, 318 Lamina densa (LD), 156–157 Lamina lucida (LL), subepidermal blistering diseases, 156 Laminin, 587, 700, 889 angiosarcoma and, 830 hemangiopericytoma and, 825 Laminin 5, 156 LANA-1, KS and, 823 Langerhans cell histiocytosis, 116–117 clinical features, 117 differential diagnosis, 117 histopathological features, 117 Langerhans cell microvesicles, 22f Langerhans cell proliferative disorders, 118t Langerhans cells (LCs), 306, 500, 586, 711 Langerhans histiocytosis, congenital self-healing, 117 Large B-cell lymphoma in immunocompromised patients, 937–938 clinical features, 937–938 histopathological features, 938 immunology, 938 leg type, 936 clinical features, 936 differential diagnosis, 936 histopathological features, 936 immunology, 936 Large cell acanthoma, 569 clinical features, 569 differential diagnosis, 569 histopathological features, 569 Large vessels, vasculitis of, 200–203

Large-plague parapsoriasis (LPP), 71 Larva currens, 536 Lassa, 503 Lateral viral infections, 495 Latrodectus mactans, 308 Laugler-Hunziker-Baran syndrome, 997 Lawrence-Seip syndrome, 557 LCA. See Leukocyte common antigen LCs. See Langerhans cells LCV. See Leukocytoclastic vasculitis LD. See Lamina densa Lead, 355 histopathological features, 355 Ledderhose disease, 773 Leiomyomas, 869 congenital smooth muscle hamartoma and, 868 leiomyosarcoma and, 872t Leiomyomas with fatty infiltration, myolipoma and, 862 Leiomyosarcoma, 589, 780, 870–872, 871f, 871t, 972 dedifferentiated liposarcoma and, 867 embryonal rhabdomyosarcoma and, 874 leiomyoma and, 869, 872t metastatic, 972f pilar, 718 Leishman-Donovan bodies, 519 Leishmaniasis, 517–520, 518t differential diagnosis, 519–520 disseminated cutaneous, 518 histopathological features, 519 in HIV, 518 mucocutaneous, 518 New World, 518 post-kala-azar dermal, 518 recidivans, 518 visceral, 518 Lentigines, 616, 617 Lentiginous compound nevus, 619f, 621 differential diagnosis, 621 Lentiginous cutaneous melanoma, 656 Lentiginous intraepidermal component, melanoma with, 660–662 Lentiginous intraepithelial component of acral skin, 661–662 of mucosal surfaces, 661–662 of nail apparatus, 661–662 Lentiginous junctional nevus, 621 differential diagnosis, 621 Lentiginous melanoma, 666 of acral skin, 665f Lentigo maligna, 655 Lentigo maligna melanoma, 657 Lentigo simplex, 341f, 997 clinical features, 616, 617 differential diagnosis, 616, 617 histopathological features, 616, 617 LEOPARD, 616 Leopard skin, 532 LEOPARD syndrome, 347–348 Leprechaunism, 405 Lepromatous leprosy, 438f, 439f Leprosy, 270, 437t clinical features, 432–433 differential diagnosis, 433 lepromatous, 438f, 439f tuberculoid, 438f

Leptomeningeal melanocytosis, 632 Lesions inflammatory, 5–8 reactive, 5–8 Lethal midline granuloma, 99 Leukemia, 276. See also specific types acute monocytic, 943f, 944f, 945f acute myeloid, 941–942, 942t, 943 acute promyelotic, 941 adult T-cell, 915, 952 chronic lymphocytic, 146, 948–949, 948t, 949f, 950f chronic myeloid, 944–946 classification of, 941 hairy cell, 951–952 monocytic, 942–943, 946f myelomonocytic, 943–944 T-cell prolymphocytic, 949–951 Leukemic infiltrates, 905–952 cutaneous, 940–952 Leukocyte common antigen (LCA), 962 Leukocyte infiltration, 36 Leukocytoclasis, 179 Leukocytoclastic vasculitis (LCV), 181, 182–183, 281 clinical features, 182 histopathological features, 182–183 Leukoderma patterned, 338–339 postinflammatory, 345 Leukoedema, 1002–1003 clinical features, 1002 differential diagnosis, 1002–1003 histopathologic features, 1002–1003 Leukoplakia, 464, 1016–1017 clinical features, 1016 differential diagnosis, 1017 histopathologic features, 1016–1017 Lewandowsky rosacea, 99 LI. See Lamellar ichthyosis Lichen amyloidosis, 61, 375, 375f colloid milium, 374t Lichen aureus, 193 Lichen myxedematosus, 365–366 clinical features, 365 differential diagnosis, 366 histopathologic features, 365–366 Lichen nitidus, 59–60 clinical features, 59 differential diagnosis, 60 histopathological features, 59–60 lichen striatus v., 60t Lichen planopilaris, 37, 226–227, 233f clinical features, 226 differential diagnosis, 227 histopathological features, 226 Lichen planus, 37t, 991f bullous, 39f clinical features, 990 differential diagnosis, 39–40, 990 histopathologic features, 990 histopathological features, 38–39 hypertrophic, 39f Lichen planus pemphigoides (LPP), 156, 162 clinical features, 162 diagnostic tests, 162 differential diagnosis, 162 histopathological features, 162

INDEX

Klebsiella, 234, 520 Klebsiella rhinoscleromatis, 438 Klippel-Trenaunay syndrome AAD and, 818 SCH and, 807 Klippel-Trenaunay-Weber syndrome, 832 KMS. See Kasabach-Merritt syndrome Knuckle pad, 773 clinical features, 773 differential diagnosis, 773 histopathologic features, 773 Koebner phenomenon, 580 Koebner response, 333 Koenen tumor, 392 Koplik spots, 496 KPA. See Keratosis pilaris atrophicans KPSD. See Keratosis pilaris spinulosa decalvans KS. See Kaposi sarcoma Kyrle disease, 240, 333

1061

INDEX 1062

Lichen sclerosus, 54–55 clinical features, 54 differential diagnosis, 55 histopathological features, 54 Lichen simplex chronicus, 24f, 70–71, 72f clinical features, 71 differential diagnosis, 71 histopathological features, 71 Lichen spinulosis. See Follicular hyperkeratosis Lichen striatus, 60 clinical features, 60 differential diagnosis, 60 histopathological features, 60 lichen nitidus v., 60t Lichenification, 991 Lichenoid actinic keratosis, 39, 571, 572f Lichenoid drug eruptions, 39, 283–284, 283t causes of, 284t clinical features, 40, 283 differential diagnosis, 40, 283 histopathological features, 40, 283 Lichenoid dysplasia, 1017 Lichenoid graft-versus-host reaction, 47f Lichenoid interface dermatitis, 37–40 histopathological features of, 38–39 Lichenoid keratosis, lichen planus-like keratosis, 40, 616 clinical features, 40 differential diagnosis, 40 histopathological features, 40 Lichenoid pigmented purpuric eruption of Gougerot and Blum, 60 Light reactions, 304–307, 305t differential diagnosis, 306–307 histopathological features, 305–306 Limb defects syndrome, 322–323 Linear IgA disease, 165–167 autoantigens of, 167t clinical presentation, 165 diagnosis, 166–167 differential diagnosis, 167 drug-induced, 288–289 histopathological features, 165–166, 166f Linear sebaceous hyperplasia, 690 Lining up, 909 Linuche unguiculata, 307 Lipedematous alopecia, 232 clinical features, 232 histopathological features, 232 Lipid-lowering agents, 93 Lipoatrophy, 274–275, 275f histopathological features, 274–275 HIV and, 274 Lipoblastoma, 864, 864f WDL/ALT and, 865, 866 Lipoblastomatosis, 864 Lipodermatosclerosis, 255–258, 257t, 258t clinical features, 255–257 differential diagnosis, 257–258 histopathological features, 257 Lipodystrophy, 274–275 centrifugal, 274 histopathological features, 274–275 HIV and, 274 Lipoid proteinosis, 375, 378

Lipoma, 858, 858f, 858t chondroid, 861, 862f encapsulated, 270 mobile encapsulated, 271 pleomorphic, 860–861, 860t, 861f, 865, 866 spindle cell, 859–860, 860f, 860t, 862, 866 WDL/ALT and, 866 Lipoma-like liposarcoma, 865 Lipomatous hemangiopericytoma, 860 Lipophagic granulomas, 257 Liposarcoma, 864–865 dedifferentiated, 866–867, 866f, 879 hibernoma and, 863 lipoblastoma and, 864 myolipoma and, 862 myxoid, 596, 796, 861, 867–868, 867f, 867t, 877 pleomorphic, 780, 868, 868f, 868t round cell, 596, 867–868 sclerosing, 860, 865 spindle cell, 865 well-differentiated, 858, 860, 862, 864, 865–866, 865f, 865t, 867 Liquefying panniculitis, 261 Livedo reticularis, 205 clinical features, 205 CMTC and, 835 histopathological features, 205 Liver disease HHT and, 834 unilateral nevoid telangiectasia and, 835 Lizard skin, 532 LL. See Lamina lucida LMNA, 274 Loa loa, 534 Loboa loboi, 488 Lobomyces loboi, 488 Lobomycosis, 460t Lobular capillary hemangioma AAD and, 819 BA and, 817 cherry angioma and, 850 IPEH and, 816 KS and, 821 MVH and, 809 PWSs and, 832 TA and, 805 Lobular panniculitis, 261–275 acute, 262f idiopathic, 261 Lobulated tumor, 797 Localized fibrosing small-vessel vasculitis, 187 Localized melanoma, 681t L’oedeme bleu, 270 Louis-Bar syndrome. See Ataxia telangiectasia Low-grade fibromyxoid sarcoma, 794–795, 794f clinical features, 794 differential diagnosis, 795 histopathologic features, 794–795 Loxosceles reclusa, 308 LPP. See Large-plague parapsoriasis; Lichen planus pemphigoides Lucio phenomenon, 270, 433 Lues maligna, 446

Luminal fibrin thrombi, 88 Lung carcinoma, 965–967 clinical features, 965 differential diagnosis, 966 histopathological features, 965–966 immunohistochemistry, 966–967 special stains, 966–967 Lupus band test, 91–93 Lupus erythematosus, 39, 48–55, 77, 90–91, 590 acute systemic, 49–51 bullous, 167 bullous systemic, 168–169 clinical features, 48–49, 90–91 differential diagnosis, 91 discoid, 48, 50f, 51–53, 225–226 drug-induced, 289 histopathological features, 49, 91 hypertrophic, 48 immunofluorescence manifestations, 91t neonatal, 48 nodular mucinosis in, 367 papular mucinosis in, 367 subacute, 50f subacute cutaneous, 48, 51 differential diagnosis, 51 subtypes of, 92t, 94t sun exposure, 92 systemic, 284 classification of, 92t tumid, 50 variants, 48t Lupus miliaris disseminatus faciei, 102–103 clinical features, 102–103 histopathological features, 103 Lupus panniculitis, 48, 272–273 Lupus vulgaris, 434f Lutzner cell, 906 Lutz-Splendore-Almeida disease. See Paracoccidioidomycosis Lyell syndrome. See Toxic epidermal necrolysis Lyme disease, 451 stage I, 451–452 differential diagnosis, 452 histopathological features, 452 stage III, 452–453 differential diagnosis, 453 histopathological features, 453 Lymph nodes in cellular blue nevus, 647 metastasis, 668 in Spitz nevus, 638 Lymphadenopathy, 472, 924 angioimmunoblastic, 925f Lymphadenosis benigna cutis, 928 Lymphangioendothelioma, KS and, 823 Lymphangioleiomyomatosis (LAM), 343 Lymphangioma circumscriptum, 841–842, 842f, 843, 850 APL and, 844 Lymphangioma simplex, 841 APL and, 842 Lymphangiomatosis (LM). See Lymphatic malformation Lymphangiosarcoma. See Angiosarcoma

Lymphoma (Cont.): primary cutaneous anaplastic large cell, 917–919 primary cutaneous CD8+ T-cell, 921–922 primary cutaneous follicle center cell, 931f primary cutaneous marginal zone B-cell, 935f primary cutaneous peripheral T-cell, 921 subcutaneous panniculitic, 263–265 subcutaneous panniculitis-like T-cell, 919, 920f unspecified primary cutaneous peripheral T-cell, 922–924 Lymphomatoid drug eruptions, 290–291 clinical features, 290 differential diagnosis, 291 histopathological features, 290–291 Lymphomatoid hypersensitivity reaction, 291t Lymphomatoid papulosis, 913, 915–917, 916f clinical features, 916 differential diagnosis, 916 genotypic features, 916 histopathologic features, 916 immunophenotypic features, 916 Lymphomatoid vascular reactions, 194 differential diagnosis of, 195t Lymphomatoid vasculitis, 194 differential diagnosis, 195t Lymphoplasmacytoid cells, 929 Lysozyme, 553 LYVE angiosarcoma and, 830 KS and, 822 M MAC. See Microcystic adnexal carcinoma Machupo, 503 Macrophages, 907, 929 Macular amyloidosus, 61, 375 Macular atrophy, 402 clinical features, 402 histopathological features, 402 Macular seborrheic keratosis, 565 Macules of McCune-Albright syndrome, 351 differential diagnosis, 351 histopathological features, 351 Maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP), 130 Madelung disease, 859, 864 Madurella grisea, 479 Madurella mycetomatis, 479 Maffucci syndrome CH and, 827 LM and, 838 phlebectasias and, 838 SCH and, 807–808 Spindle cell hemangioma and, 838 VM and, 838 Majocchi disease, 193 Majocchi granuloma, 240f Major inflammatory reaction patterns, 8–14 Major psoriasiform dermatoses, 64–66 Malakoplakia, 123, 442 clinical features, 123, 442 differential diagnosis, 123, 442 histopathological features, 123, 442

Malassezia folliculitis, 465–467 clinical features, 466 differential diagnosis, 467 histopathological features, 466–467 Malassezia furfur, 234, 463, 465, 989 Malignant acrospiroma, 739–740 clinical features, 739 differential diagnosis, 740 histopathologic features, 739–740 Malignant atrophic papulosis (MAP), 206 Malignant basomelanocytic tumor, 581 Malignant chondroid syringoma, 588 Malignant edema, 434 Malignant endovascular papillary angioendothelioma. See Papillary intralymphatic angioendothelioma Malignant fibrohistiocytic tumors, 791–795 Malignant fibrous histiocytoma, 791–792 giant cell variant, 791–792 hemangiopericytoma and, 825 pleomorphic, 791–792 Malignant fibrous tumors, 791–795 Malignant hemangioendothelioma. See Angiosarcoma Malignant lymphoma, 453–454 histopathological features, 453–454 Malignant melanoma, 656–665 blue nevus and, 675 clinical features, 675 differential diagnosis, 675 histopathological features, 675 EHE and, 829 histological diagnosis of, 679–680 historical classification of, 657t regression, 678t Malignant mixed tumors, 748–749 Malignant neoplasms distinguishing benign from, 5f features of, 5 Malignant peripheral nerve sheath tumor (MPNST), 887, 895–896, 896t clinical features, 895 differential diagnosis, 896 extra skeletal osteosarcoma and, 879 histopathological features, 895–896 Malignant pilar neoplasms, 715–718 Malignant proliferating pilar tumor, 716–717, 717f clinical features, 716 differential diagnosis, 716–717 histopathologic features, 716 Malignant pustule, 433 Malignant schwannoma, 895 hemangiopericytoma and, 825 Malignant sweat gland tumors, 737–738 Malignant trichoepithelioma, 717 Malignant tumors, 578–600 Mammaglobin, 963 Mammary Paget disease (MPD), 750, 752t Mansonella streptocerca, 532 Mantleomas, 713 MAP. See Malignant atrophic papulosis Marburg, 503 Marfan syndrome, 398, 405 clinical features, 398 histopathological features, 398 Marginal zone B lymphocytes, 930

INDEX

Lymphatic filariasis, 534 clinical features, 533 differential diagnosis, 534 histopathological features, 533–534 Lymphatic malformation, 823 angiokeratoma and, 836 APL and, 844 IPEH and, 816 Maffucci syndrome and, 838 PILA and, 826 VH and, 838 VM and, 839 Lymphatic malformation (LM), 806, 841–843, 842f Lymphoblasts, 929 Lymphocyte exocytosis, follicular spongiosis with, 29f Lymphocyte satellitosis, 36 Lymphocyte-associated primary scarring alopecia, 225 Lymphocytes, marginal zone, 930 Lymphocytic vascular reaction, 192 Lymphocytic vasculitides, 192 Lymphocytic vasculitis, differential diagnosis, 192t Lymphocytic vasculopathy, 193 Lymphocytic-plasma cellular infiltrates, 128–129 Lymphocytoma cutis, 453–454 differential diagnosis, 454 histopathological features, 453–454 Lymphoepithelioma-like carcinoma, 599–600, 711, 753–754 clinical features, 600 differential diagnosis, 600, 754 histopathological features, 600 Lymphogranuloma venereum, 443 clinical features, 443 differential diagnosis, 443 histopathological features, 443 Lymphoid hyperplasia, 905 Lymphoid infiltrates, 905–952 Lymphoma, 276. See also specific types alveolar rhabdomyosarcoma and, 875 B-cell, 937–938 B-lymphoblastic, 938 cutaneous, 905 cutaneous B-cell, 929–932 cutaneous gamma/delta T-cell, 922 cutaneous Hodgkin, 939–940 cutaneous T-cell, 7, 71, 74–75, 229, 276, 291, 905t, 906–907, 912 clinical features, 74–75 differential diagnosis, 75 histopathological features, 75 cytotoxic cutaneous, 919 extranodal NK/T-cell, 919–921 follicle center, 932–933, 932t hidroa vacciniforme-like, 921 intravascular large B-cell, 937 large B-cell leg type, 936 other, 936–938 malignant, 453–454 marginal zone, 129 marginal zone B-cell, 933–936 nodal, 924 precursor T-lymphoblastic, 926

1063

INDEX 1064

Marginal zone B-cell lymphoma, 933–936 clinical features, 933 differential diagnosis, 935–936 histopathologic features, 933–934 immunology, 935 primary cutaneous, 934f Marginal zone cells, 933 Marginal zone lymphoma, 129 Marine agent reactions, 307–308 clinical features, 307 differential diagnosis, 308 histopathological features, 307–308 Marjolin ulcers, 591 MART-1, 669, 676, 680, 795, 965 Mast cell degranulation, 82 Mast cell infiltrates, 130–131 Mastectomy, angiosarcoma and, 829 Mastocytomas, 841 Mastocytosis cutaneous, 130–131 systemic, 130 MATP. See Membrane-associated transporter protein gene Matrical basal cell carcinoma, 585 Matrix glutamic acid protein (MGP), 259 Matrix metalloproteinase-2 (MMP-2), 257, 578 Maturation (zonation), Spitz nevus, 635 Mayo Clinic, 197 Mazzotti reaction, 532 MC1R. See Melanocortin-1 receptor MCHR1. See Melanin-concentrating hormone receptor 1 MDM. See Minimal deviation melanoma MDM2 gene, 865 dedifferentiated liposarcoma and, 867 MDS. See Myelodysplastic syndrome Measles, 496–497, 496t clinical features, 497 differential diagnosis, 497 histopathological features, 497 Mechanobullous disorders, 313 Mechlorethamine, 356 Median raphe cysts, 552 histopathological features, 552 Median rhomboid glossitis, 1004–1006 clinical features, 1004 differential diagnosis, 1004 histopathologic features, 1004 Medication-associated pigmentation, 1016 clinical features, 1016 differential diagnosis, 1016 histopathologic features, 1016 Medium vessels, vasculitis of, 200–203 Medlar bodies, 476 Melan-A angiomyolipoma and, 862 pleomorphic liposarcoma and, 868 Melanin, 36, 568, 710, 729 dusty, 654, 660 intralaminar, 986 mapping of nail plate, 985–987 premise, 986 Melanin-concentrating hormone receptor 1 (MCHR1), 341

Melanoacanthoma, 568 clinical features, 568 differential diagnosis, 568 histopathological features, 568 Melanocortin-1 receptor (MC1R), 615 Melanocyte stem cells, 1022–1023 Melanocyte tumors, 615–681 basilar melanocyte-composed, 615–616 Melanocytes, 338 epidermal, 339f Melanocytic aggregates, 678–679 Melanocytic lesions, with phenotypic heterogeneity, 648 Melanocytic macules, 616–617 Melanocytic nevi, 997 acquired, 616, 662–663 clinical features, 618 common, 617–618, 618t histopathological features, 618 variants of, 619–627 acral skin, 623–624 clinical features, 623 compound, 624f differential diagnosis, 623–624 histopathological features, 623 of acral skin, 623–624 atypical, 651, 655 cytologic features, 654 epithelioid cell variant, 655 grading, 656 grading of, 656 halo nevus variant, 655 histological features of, 655–656 junctional, 652 as melanoma precursors, 652, 654 melanoma v., 655t severely, 655t significance of, 651–654 of breast, 625 congenital, 627–632 with atypical features, 630 giant, 632 histological features, 628 incidence, 628–630 large, 632 melanoma in, 630–631 risk factors, 628–630 small, 628–630 dysplastic, 651 embryonal rhabdomyosarcoma and, 875 flexural skin, 625 with focal atypical epithelioid cell component, 649 differential diagnosis, 649 genital skin, 624–625 clinical features, 625 differential diagnosis, 625 histopathological features, 625 with phenotypic heterogeneity, 648–649 clinical features, 648 histopathological features, 648–649 presentations of, 625t, 627 scalp, 625–627 clinical features, 626 differential diagnosis, 626–627 histopathological features, 626

Melanocytic nevi (Cont.): of scalp, 625–627 from special sites, 623–627 uncommon findings in, 625t, 627 Melanocytoma, pigmented epithelioid, 643 Melanocytosis dermal, 641, 642t leptomeningeal, 632 pagetoid, 667 Melanoma, 657, 795, 998 acral, 657, 659, 662t, 664 with adjacent intraepithelial component, 662 ancillary techniques in diagnosis of, 680 angiotropic, 669–670, 669f atypical melanocytic nevi as precursors, 652 clinical features, 652 histopathological features, 652–654 host response, 654 atypical melanocytic nevi v., 655t balloon cell, 620, 676–677 childhood, 627–632 classification of, 657t clinical features, 998 congenital, 627–632 congenital melanocytic nevi and, 630–631 conventional, 663t cutaneous, 656–665 anatomic levels of, 659t classification, 656–665 clinical features, 657–659 differential diagnosis, 662–665 histopathological features, 659–662 intraepithelial component, 659–660 invasive, 660 lentiginous, 656 metastatic, 678, 679t nested, 656 pagetoid, 656, 658f primary, 678, 679t with dermal nevi, 674–675 clinical features, 674–675 differential diagnosis, 675 histopathological features, 674–675 desmoplastic, 639, 640t, 665–669 diagnosis of borderline, 680 differential diagnosis, 998 florid intraepidermal, 667 histopathologic features, 998 histopathological reporting of, 681 invasive, 660 lentiginous, 665f, 666 with lentiginous intraepidermal component, 660–662 lentigo maligna, 657 localized, 681t malignant, 656–665, 657t, 675, 678t, 679–680, 829 blue nevus and, 675 clinical features, 675 differential diagnosis, 675 histopathological features, 675 EHE and, 829 histological diagnosis of, 679–680 historical classification of, 657t regression, 678t

Metastatic disease, umbilicus, 416 Metastatic leiomyosarcoma, 972f Metastatic melanoma, 677 cutaneous, 678, 679t diagnostic problems with, 678–679 epidermotropic, 679f generalized melanosis in, 352 melanosis in, 679 Metastatic mucinous breast carcinoma, 965f Metatypical basal cell carcinoma, 583, 585 Methenamine, 471 Methyldopa, 289 Methyltransferase, 289 Meyers-Kouvenaar (MK) body, 534 Mezomycetozoa, 527 MGP. See Matrix glutamic acid protein Microabscess, 136, 909 Microcapillary angioma, 808 Micrococcus sedentarius, 430 Microcystic adnexal carcinoma (MAC), 699, 727, 728, 743–745, 744f clinical features, 743 differential diagnosis, 744–745 histopathologic features, 743–744 Microglobulin amyloid, 374 Micrometastases, 678–679 Micronodular basal cell carcinoma, 582, 583f Microphthalmia transcription factor (MiTF), 893 Microscopic interpretation anatomic site in, 4 high magnification, 4 information integration in, 4 intermediate magnification, 4 microslide examination, 3–4 slide examination, 3 slide interpretation, 3 specimen type in, 3–4 Microscopic polyarteritis (MPA) nodosa, 184, 199 clinical features, 199 differential diagnosis, 199 histopathological features, 199 Microslide, examination of, 3–4 Microsporidia, 458, 527 Microsporidiosis, 527 Microsporum audouini, 221, 458 Microsporum canis, 221 Microvenular hemangioma (MVH), 808–809, 809f, 809t acute myelogenous leukemia and, 809 dermatofibroma and, 809 Epithelioid hemangioma (EH) and, 809 HHV and, 809 histologic features of, 823t KS and, 809 PG and, 809 POEMS and, 809 sclerosing hemangioma and, 809 TA and, 809 THH and, 809 Wiskott-Aldrich syndrome and, 809 Miescher-Melkersson-Rosenthal syndrome, 100, 101t clinical features, 100 differential diagnosis, 100 histopathological features, 100

Migratory, 259 Mikulicz cells, 438, 520 Milia, 547–548 histopathological features, 547–548 Milia-like calcinosis, 383 Miliaria, 32 algorithm for, 34 Miliaria crystallina, 13, 32–33 clinical features of, 32 differential diagnosis of, 33 histopathological features of, 32 Miliaria profunda, 13, 33 clinical features, 33 histopathological features, 33 Miliaria rubra, 13, 33 clinical features of, 33 differential diagnosis, 33 histopathological features of, 33 Miliarial spongiosis, 6f Milkers’ nodule, 512, 513, 514f Milroy disease angiosarcoma and, 829 SCH and, 807 Minimal deviation melanoma (MDM), 670 Minocycline, 287, 355–356 Minoxidil, 216 Miscellaneous ectopic tissue, 414–417 Miscellaneous seborrheic keratosis, 566 Mites, 75, 308 MiTF. See Microphthalmia transcription factor Mitosis, 588, 600 in Spitz nevus, 635 Mixed ciliated epithelium, cysts lined by, 546t, 549–552 Mixed connective tissue disease, 53, 54f, 93, 94, 390 clinical features, 94, 390 differential diagnosis, 94 histopathological features, 53, 94, 390 immunofluorescence, 94 Mixed epithelial and mesenchymal follicular proliferations, 708 Mixed tumors, malignant, 748–749 Mixed-lineage adnexal adenomas, 737 MK body. See Meyers-Kouvenaar body MLT. See Multifocal lymphangioendotheliomatosis MMP-2. See Matrix metalloproteinase-2 MNF116, 962 Mobile encapsulated lipoma, 271 Molluscum contagiosum, 105, 512–514, 514f, 515f, 589 Molting, 216 Mongolian spot, 641, 643f clinical features, 641 histopathological features, 641 Monkeypox, 512 Monoclonal gammopathy, RAE and, 817 Monocytic leukemia, 942–943, 946f acute, 943f, 944f, 945f clinical features, 942 differential diagnosis, 943 histopathologic features, 942–943 Monocytoid B cells, 933

INDEX

Melanoma (Cont.): markers, 651–652 metastatic, 352, 677, 678–679 minimal deviation, 670 neurotropic, 665, 668–669 nevoid, 670–672, 671t, 672f nodular, 657, 662, 663t, 664 with pagetoid intraepidermal component, 660 prognostic factors in, 680–681 rare presentations of, 677t regression, 677 simulating other neoplasms, 678 in situ, 739, 997–998 small cell, 631f, 670, 673–674 small-diameter, 670 solar, 660–661, 664f spindle cell, 668, 780 spitzoid, 670, 674 subungual, 659 unusual presentations of, 677t verrucous, 672–673 Melanophages, 36 Melanosis, in metastatic melanoma, 679 Melanotic macules, 617 Melasma, 350 differential diagnosis, 350 histopathologic features, 350 Meleney ulcer, 427 Membrane attack complex of complement, 92–93 Membrane-associated transporter protein gene (MATP), 342 Meningioma, cutaneous, 898 Meningococcal infections, 430–431 clinical features, 430 differential diagnosis, 431 histopathological features, 430–431 Menkes syndrome, 404 histopathological features, 404 Mental retardation, 590 Meperidine, 271 Mercury, 355 histopathological features, 355 Merkel cell carcinoma, 515 Merkel cell polyoma virus, 515 Merkel cells, 585, 588, 711, 896, 967 small cell melanoma mimicking, 673 Mesenchymal tumors, 631–632 Mesomycetozoae, 489 Metagonium yokogawai, 538f Metal deposition, 353t Metaplastic synovial cysts (MSCs), 553–554 differential diagnosis, 553–554 Metastasis apocrine carcinomas simulating, 752 cutaneous, 960–973 distant, 961 eccrine carcinomas simulating, 746 lymph nodes, 668 scalp, 961 telangiectatic, 960–961 Metastatic adenocarcinoma, 966f Metastatic basal cell carcinoma, 580 Metastatic calcinosis cutis, 381–382 histopathological features, 381–382 Metastatic Crohn disease, 100

1065

INDEX 1066

Monsel solution reaction, 123–124, 124f clinical features, 123 differential diagnosis, 124 histopathological features, 123 Montgomery syndrome. See Xanthoma disseminatum Morbid obesity, angiosarcoma and, 829 Morbilliform drug eruption, 61 Morbilliform viral exanthem, 61 Morphea, 387, 389t inflammatory, 387 Morphea profunda, 259–261, 260t clinical features, 260 differential diagnosis, 261 histopathological features, 260–261 Morpheaform basal cell carcinoma, 588, 706, 727 Morphine, 271 Morphological features, cutaneous metastases, 960–961 Mother patch, 73 Moynahan’s syndrome, 347–348 MPA nodosa. See Microscopic polyarteritis MPCM/UP. See Maculopapular cutaneous mastocytosis/urticaria pigmentosa MPD. See Mammary Paget disease MSCs. See Metaplastic synovial cysts MTB. See Mycobacterium tuberculosis Mucin, 586, 594, 598, 712, 713 desmoplastic melanoma, 669 Mucinous carcinoma, 740–741 clinical features, 740 differential diagnosis, 740–741 histopathologic features, 740 Mucinous eccrine carcinoma, 740t Mucinous nevus, 370 histopathological features, 370 Muckle-Wells syndrome, 373 Mucocele, 1010–1011 clinical features, 1010 differential diagnosis, 1011 histopathologic features, 1010–1011 Mucocutaneous candidiasis, 463t Mucocutaneous leishmaniasis, 518 Mucocutaneous lentigines, 616–617 Mucoepidermoid carcinoma, 598–599 clinical features, 599 differential diagnosis, 599 histopathological features, 599 primary, 745 Mucoid carcinoma, 963 Mucopolysaccharides, 385, 792 histopathological features, 385 Mucor, 483 Mucorales, 483 Mucormycosis, 459t, 484 clinical features, 484 differential diagnosis, 484 histopathological features, 484 Mucormycotina, 483 Mucosal surfaces, lentiginous intraepithelial component, 661–662 Muir-Torre syndrome, 576, 690, 691 Multicentric basal cell carcinoma, 580 superficial, 582

Multicentric Castleman disease, 129 clinical features, 129 differential diagnosis, 129 histopathological features, 129 Multicentric reticulohistiocytosis, 121 clinical features, 121 differential diagnosis, 121 histopathological features, 121 Multifocal lymphangioendotheliomatosis (MLT), 811 Multinucleate cell angiohistiocytoma, 122–123 clinical features, 122 differential diagnosis, 122–123 histopathological features, 122–123 Multinucleate giant cells, 646 Multiple lentigines syndrome, 347–348 Multiple sclerosis, 296 Multiple symmetric lipomatosis. See Madelung disease Münchhausen syndrome, 271 Munro microabscesses, 67, 68 Muscle, 868–876 MVH. See Microvenular hemangioma MXA. See Myxovirus protein Mycetoma, 459t, 478–483 clinical features, 479 differential diagnosis, 480 histopathological features, 479–480 organisms causing, 480t Mycobacterium avium-intracellulare, 123, 432, 501 Mycobacterium chelonei, 432 Mycobacterium fortuitum, 432 Mycobacterium haemophilum, 501 Mycobacterium leprae, 421, 432 Mycobacterium marinum, 236, 432 Mycobacterium tuberculosis (MTB), 268, 269, 431, 432, 481 Mycobacterium ulcerans, 435f Mycoplasma pneumoniae, 110, 294 Mycosis fungoides, 12, 74–75, 297f, 906 clinical features, 74–75, 909 clinicopathological variants, 910 definition, 909 d’emblée form of, 909 differential diagnosis, 75, 914 folliculotropic, 910 genotypic features of, 914 granulomatous, 911–912, 912f histopathological features, 75, 909–910 immunotypic features of, 914 patch stage, 910f plaque stage, 910f subtypes, 910 syringotropic, 911–912, 912f transformation, 909 tumor stage of, 911f Myeloblasts, 941 Myelodysplasia, 188 Myelodysplastic syndrome (MDS), 946, 947–948 clinical features, 947 differential diagnosis of, 948 histochemical findings, 948 histopathologic features, 947–948 immunohistochemical findings, 948

Myelomonocytic leukemia, 943–944 clinical features, 943 differential diagnosis, 944 histochemical findings, 944 histopathological features, 944 immunohistochemical findings, 944 Myeloperoxidase, 943 Myo-D1 embryonal rhabdomyosarcoma and, 874 leiomyosarcoma and, 871 pleomorphic leiomyosarcoma and, 876 Myoepithelial differentiation, 585–586 Myoepithelioma, 889 Myofibroma, solitary, 782–784, 783t Myofibromatosis, 783t infantile, 782–784, 783t Myogenin embryonal rhabdomyosarcoma and, 874 leiomyosarcoma and, 871 pleomorphic leiomyosarcoma and, 876 Myolipoma, 861–862, 862f Myopathic dermatomyositis, 93t Myopericytoma, hemangiopericytoma and, 825 Myosin, 586 Myositis ossificans, 877, 878, 878f Myxedema, 320, 362, 404 generalized, 363–364 pretibial, 364–365 Myxofibrosarcoma, 792–793, 867 clinical features, 792 differential diagnosis, 793 extraskeletal myxoid chondrosarcoma and, 877 histopathologic features, 792–793 leiomyosarcoma and, 871 Myxoid cyst, 368 Myxoid liposarcoma, 596, 796, 867–868, 867f, 867t chondroid lipoma and, 861 extraskeletal myxoid chondrosarcoma and, 877 Myxoid tumor, 797 Myxolipoma, 858, 859f Myxoma cutaneous, 370–371, 795–796 follicular, 714 nerve sheath, 668, 891–892, 893f, 894t Myxovirus protein (MXA), 926 N NADPH. See Nicotinamide adenine dinucleotide phosphate Nadroparin, 383 Naegeli-Franceschetti-Jadassohn, 348 Naevus anelasticus, 402 Nail diseases, 983–998. See also specific disorders biopsy, 983–985, 988f clinical anatomy of, 984f diagnosis of, 987–998 fungal morphology, 984 fungi in, 983–985 diagnosis yield, 984 flowchart, 984 rationale, 984 results, 984

Neuroendocrine carcinoma, 673, 897t immunohistochemistry, 971 primary, 896–897, 898f special stains, 971 Neuroendocrine tumors, 971 classification, 883 clinical features, 971 differential diagnosis, 971 histopathologic features, 971 Neurofibromas, 884–887, 887t, 888f clinical features, 886 cytologic atypia in, 887 histopathologic features, 886–887 leiomyoma and, 869 plexiform, 887, 888f Neurofollicular and pilar neurocristic hamartomas, 719–720 clinical features, 720 histopathologic features, 720 Neuromas, 883–884 clinical features, 884 differential diagnosis, 884 encapsulated, 886t palisaded, 886t traumatic, 886t, 887f Neurothekeoma, 668, 892–894 cellular, 894f clinical features, 892–893 differential diagnosis, 893–894 histopathological features, 893 Neurotized nevus, 621 Neurotropic melanoma, 665, 668–669 differential diagnosis, 668–669 Neurotropism, 668 desmoplastic melanoma with, 665, 666t desmoplastic melanoma without, 665 Neutral lipid storage disease, 318–319 with ichthyotic erythroderma, 318–319 Neutrophilic dermatitides, 275–276 Neutrophilic dermatosis, 188 acute febrile, 188–190 differential diagnosis, 190, 190t Neutrophilic eccrine hidradenitis, 244 clinical features, 244 differential diagnosis, 245 Neutrophilic infiltrates, 124–127 infectious causes of, 125t Neutrophilic spongiosis, 6f, 15, 26f skin diseases with, 26t Neutrophilic vascular reactions, 180, 188 Nevi. See specific types Nevoid basal cell carcinoma, 589–590 clinical features, 589–590 histopathological features, 590 Nevoid melanoma, 670–672, 671t, 672f clinical features, 671 differential diagnosis, 672 histopathologic features, 671 Nevus acquired melanocytic, 616, 662–663 clinical features, 618 common, 617–618, 618t histopathological features, 618 variants of, 619–627 apocrine, 755 atypical halo, 663 atypical melanocytic, 651

Nevus (Cont.): cytologic features, 654 epithelioid cell variant, 655 grading of, 656 halo nevus variant, 655 histological features of, 655–656 junctional, 652 as melanoma precursors, 652, 654 melanoma v., 655t severely, 655t significance of, 651–654 atypical Spitz, 636 assessment of, 637t balloon cell, 620 clinical features, 620 differential diagnosis, 620 histopathological features, 620 becker, 719 clinical features, 719 congenital smooth muscle hamartoma and, 868 differential diagnosis, 719 histopathologic features, 719 becker pigmented hairy, 351–352 clinical features, 351 differential diagnosis, 351–352 histopathologic features, 351 blue, 641, 642–643 atypical cellular, 647 cellular, 645, 646f, 647 common, 643, 644f compound, 645 epithelioid, 643, 644f hypopigmented, 645 malignant melanoma arising in, 675 patchlike, 647 plaque-type, 647–648 sclerosing, 645 target, 648 breast melanocytic, 625 cellular blue, 645, 646f atypical, 647 clinical features, 645 histopathologic features, 645–646 lymph nodes in, 647 occasional, 646–647 combined, 648 common blue, 643, 644f clinical features, 643 differential diagnosis, 643 histopathologic features, 643 compound, 618 of acral skin, 624f with architectural disorder, 653f, 654f and cytologic atypia, 653f, 654f of vulva, 626f compound blue, 645 compound Spitz, 637f congenital melanocytic, 627–632 with atypical features, 630 giant, 632 histological features, 628 incidence, 628–630 large, 632 melanoma in, 630–631 risk factors, 628–630 small, 628–630

INDEX

Nail diseases (Cont.): histology of, 985f keratins, 986t lentiginous intraepithelial component, 661–662 melanin mapping of, 985–987 matrical area calculation, 986–987 premise, 986 microscopic signs of diseases, 983 Nasal glioma, 899, 900f National Cancer Institute, 302 Nattrassia mangiferae, 463 Natural killer cells, 99, 907 NC-16A, 289 Necrobiosis, 261 Necrobiosis lipoidica (NL), 105, 107–108 clinical features, 108 differential diagnosis, 108 histopathological features, 108 Necrobiotic xanthogranuloma, 109 clinical features, 109 differential diagnosis, 109 histopathological features, 109 Necrosis, in basal cell carcinoma, 588 Necrotizing fasciitis (NF), 276, 426, 427–428 clinical features, 428 differential diagnosis, 428 histopathological features, 428 Necrotizing sialometaplasia clinical features, 1011 different diagnosis, 1011 histopathological features, 1011 Neisseria gonorrhoeae, 431 Neisseria meningitidis, 184, 430 Nematodes, 531–536 adult, 530–531 NEMO gene, 349 Neocallimastigomycota, 458 Neonatal lupus erythematosus, 48 Neoplasms, distinguishing benign from malignant, 5f Neoplastic angioendotheliosis. See Angioendotheliomatosis Neoplastic conditions, 13. See also specific neoplastic conditions Neoplastic cutaneous mucinoses, 370–371 Nephrogenic fibrosing dermopathy, 390–391, 391f clinical features, 391 differential diagnosis, 391 histopathologic features, 391 Nerve sheath myxoma, 668, 891–892, 893f, 894t clinical features, 891 histopathologic features, 891–892 immature, 892 Nested cutaneous melanoma, 656 Neural differentiation, 666 Neural heterotopias, 897–901 Neural nevus, 621 Neural tumors, 883–901 classification, 883 cutaneous, 883t Neuroblastic tumors, 900 Neuroblastoma, 900–901 embryonal rhabdomyosarcoma and, 874

1067

INDEX 1068

Nevus (Cont.): connective tissue, 391–392 clinical features, 392 differential diagnosis, 392 histopathological features, 392 deep penetrating, 648, 649–650, 650t clinical features, 649–650 histopathologic features, 649–650 dermal, 619f melanoma in, 674–675 papillomatous, 672 desmoplastic Spitz, 638–639, 639t clinical features, 638 differential diagnosis, 639 DM v., 640t histopathologic features, 638–639 dysplastic melanocytic, 651, 656 eccrine, 755 epidermal, 556–561 differential diagnosis, 556 histopathological features, 556 epithelioid blue, 643, 644f clinical features, 643 histopathologic features, 643 epithelioid cell atypical melanocytic, 655 flexural skin melanocytic, 625 genital skin melanocytic, 624–625 clinical features, 625 differential diagnosis, 625 histopathological features, 625 hair follicle, 719 clinical features, 719 differential diagnosis, 719 histopathologic features, 719 halo, 620–621, 663 atypical, 663 clinical features, 620 differential diagnosis, 621 histopathological features, 620–621 halo atypical melanocytic, 655 halo Spitz, 639 hyalinizing Spitz, 639 hypopigmented blue, 645 inflammatory linear verrucous epidermal, 60, 76, 114, 558–559 clinical features, 76, 558 differential diagnosis, 76, 559 histopathological features, 76, 558–559 junctional, 618 architectural disorder with, 654f junctional atypical melanocytic, 652 lentiginous compound, 619f, 621 differential diagnosis, 621 lentiginous junctional, 621 differential diagnosis, 621 melanocytic, 997 acquired, 616, 619–627, 662–663 acral skin, 623–624 of acral skin, 623–624 atypical, 651–654, 654, 655, 655t, 656 of breast, 625 congenital, 627–632 dysplastic, 651 embryonal rhabdomyosarcoma and, 875 flexural skin, 625 with focal atypical epithelioid cell component, 649

Nevus, melanocytic (Cont.): genital skin, 624–625 with phenotypic heterogeneity, 648–649 presentations of, 625t, 627 scalp, 625–627 from special sites, 623–627 uncommon findings in, 625t, 627 mucinous, 370 neural, 621 neurotized, 621 nipple, 409 pagetoid Spitz, 636 papillomatous dermal, 672 patchlike blue, 647 pigmented spindle cell, 640 with atypical features, 640–641 clinical features, 640 differential diagnosis, 640–641 histopathologic features, 640 plaque-type blue clinical features, 647–648 histopathologic features, 647–648 plexiform spindle cell, 650 clinical features, 650 differential diagnosis, 650 histopathological features, 650 plexiform Spitz, 639 pseudoangiomatous melanocytic, 841 recurrent melanocytic, 622 clinical features, 622 differential diagnosis, 622 histopathological features, 622 scalp melanocytic, 625–627 clinical features, 626 differential diagnosis, 626–627 histopathological features, 626 sclerosing blue, 645 differential diagnosis, 645 histopathological features, 645 small congenital, 628–630 Spitz, 620, 632–635, 633f, 633t, 663 absent or rare mitosis in, 635 adnexal epithelium, 635 angiomatoid, 639 atypical, 636, 637t clinical features, 632–635 compound, 637f dermal component, 637–638 desmoplastic, 638–639, 639t, 640t epidermal hyperplasia, 635 halo, 639 histopathologic features, 634–635 hyalinizing, 639 intraepidermal component, 636 junctional cleavage, 635 kamino bodies, 635 lymph node involvement, 638 maturation (zonation), 635 pagetoid, 636 pagetoid spread, 635 perivascular inflammatory cell infiltrates, 635 plexiform, 639 prominent pagetoid spread, 636 tubular, 639 variants, 639 target blue, 648 tubular Spitz, 639

Nevus (Cont.): white sponge, 1003f clinical features, 1002 differential diagnosis, 1002 histopathologic features, 1002 Nevus anemicus, 345–346 Nevus araneus. See Arterial spider Nevus cells cytology of, 618–619 maturational sequence of, 618–619 Nevus comedonicus, 559–560 clinical features, 559 differential diagnosis, 560 histopathological features, 559 Nevus depigmentosus, 344–345 differential diagnosis, 345 histopathological features, 345 Nevus flammeus. See Port wine stains Nevus fuscoceruleus acromiodeltoideus, 642 Nevus fuscoceruleus ophthalmomaxillaris, 641 Nevus fuscoceruleus zygomaticus, 641–642 Nevus lipomatous superficialis, 857–858, 857f Nevus of Ito, 642 Nevus of Ota, 641 Nevus sebaceous, 695–696 clinical features, 695–696 histopathologic features, 696 Nevus sebaceous adenoma, 690 Nevus spilus, 622 clinical features, 622 differential diagnosis, 622 histopathological features, 622 NF. See Necrotizing fasciitis NHL. See non-Hodgkin lymphomas Niacin deficiency, 76–77 NICH. See Noninvoluting congenital hemangioma Nicotinamide adenine dinucleotide phosphate (NADPH), 322 Nicotine stomatitis, 1008 clinical features, 1008 differential diagnosis, 1008 histopathologic features, 1008 Nikolsky sign, 424 Nipple nevus, 409 NKIC3 gene, 871 NL. See Necrobiosis lipoidica NM. See Nodular melanoma NNN. See Novy-MacNeal-Nicolle Nocardia, 267, 459t, 475, 478, 480–481 differential diagnosis, 481 Nocardiosis, 480–481, 481t clinical features, 480–481 histopathological features, 480–481 Nodal lymphomas, 924 Nodular amyloidosis, 376–377, 377f Nodular angioblastic hyperplasia with eosinophilia and lymphofolliculosis. See Epithelioid hemangioma Nodular basal cell carcinoma, 580f histopathological features, 580–582 Nodular colloid degeneration, 379 Nodular dermal infiltrates, 11f, 98–133 Nodular fasciitis, 771–773, 772f, 772t, 877, 972 clinical features, 771 differential diagnosis, 773 histopathologic features, 771

O Ochronosis, 353–354, 384–385 histopathological features, 354, 384–385 Oculocutaneous albinism, 341–342 Oculocutaneous tyrosinosis, 320 Ohio Valley disease. See Classic histoplasmosis Oil red O, 693 OIN. See Oral intraepithelial neoplasia Omphalith, 416 clinical features, 416 histopathological features, 416 Omphalomesenteric duct remnants, 413–414, 414t differential diagnosis, 413–414 histopathological features, 413

Onchocerca volvulus, 531, 533, 534 Onchocerciasis, 531–533 clinical features, 531–532 histopathological features, 532 Onychitis eczematous, 989–990 traumatic, 991–992 Onychomatricoma, 993 clinical features, 993 differential diagnosis, 993 histopathologic features, 993 Onychomycosis, 462, 478, 987–988 clinical features, 987 differential diagnosis, 989 distal lateral subungual onychomycosis, 462 false-negative cases, 984–985 histopathologic features, 987–988 proximal subungual, 462–463 proximal white subungual, 463 O’Nyong-Nyong, 503 OPN. See Osteopontin Oral carcinomas, 968 clinical features, 968 differential diagnosis, 968 histopathologic features, 968 immunohistochemistry, 968 special stains, 968 Oral contraceptives, 287 Oral hairy leukoplakia, 1005 clinical features, 1005 differential diagnosis, 1005 histopathologic features, 1005 Oral hygiene, 596 Oral intraepithelial neoplasia (OIN), 1016 Oral lichen planus, 1007–1008 clinical features, 1007 differential diagnosis, 1008 histopathologic features, 1007–1008 Oral lymphoepithelial cyst, 1003, 1004f clinical features, 1003 differential diagnosis, 1003 histopathologic features, 1003 Oral melanoacanthosis, 1016 clinical features, 1016 differential diagnosis, 1016 histopathologic features, 1016 Oral melanotic macule, 1015–1016 clinical features, 1015 differential diagnosis, 1015–1016 histopathologic features, 1015 Oral mucosa, 1002–1018. See also specific disorders developmental conditions, 1002–1004 dysplastic conditions, 1016–1018 immune-mediated conditions, 1006–1014 infectious conditions, 1004–1006 neoplastic conditions, 1016–1018 pigmented conditions, 1015–1016 reactive conditions, 1006–1014 Oral mucous cyst, 369 histopathological features, 369 Oral submucous fibrosis, 1017 clinical features, 1017 differential diagnosis, 1017 histopathologic features, 1017

Oral verrucous carcinoma, 596 clinical features, 597 differential diagnosis, 598 histopathological features, 597 Orf, 512, 513f Organ transplants, squamous cell carcinoma nad, 591 Oriental sore, 518 Orientia, 454 Ornithodoros, 451 Orofacial granulomatosis, 1009–1010 clinical features, 1009 Oroya fever, 442 Orthohyperkaratosis, 52, 577 Orventral cuticle, 983 Osler disease. See Hereditary hemorrhagic telangiectasia Osler-Weber-Rendu disease. See Hereditary hemorrhagic telangiectasia Osteoblasts, 383 Osteocartilaginous tumors, 994–996 clinical features, 994 histopathologic features, 994 Osteochondroma, 384 extraskeletal chondroma and, 876 fibroosseous pseudotumor and, 877 Osteoclast-like giant cells, 593 Osteogenesis imperfecta, 398 histopathological features, 398 Osteogenic sarcoma, 972 Osteoma cutis, 384, 877 Osteomyelitis, 470, 591 Osteopoikilosis, 392 Osteopontin (OPN), 259 Osteosarcoma, fibroosseous pseudotumor and, 878 Osteosarcomas, soft tissue, 792 Oxalosis, 208, 259 clinical features, 208, 259 differential diagnosis, 208, 259 histopathological features, 208, 259 P p27, 575 p53, 297, 585, 587, 593, 744 Pachyonychia congenita, 320, 329–330 differential diagnosis, 330 histopathological features of, 330 Paecilomyces, 487 histopathological features, 487 Paget disease, 75, 409, 753f, 960 apocrine type, 750–752 clinical features, 751 histopathological features, 751 of breast, 961, 963 Pagetoid cutaneous melanoma, 656, 658f Pagetoid intraepidermal component, melanoma with, 660 Pagetoid melanocytosis, 667 Pagetoid reticulosis (PR), 910, 912–913, 913f clinical features, 912 differential diagnosis, 913 histopathologic features, 912 Pagetoid Spitz nevus, 636 Pagetoid spread, 671 prominent, 636 Spitz nevus, 635 Palisaded granulomatous dermatitis, 107t

INDEX

Nodular growth pattern, 907f Nodular hidradenomas, 588 Nodular melanoma (NM), 657, 662, 663t, 664 Nodular mucinosis, in lupus erythematosus, 367 Nodular vasculitis, 255, 268–269 Nodular venous malformations, 838 Nodular-cystic fat necrosis, 858 Nonbullous ichthyoses, 313 differential diagnosis of, 314t Non-Hallopeau-Siemens syndrome, 171t non-Hodgkin lymphomas (NHL), 905 Noninfectious granulomatous, panniculitis, 275–276 Noninfectious granulomatous panniculitis, 275–276 Noninflammatory conditions, 13–14 Noninflammatory disorders, 7f Noninflammatory purpura, 209 Noninvoluting congenital hemangioma (NICH), 804–805, 805f GLUT-1 and, 805 PH and, 807 Nonscarring alopecia, 13, 215–223 causes of, 221–223 clinical features, 221 differential diagnosis, 223 histopathological features, 222–223 differential diagnosis, 216 histopathological features, 217t, 222–223 scarring v., 215 Nonsteroidal anti-inflammatory drugs (NSAIDs), 66, 287 Nonvenereal treponematoses, 449–456 NOR1, extraskeletal myxoid chondrosarcoma and, 877 Normal skin, differential diagnosis of, 14t North American blastomycosis, 459t, 469–471, 470t clinical features, 469–470 differential diagnosis, 470–471 histopathological features, 470 Novy-MacNeal-Nicolle (NNN), 519 NSAIDs. See Nonsteroidal anti-inflammatory drugs Nuclear dust, 182 Nuclear hyperchromasia, 771 Nummular dermatitis, 21, 29f clinical features of, 21 histopathological features of, 21

1069

INDEX 1070

Palisaded granulomatous form, 105 histopathological features, 105 Palisaded granulomatous infiltrates, 104–111 actinic granuloma, 107 deep granuloma annulare, 106–107 granuloma annulare, 104–105 Infectious palisaded granulomatous dermatitis, 110–111 interstitial or incomplete form, 105–106 necrobiosis lipoidica, 107–108 necrobiotic xanthogranuloma, 109 palisaded granulomatous form, 105 palisaded neutrophilic and granulomatous dermatitis, 109–110 rheumatic fever nodule, 109 rheumatoid nodule, 108–109 Palisaded neuromas, 886t Palisaded neutrophilic and granulomatous dermatitis, 109–111 differential diagnosis, 110 histopathological features, 110 Palisading granulomas, panniculitis associated with, 261 Palisading schwannomas, 890 Palmar fibromatosis, 773–774 clinical features, 773 differential diagnosis, 774 histopathologic features, 773–774 Palmoplantar eccrine hidradenitis, 245 clinical features, 245 differential diagnosis, 245 histopathological features, 245 Palmoplantar keratoderma, 319–320 clinical features, 320 differential diagnosis, 320 Meleda type, 320 of Vomer, 329 Palmoplantar neutrophilic eccrine hidradenitis, 128 Palmoplantar pustular psoriasis of Barber, 67 Palmoplantar pustulosis, 67, 69f Palpable purpura, 179, 182 PAN. See Polyarteritis nodosa Pan T-cell marker, 907 Pancreatic panniculitis, 265, 266f clinical features, 265 differential diagnosis, 265 histopathological features, 265 Pan-keratin, pleomorphic liposarcoma and, 868 Panniculitis, 13, 90, 250–276 algorithm, 251f–252f atrophic connective tissue, 274 chemical, 271 cold, 270 connective tissue, 274 crystal-related, 265–266, 266t cytophagic histiocytic, 263–265 in dermatomyositis, 273–274 clinical features, 273–274 histopathological features, 273–274 diagnosis of, 251f–252f diffuse, 269 eosinophilic, 275t evaluation of, 250t factitial, 271 focal, 269

Panniculitis (Cont.): histopathological features, 253t idiopathic lobular, 261 infection-related, 267–268, 269f interpretation, 251 liquefying, 261 lobular, 261–275 acute, 262f idiopathic, 261 lupus, 48, 272–273 ossificans, 878 palisading granulomas and, 261 pancreatic, 265, 266f of Pinol, 252 in polymyositis, 273–274 clinical features, 273–274 histopathological features, 273–274 poststeroid, 265, 267 predominant patterns of, 253t septal, 251–261, 255t trauma-related, 270–271 of Villanova, 252 Papillae, squiring, 66 Papillary dermis, alterations of, 14 Papillary digital eccrine adenocarcinoma (PDEA), 741–743, 742f, 743f clinical features, 742 histopathologic features, 742–743 Papillary eccrine adenoma, 731, 732f clinical features, 731 differential diagnosis, 731 histopathological features, 731 Papillary hemangioma (PH), 807, 807f GH and, 807 hyaline globules and, 807 NICH and, 807 POEMS and, 807 Papillary intralymphatic angioendothelioma, GH and, 816 Papillary intralymphatic angioendothelioma (PILA), 825–826, 826f RH and, 827 Papillary squamous cell carcinoma, 595 Papillary tubular adenoma, 731 Papillomatosis, 837 Papillomatosis cutis, 596 Papillomatous dermal nevi, 672 Papillon-Lefèvre syndrome, 320 Papular hemangioma. See also Epithelioid hemangioma Papular mucinosis, 365–366 in lupus erythematosus, 367 Papular purpuric gloves and socks syndrome, 498 Papular xanthoma, 115–116 clinical features, 115 differential diagnosis, 115–116 histopathological features, 115 Papules, erythematous, 200f Parabasal mitoses, 597 Paracoccidioides brasiliensis, 472, 488, 489 Paracoccidioidomycosis, 459t, 472–473 clinical features, 472 differential diagnosis, 472 histopathological features, 472 pulmonary, 472

Paraffin, 271 Paragangliomas, adult rhabdomyoma and, 873 Paragonimiasis, 530, 538 clinical features, 538 cutaneous, 538 differential diagnosis, 538 histopathological features, 538 Paragonimus westermani, 548 Parakeratin, 448 Parakeratosis, 67, 448, 592 focal, 74 shoulder, 69 Paramyxovirus, 496 Paraneoplastic pemphigus, 61, 143, 145–147, 146f, 146t clinical features, 145–146 histopathological features, 146t Paraneoplastic vasculitis, diagnosis, 186 Parapoxviruses, 513 Paraproteins, 185 Parapsoriasis, 71–72, 913–914 clinical features of, 71–72, 913 differential diagnosis, 72, 914 histopathologic features, 913 histopathological features, 72 large-plague, 71 small-plague, 71 Parathormone, 266 Parinaud oculoglandular syndrome, 441 Parkes Weber syndrome, 832–833 Paronychia, 990–991 clinical features, 990 differential diagnosis, 991 histopathologic features, 990–991 Parosteal fasciitis. See Fibroosseous pseudotumor Parvovirus B9, 93 PAS. See Periodic acid-Schiff PATCHED gene, 587, 589, 591 Patchlike blue nevus, 647 Pathogenesis, polymorphous light eruption, 89 Pattern recognition, 5f Patterned hypermelanosis, 347–348 Patterned leukoderma, 338–339 Paucicellular nodule, 797 Paucicellular tumor, 797 Pauci-immune vasculitides, 196 Pautrier microabscesses, 286, 306 PAX3-FKHR, 875 PCR. See Polymerase chain reaction PDCs. See Plasmacytoid dendritic cells PDEA. See Papillary digital eccrine adenocarcinoma PDFGB. See B-chain gene PDGF. See Platelet-derived growth factor Pearly penile papules, 767–768 clinical features, 767–768 differential diagnosis, 768 histopathological features, 768 Peau d’orange, 270 PEComas, angiomyolipoma and, 862 PECs. See Proliferating epithelial cysts Pediculus humanus, 309 Pedunculated seborrheic keratosis, 565–566, 767

Perineural invasion, 666 Perineuriomas, 889 clinical features, 889 differential diagnosis, 889 histopathologic features, 889 soft tissue, 889f, 890t Perineurium, 883 Periodic acid-Schiff (PAS), 52, 66, 740, 894, 986t chondroid lipoma and, 861 TA and, 806 Perioral dermatitis, 99–100, 237–240 clinical features, 237–238 histopathological features, 100, 239–240 Peripheral nerve hamartomatous lesions of, 883–884 reactive lesions of, 883–884 Peripheral nerve sheath neoplasms, 884–896 Peripheral neuroectodermal tumor (PNET), 963 Periungual fibroma, 768–769 clinical features, 768 differential diagnosis, 769 histopathologic features, 768 Perivascular dermatitis, 81–94 Perivascular inflammatory cell infiltrates, 81t, 160f Spitz nevus, 635 Perniosis, 88–89, 94, 192–193, 304, 304f clinical features, 88 differential diagnosis, 89, 192–193 histopathological features, 88 Peutz-Jeghers syndrome, 348, 616 PEX1, 315 PEX6, 315 PG. See Epithelioid hemangioma; Lobular capillary hemangioma PH. See Papillary hemangioma PHACE. See Posterior fossa brain malformations, infantile hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities syndrome Phaeohyphomycosis, 459t, 477, 478f clinical features, 477 differential diagnosis, 477 histopathological features, 477 Phagocytosis-inducing factor (PIF), 264 Phenol, 353 Phenotypic heterogeneity melanocytic lesions with, 648 melanocytic nevi with, 648–649 clinical features, 648 histopathological features, 648–649 Phenytoin-induced exanthems, 295t Phlebectasias, Maffucci syndrome and, 838 Phlebolith, SCH and, 808 Phlebotomus, 442 Phlebotomus, 517 Photoallergic dermatitis, 17–18, 28f clinical features of, 18 histopathologic features of, 18 Photochemotherapy-induced (PUVA) lentigo, 615 Photodermatosis, 90 Photophobia syndrome, 321 Photosensitivity dermatitis, 286

Photosensitivity drug eruptions, 285–287 differential diagnosis, 286–287 histopathological features, 286 Phototoxic dermatitis, 18 clinical features of, 18 histopathological features of, 18 Phrynoderma, 233 Phthirus pubis, 309 Physalia physalis, 307 Phytonadione, 390 Piannic onychia, 450 Piebaldism, 338–339 clinical features, 338–339 differential diagnosis, 339 histopathological features, 339 Piedra, 467–468 black, 459t, 467 differential diagnosis, 468 histopathological features, 468 white, 459t, 467t Piedraia hortae, 430, 467 PIF. See Phagocytosis-inducing factor Pigment deposits, 353 Pigmentation disorders, 338–357, 338t. See also specific disorders evaluation of, 341t hyperpigmentation, 339f, 346–357 acromelanosis, 347 Addison disease, 346 clofazimine-induced, 123 Crow-Fukase syndrome, 347 diffuse, 346 generalized, 346 Nelson syndrome, 346 POEMS, 347 postinflammatory, 352 differential diagnosis, 352 histopathological features, 352 zosteriform, 352 hypopigmentation, 338–346, 342t ash leaf spots, 343 Chédiak-Higashi syndrome, 343 Hermansky-Pudlak syndrome, 342–343 hypomelanosis, 345 hypomelanosis of Ito, 344 idiopathic guttate hypomelanosis, 344 incontinentia pigmenti achromians, 344 nevus anemicus, 345–346 nevus depigmentosus, 344–345 oculocutaneous albinism, 341–342 piebaldism, 338–339 pityriasis alba, 345 postinflammatory leukoderma, 345 vitiligo, 340–341 Vogt-Koyanagi-Harada syndrome, 340–341 Pigmented basal cell carcinoma, 581f Pigmented conditions, 1015–1016 Pigmented dermatofibrosarcoma protuberans, 787, 788f Pigmented epithelioid melanocytoma, 643 Pigmented follicular cyst, 548 Pigmented purpuric dermatoses, 88, 193–194, 195f clinical features, 193–194 differential diagnosis, 194 of Gougerot and Blum, 193 of Schamberg, 193

INDEX

Peeling skin syndrome, 332–333 clinical features, 332 differential diagnosis, 332 histopathological features, 332 Pellagra, 76–77 clinical features, 77 histopathological features, 77 PELVIS. See Perineal IH, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag syndrome Pemphigoid bullous, 157–160, 288 cell-poor, 159f clinical features, 158 diagnosis, 159 differential diagnosis, 159–160 direct immunofluorescence, 159 histopathological features, 158 indirect immunofluorescence, 159 urticarial lesion of, 160f cell-poor bullous, 159f cicatricial, 162–163 antigenic targets in, 163t clinical features, 162 differential diagnosis, 163 histopathological features, 162 drug-induced, 288 clinical features, 288 histopathological features, 288 Pemphigus erythematosus, 143–144 differential diagnosis, 144 histopathological features, 143–144 Pemphigus foliaceus, 143, 144f Pemphigus vegetans, 138, 143f, 428 differential diagnosis, 142–143 Pemphigus vulgaris, 138–143, 138f histopathological features, 140–142 Penicillin, 281 Penicillium, 458 Penicillium marneffei, 488 Penile fibromatosis, 774 clinical features, 774 differential diagnosis, 774 histopathologic features, 774 Penile lentigo, 617f Pentazocine, 271, 390 Perforating collagenoses, 397 reactive, 397 Perforating dermatoses, 332–335 acquired, 333, 333t, 334f Perforating folliculitis, 240–241 clinical features, 240 differential diagnosis, 240–241 histopathological features, 240 Peribulbar lymphocytic infiltration, 219 Pericytes, endothelial cells and, 802 Perifollicular elastolysis, 402 Perifollicular fibroma, 712t, 713 Perifollicular inflammation, 52 Perifolliculitis capitis abscedens et suffodiens. See Dissecting cellulitis Perineal IH, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag syndrome (PELVIS), 831

1071

INDEX 1072

Pigmented schwannomas, 890 Pigmented spindle cell nevus (PSCN), 640 with atypical features, 640–641 clinical features, 640 differential diagnosis, 640–641 histopathologic features, 640 PILA. See Papillary intralymphatic angioendothelioma PILA and, 826 Pilar basal cell carcinoma, 584–585 Pilar cysts, 544 differential diagnosis, 544 histopathological features, 544 proliferating, 544 Pilar leiomyoma, 714, 869t, 870f clinical features, 714 differential diagnosis, 714 histopathologic features, 714 Pilar leiomyosarcoma, 718 Pilar neoplasms, 696 malignant, 715–718 Pilar neurocristic hamartoma, 648 Pilar sheath acanthoma (PSA), 697–698 clinical features, 697 histopathologic features, 697–698 Pilar tumors benign proliferating, 701–702 clinical features, 701 cytologic features of, 701–702 differential diagnosis, 702 histopathologic features, 701–702 malignant proliferating, 716–717, 717f clinical features, 716 differential diagnosis, 716–717 histopathologic features, 716 proliferating, 702f benign, 701–702 malignant, 716–717 Pilomatricoma (PM), 702, 706, 706t, 708f clinical features, 706 differential diagnosis, 707 histopathological features, 706–707 invasive, 717, 718t Pilomatrix carcinoma, 717, 718t clinical features, 717 differential diagnosis, 717 histopathological features, 717 Pilonidal cysts, 553 Pilonidal sinus, 416–417 Pink amorphous deposits, 372t Pink nodule, 930 Pinkus follicular mucinosis, 369 differential diagnosis, 369 histopathological features, 369 Pinta, 450 histopathological features, 450 Pintids, 451 Pitted keratolysis, 430 clinical features, 430 differential diagnosis, 430 histopathological features, 430 Pityriasiform dermatitis, 10 Pityriasiform eruptions, 293 clinical features, 293 differential diagnosis, 293 histopathological features, 293

Pityriasis alba, 20–21, 345 clinical features, 20–21 differential diagnosis, 345 histopathological features, 20–21, 345 Pityriasis lichenoides, 87–88 clinical features, 87 differential diagnosis, 87–88 histopathological features, 87 Pityriasis lichenoides chronica (PLC), 42, 57–58 clinical features, 57–58 differential diagnosis, 58 histopathological features, 58 Pityriasis lichenoides varioliformis acuta (PLEVA), 42, 51, 55–58 clinical features, 55 differential diagnosis, 57 histopathological features, 55–57 Pityriasis rosea, 23–24, 32f, 72–74, 510 clinical features, 73–74 Pityriasis rubra pilaris (PRP), 68–70, 70t, 71f clinical features, 69 differential diagnosis, 70 histopathological features, 69–70 inherited, 321–322 Pityriasis versicolor, 459t, 465 histopathological features, 465 Pityrosporum orbiculare, 465 Pityrosporum ovale, 234, 240, 465 Placenta-like alkaline phosphatase (PLAP), 963 Plague, 436 Plakoglobin, 593 Plantar fibromatosis, 773–774 clinical features, 773 differential diagnosis, 774 histopathologic features, 773–774 Plantar verrucous carcinoma, 596 clinical features, 597 differential diagnosis, 598 histopathological features, 597 PLAP. See Placenta-like alkaline phosphatase Plaques of pregnancy, 29–30, 84 clinical features, 29, 84 differential diagnosis of, 30, 84 histopathological features, 29, 84 Plaque-type blue nevus clinical features, 647–648 histopathologic features, 647–648 Plasma cell stomatitis, 1010 clinical features, 1010 differential diagnosis, 1010 histopathologic features, 1010 Plasma cell vulvitis, 128 Plasma cells, 907, 929 Plasmacytoid dendritic cells (PDCs), 926 Plasmacytosis circumorificialis, 128 Plasmacytosis mucosae, 128–129 clinical features, 128 histopathological features, 128–129 Platelet-derived growth factor (PDGF), 785, 786 Platelets IH and, 802 KHE and, 824 PLC. See Pityriasis lichenoids chronica Plectin, 156

Pleomorphic basal cell carcinoma, 582 Pleomorphic lipoma, 860–861, 860t, 861f WDL/ALT and, 865, 866 Pleomorphic liposarcoma, 780, 868, 868f, 868t Pleomorphic malignant fibrous histiocytoma, 791–792 Pleomorphic rhabdomyosarcoma,875–876, 875f adult rhabdomyoma and, 873 Pleomorphism, 906 Pleurodynia, 503 PLEVA. See Pityriasis lichenoids varioliformis acuta Plexiform fibrohistiocytic tumor, 101, 788–789 clinical features, 788 differential diagnosis, 789 histopathologic features, 788–789 Plexiform neurofibromas, 887, 888f Plexiform schwannoma, 892f Plexiform spindle cell nevus, 650 clinical features, 650 differential diagnosis, 650 histopathological features, 650 Plexiform Spitz nevus, 639 Plexiform xanthoma, 116 clinical features, 116 differential diagnosis, 116 histopathological features, 116 PM. See Pilomatricoma PNET. See Peripheral neuroectodermal tumor; Primitive neuroectodermal tumor Pneumocystis carinii, HIV and, 501 POEMS. See Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes Poikiloderma, 58–59 accompanying dermatomyositis, 59 of Civatte, 59 congenitale, 59 mycosis fungoides, 59 Polyarteritis nodosa (PAN), 179, 200t clinical features, 200–201 differential diagnosis, 201 histopathological features, 201 Polydactyly. See Supernumerary digit Polymerase chain reaction (PCR), 268, 269, 421, 446, 467, 517, 907, 928 APL and, 844 RH and, 827 Polymethylsiloxane, 271 Polymorphous light eruption, 89–90 clinical features, 89 differential diagnosis, 90 histopathological features, 89 pathogenesis, 89 Polymyositis, panniculitis in, 273–274 clinical features, 273–274 histopathological features, 273–274 Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS), 347, 806, 815 GH and, 816 MVH and, 809 PH and, 807 RAE and, 818 Polyoma virus, 515

Primary cutaneous CD4+ pleomorphic T-cell lymphoma (SM-PTL), 921 clinical features, 921 definition, 921 differential diagnosis, 921 genotypic features, 921 histopathological features, 921 immunophenotypic features, 921 Primary cutaneous CD8+ T-cell lymphoma, 921–922 clinical features, 921 differential diagnosis, 921–922 genotypic features, 921 histopathologic features, 921 immunophenotypic features, 921 Primary cutaneous CD30+ lymphoproliferative disorders, 915 Primary cutaneous follicle center cell lymphoma, 931f Primary cutaneous follicle center lymphoma, 934f Primary cutaneous marginal zone B-cell lymphoma, 934f, 935f Primary cutaneous melanoma, 678, 679t Primary cutaneous meningioma, 900f Primary cutaneous mucinoses dermal degenerative, 363–369 follicular degenerative, 369 inflammatory, 363–369, 369 Primary cutaneous ossification, 384 Primary cutaneous peripheral T-cell lymphoma, 921 unspecified, 922–924 clinical features, 923 definition, 922 differential diagnosis, 924 genotypic features, 924 histopathological features, 923 immunophenotypic features, 924 Primary mucoepidermoid carcinoma, 745 Primary neuroendocrine carcinoma, 896–897, 898f clinical features, 896–897 differential diagnosis, 897 histopathological features, 897 Primary scarring alopecia, 224–225 lymphocyte-associated, 225, 231t pustulofollicular, neutrophil-associated, 230, 236t Primary signet ring cell adenocarcinoma, 752–753, 754f clinical features, 752–753 differential diagnosis, 753 histopathologic features, 752–753 Primary syphilis, 446, 447–448, 447t differential diagnosis, 448 Primary yaws, 449–450 Primitive neuroectodermal tumor (PNET), 874, 897 alveolar rhabdomyosarcoma and, 875 extraskeletal osteosarcoma and, 879 Procainamide, 289 Proflaggrin, 314 Progeria, 399–400 adult, 399 clinical features, 400 histopathological features, 400

Progressive capillary hemangioma. See Tufted angioma Progressive nodular histiocytoma, 122 clinical features, 122 differential diagnosis, 122 histopathological features, 122 Progressive symmetric erythrokeratoderma, 320 clinical features, 320 differential diagnosis, 320 histopathological features, 320 Progressive systemic sclerosis (PSS), 388–390 Proliferating epithelial cysts (PECs), 543, 554 differential diagnosis, 554 histopathological features, 554 Proliferating pilar cysts, 544 Proliferating pilar tumor, 702f benign, 701–702 malignant, 716–717 Proliferative conditions, 13. See also specific proliferative conditions Proliferative fasciitis, 772f Prominent myxoid component, 797 Prominent pagetoid spread, Spitz nevus, 636 Promontory sign, KS and, 821 Prostaglandins, 81–82, 266 Prostate-specific antigen (PSA), 962 Prostate-specific membrane antigen (PSMA), 963 Protein tyrosine phosphatases, 593 Proteus, 276, 427, 428, 482 Prototheca wickerhamii, 526, 989 Prototheca zopfii, 526 Protothecosis, 526–527, 526t differential diagnosis, 527 Protozoal infections, 517–527 diagnosis, 517 Proximal subungual onychomycosis (PSO), 462–463 Proximal white subungual onychomycosis (PWSO), 463 PRP. See Pityriasis rubra pilaris Prurigo nodularis, 24f, 72f, 562t clinical features, 561 differential diagnosis, 562 histopathological features, 561 Prurigo pigmentosa, 352 differential diagnosis, 352 histopathological features, 352 Pruritic papules, 29–30 clinical features, 29 differential diagnosis of, 30 histopathological features, 29 Pruritic urticarial papules, 84 clinical features, 84 differential diagnosis of, 84 histopathological features of, 84 Pruritic urticarial papules of pregnancy clinical features, 84 histopathological features, 84 PSA. See Pilar sheath acanthoma; Prostatespecific antigen Psammoma, 99 bodies, 898 Psammomatous melanotic schwannomas, 796 PSCN. See Pigmented spindle cell nevus

INDEX

Polypoid basal cell carcinoma, 580 Polythelia. See Accessory nipple Pompholyx eczema clinical features, 21–22 histopathological features, 21–22 Porocarcinomas, 729 Poroid hidradenoma, 729 Porokeratosis, 323–324, 590 clinical features, 323 differential diagnosis, 324 histopathological features, 323–324 Poroma, 730f, 731f Porphyria, 379–380 histopathological features, 380 Porphyria cutanea tarda, 172–173, 173t, 380, 380f Port wine stains (PWSs), 813, 832, 834f AVMs, 847 Portuguese man-of-war, 307t Posterior fossa brain malformations, infantile hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities syndrome (PHACE), 831 Postfebrile anagen, 216 Postinflammatory hyperpigmentation, 352 differential diagnosis, 352 histopathological features, 352 Postinflammatory leukoderma, 345 Post-kala-azar dermal leishmaniasis, 518 Postpartum anagen, 216 Poststeroid panniculitis (PSP), 265, 267 Povidone-iodine, 271, 421 Poxvirus infections, 512–514 animal, 512 clinical features, 512 differential diagnosis, 514 histopathological features, 513 PPARG, 274 PR. See Pagetoid reticulosis Precursor hematologic neoplasms, 926 Precursor lesions, 591. See also specific types Precursor T-lymphoblastic lymphoma, 926 Prednisone, 264 Pregnancy, PG and, 813 Premature aging syndromes, 399–400, 405 Pressure alopecia, 220–221, 226 clinical features, 220 differential diagnosis, 220 histopathological features, 220 Pretibial myxedema, 364–365 differential diagnosis, 364–365 histopathological features, 364 Primary apocrine carcinomas, 749 Primary cutaneous adenosquamous carcinoma, 745 clinical features, 745 differential diagnosis, 745 histopathologic features, 745 Primary cutaneous anaplastic large cell lymphoma, 917–919, 918f clinical features, 917 definition, 917 differential diagnosis, 917–919 genotypic features, 917 histopathological features, 917 immunophenotypic features, 917 Primary cutaneous B-cell lymphomas, 931

1073

INDEX 1074

Pseudoainhum constricting bands, 396 Pseudoallescheria boydii, 479, 487 Pseudoangiomatous melanocytic nevi, 841 Pseudocysts, 523 of auricle, 553 Pseudoepitheliomatous hyperplasia, 434f, 519, 561–562 Pseudofolliculitis barbae, 238 clinical features, 238 histopathological features, 238 Pseudoglandular squamous cell carcinoma, 1018 Pseudohyphae, 464 Pseudohypoparathyroidism, 384 Pseudo-Kaposi sarcoma. See Acroangiodermatitis Pseudolipoblasts, 792 Pseudolymphomas (PSLs), 298, 905 Pseudolymphomata, drugs implicated in, 291t Pseudomonas aeruginosa, 234, 276, 423, 428, 482, 990 Pseudoneoplastic lesions, 696 of sweat glands, 755–759 Pseudoneoplastic proliferations of follicle-related mesenchyme, 718–720 of hair follicles, 718–720 Pseudoneoplastic sebaceous proliferations, 695–696 clinical features, 695–696 differential diagnosis, 696 histopathologic features, 696 Pseudopelade, 227 Pseudoporphyria, 173–174 clinical features, 173–174 diagnosis, 174 differential diagnosis, 174 drug-induced, 288 histopathological features, 174 Pseudostratified columnar epithelium, 552 Pseudovascular adenoid squamous cell carcinoma, 594–595 Pseudovasculitis, 203–209, 204t atrophie blanche, 206, 207f calciphylaxis, 207–208, 208t, 209f coagulopathies, 203 cryoglobulinemias, 203–204 cutaneous cholesterol embolism, 204 Degos syndrome, 206 livedo reticularis, 205 vascular occlusive conditions, 203 Pseudoxanthoma elasticum, 401 clinical features, 401 differential diagnosis, 401 histopathological features, 401 Psittacosis, 442–443 clinical features, 443 differential diagnosis, 443 histopathological features, 443 PSLs. See Pseudolymphomas PSMA. See Prostate-specific membrane antigen PSO. See Proximal subungual onychomycosis Psoriasiform dermatitis, 9, 64–78 Psoriasiform drug reactions, 293 Psoriasiform keratosis, 566

Psoriasis, 64–66, 65t, 73, 989 clinical features, 64, 989 differential diagnosis, 66, 989 guttate, 66f, 67f histopathologic features, 989 histopathological features, 64–65 pustular, 66–68 clinical features, 67 differential diagnosis of, 67–68 histopathological features, 67 palmoplantar, of Barber, 67 of von Zumbusch, 67 verrucous, 66 Psorospermium, 489 PSP. See Poststeroid panniculitis PSS. See Progressive systemic sclerosis Psychotropic drugs, 356 PTCH gene, 872 Pulmonary adenocarcinoma, 966 Pulmonary paracoccidioidomycosis, 472 Punch specimen, 3 Punctate keratoses, 602 clinical features, 602 differential diagnosis, 602 histopathological features, 602 Purpura, 179. See also Henoch-Schönlein purpura eczematid-like, of Doucas and Kapetanakis, 193 noninflammatory, 209 palpable, 179, 182 senile, 209f Purpura annularis telangiectodes of Majocchi, 193 Pustular drug reaction, 153–154 clinical features, 153 histopathological features, 153 Pustular eruptions, 287 clinical features, 287 differential diagnosis, 287 histopathological features, 287 Pustular psoriasis, 66–68 clinical features, 67 differential diagnosis of, 67–68 histopathological features, 67 palmoplantar, of Barber, 67 of von Zumbusch, 67 Pustular secondary lues, 153 clinical features, 153 histopathological features, 153 Pustular vasculitis, 182 Pustule, 136 Pustulofollicular, neutrophil-associated primary scarring alopecia, 230, 236t Pustulosis, palmoplantar, 67, 69f PUVA lentigo. See Photochemotherapyinduced lentigo PWSO. See Proximal white subungual onychomycosis PWSs. See Port wine stains Pyoderma faciale, 99 Pyoderma gangrenosum, 126, 186t, 191, 428 clinical features, 126, 191 histopathological features, 126, 192 Pyoderma vegetans, 428–429 differential diagnosis, 429 histopathological features, 428

Pyogenic granuloma (PG), 803t, 813–815, 814f, 814t, 1013f histologic features of, 823t Pyostomatitis vegetans, 1009 clinical features, 1009 differential diagnosis, 1009 histopathologic features, 1009 Pyrazolone, 281 Pyridoxine, 259 Q Quinine, 353 R Radial growth phase, 657 Radiation angiosarcoma and, 829 benign acquired vascular lesions with, 850 Radiation dermatitis, 301–303, 302f, 303f, 394–395 differential diagnosis, 394 Radiation reactions, 301–303 clinical features, 301–302 differential diagnosis, 302–303 histopathological features, 302 Radiation-induced morphea, 301 RAE. See Reactive angioendotheliomatosis Ramichloridium obovoideum, 477 Rapamycin, 343 Rapid plasma regain (RPR), 437 Rapidly involuting congenital hemangioma (RICH), 804–805 GLUT-1 and, 805 RASA1 gene, 833 Raynaud disease, 93 Raynaud phenomenon, 388 Reaction patterns. See also specific types in diagnosis, 5f erythema nodosum, 256f Reactive angioendotheliomatosis (RAE), 806, 817–818, 818f angioendotheliomatosis and, 817 GH and, 816 Reactive conditions, 1006–1014 Reactive follicles, 928 Reactive lesions features of, 5–8 of peripheral nerve, 883–884 Reactive lymphocytes, 907 Reactive perforating collagenosis (RPC), 240, 397 REAL. See Revised European-American Classification of Lymphoid Neoplasms Recurrent aphthous ulcer, 1006 clinical features, 1006 different diagnosis, 1006 histopathologic features, 1006 Recurrent melanocytic nevus, 622 clinical features, 622 differential diagnosis, 622 histopathological features, 622 Recurring digital fibrous tumor of childhood, 781 Refsum syndrome, 315–316 clinical features, 315–316 differential diagnosis, 316 histopathological features, 316

Rhinosporidiosis, 460t, 489–490, 527 clinical features, 489 differential diagnosis, 489–490 histopathological features, 489 Rhinosporidium, 489, 490f Rhinosporidium seeberi, 527 Rhizomucor, 483 Rhizopus, 483 Ribonucleoprotein (RNP), 53 RICH. See Rapidly involuting congenital hemangioma Rickettsial and viral infections, 89, 454 clinical features, 454 differential diagnosis, 455–456 histopathological features, 454–455 Riga-Fede disease, 1006 Ringworm, 459 cray-patch, 460 Ritter disease, 147 clinical features, 147 histopathological features, 147 RMSP. See Rocky Mountain spotted fever RNP. See Ribonucleoprotein Rochalimaea, 501 Rocky Mountain spotted fever (RMSP), 184, 454, 455f, 497 Romanovsky stains, 521 Rosacea, 237–240, 241t, 243f clinical features, 237–238 granulomatous, 243f histopathological features, 239–240 Rosacea fulminans, 99 Rosal-Dorfman disease, 118–119 clinical features, 118 differential diagnosis, 118–119 histopathological features, 118 Roseola, 496t, 498–499 clinical features, 498–499 differential diagnosis, 499 histopathological features, 499 Ross River, 503 Rothmund-Thomson syndrome, 59 ataxia telangiectasia and, 835 Round cell liposarcoma, 596, 867–868 RPC. See Reactive perforating collagenosis RPR. See Rapid plasma regain RT-PCR. See Reverse transcription polymerase chain reaction Rubella, 496t, 497–498 clinical features, 497 differential diagnosis, 498 histopathological features, 497–498 Rudimentary digit. See Supernumerary digit Rue histiocytes, 421 Ruptured follicles, 111–113 clinical features, 112 histopathological features, 112 S S-100 protein, 593, 595, 600, 670, 676, 680, 694, 794, 889, 894, 962 chondroid lipoma and, 861 EHE and, 829 extraskeletal myxoid chondrosarcoma and, 877 extraskeletal osteosarcoma and, 879 leiomyoma and, 869 leiomyosarcoma and, 871, 872

S-100 protein (Cont.): myxoid liposarcoma and, 867 pleomorphic liposarcoma and, 868 spindle cell lipoma and, 860 WDL/ALT and, 866 SACRAL. See Spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with angioma of lumbosacral localization syndrome Salicylates, 281 Salivary glands, ectopic, 414, 415f SAN. See Syringomatous adenoma of nipple Sarcoidosis, 101–102, 911 clinical features, 101 differential diagnosis, 101–102 histopathological features, 101 RAE and, 817 Sarcoma, 971–973. See also specific types clear cell, 676 clinical features, 971 differential diagnosis, 972 epithelioid, 795, 829, 872, 972 granulocytic, 946–947 high-grade pleomorphic, 791 immunohistochemistry, 972–973 low-grade fibromyxoid, 794–795, 794f osteogenic, 972 special stains, 972–973 synovial, 825, 879 undifferentiated pleomorphic, 791–792, 972 Sarcoptes scabiei, 75 Satellite cell necrosis, 36 Scabala, 75 Scabies, 75–76 clinical features, 75 histopathological features, 75–76 in HIV, 75 Scalp biopsies, 213 Scalp melanocytic nevi, 625–627 clinical features, 626 differential diagnosis, 626–627 histopathological features, 626 Scalp metastases, 961 Scanning magnification, microslide examination at, 3–4 Scarring alopecia, 13, 223–232 central centrifugal, 227–229 end-stage, 235 nonscarring v., 215 primary, 224–225 lymphocyte-associated, 225, 231t pustulofollicular, neutrophil-associated primary, 230, 236t secondary, 224–225, 232, 238t Scarring follicular keratosis, 233 Scars, hypertrophic, 392–393 Scedosporium, 487–488 SCH. See Spindle cell hemangioma Schaumann bodies, 101 Schistosoma haematobium, 539, 540 Schistosoma japonicum, 539 Schistosoma mansoni, 539, 540f Schistosomiasis, 539–540 differential diagnosis, 540 Schizophrenia, 590 Schwann cells, 618, 671, 887

INDEX

Regression of malignant melanoma, 678t melanoma, 677 Reiter syndrome, 68, 69t clinical features of, 68 differential diagnosis, 68 histopathological features of, 68 Relapsing polychondritis, 90, 398–399 clinical features, 398 histopathological features, 398–399 Related lesions, 543–554 Remicade, 297 Renal cell carcinomas, 960 marker, 963, 969 Renal transplantation KS and, 820 RAE and, 817 Resorcinol, 353 Reticular dermis, alterations of, 14 Reticular erythematous mucinosis, 366–367 differential diagnosis, 366–367 histopathological features, 366 Reticulated pigmented dermatosis, 348 Reticulin, EHE and, 828 Reticulohistiocytoma, 121–122 clinical features, 121 differential diagnosis, 121–122 histopathological features, 121 Reticulohistiocytosis. See Congenital selfhealing Langerhans histiocytosis Retiform hemangioendothelioma (RH), 826–827, 827f CH and, 827 PILA and, 826 THH and, 810, 811 Retinoids, PG from, 813 Reverse transcription polymerase chain reaction (RT-PCR), 866 alveolar rhabdomyosarcoma and, 875 Revised European-American Classification of Lymphoid Neoplasms (REAL), 264 RH. See Retiform hemangioendothelioma Rhabdomyoma, 872 Rhabdomyomatous mesenchymal hamartoma, 872, 872f Rhabdomyosarcoma, 874–876, 874t, 972, 973 leiomyosarcoma and, 871 Rheumatic fever nodule, 109 clinical features, 109 differential diagnosis, 109 histopathological features, 109 Rheumatoid arthritis, RAE and, 817 Rheumatoid neutrophilic dermatitis, 126 clinical features, 126 differential diagnosis, 126 histopathological features, 126 Rheumatoid nodule, 108–109 clinical features, 108 differential diagnosis, 108–109 histopathological features, 108 Rhinocladiella aquaspersa, 476 Rhinophyma, 241t Rhinoscleroma, 438–439, 520 clinical features, 438 differential diagnosis, 439 histopathological features, 438

1075

INDEX 1076

Schwannoma, 893t ancient, 891, 891f cellular, 890, 892f differential diagnosis, 890–891, 892 immunohistochemistry of, 890 malignant, 895 pigmented, 890 plexiform, 892f Schwannomas, 536, 889 ancient, 890 clinical features, 890 histopathologic features, 890 palisading, 890 psammomatous melanotic, 796 Scleredema adultorum, 367–368 histopathological features, 367–368 Sclerema neonatorum (SN), 265, 267 clinical features, 267 differential diagnosis, 267 histopathological features, 267 Scleroderma, 259–261, 260t, 387–390, 389t clinical features, 260 differential diagnosis, 261 histopathological features, 260–261 localized, 387–388 systemic, 388–390 Sclerodermatoid tissue reactions, 291 differential diagnosis, 291 histopathological features, 291 Sclerodermoid disorders, 390–391 Sclerodermoid reaction, 46 Scleromyxedema, 362, 365–366 clinical features, 365 differential diagnosis, 366 histopathologic features, 365–366 Sclerosing angiogenic tumor. See Epithelioid hemangioendothelioma Sclerosing basal cell carcinoma, 583 Sclerosing blue nevus, 645 differential diagnosis, 645 histopathological features, 645 Sclerosing endothelial tumor. See Epithelioid hemangioendothelioma Sclerosing epithelioid angiosarcoma. See Epithelioid hemangioendothelioma Sclerosing hemangioma, 776 MVH and, 809 THH and, 811 Sclerosing interstitial vascular sarcoma. See Epithelioid hemangioendothelioma Sclerosing liposarcoma, 860, 865 Sclerosing rhabdomyosarcoma, 874 Sclerosing sweat duct carcinoma, 743 Sclerotic bodies, 476 Sclerotic fibroma, 769 clinical features, 769 histopathologic features, 769 Scrotal angiokeratomas, VH and, 838 SCs. See Sebaceous carcinomas SCSCCs. See Spindle cell squamous cell carcinomas Sea urchin spines, 307f, 307t Seabather’s eruption, 307t Sebaceoma, 692

Sebaceous adenoma, 690–691, 691f clinical features, 690 Sebaceous carcinomas (SCs), 690, 693–695, 694f, 695f basaloid, 694 clinical features, 693 differential diagnosis, 694–695 grade of, 693 histopathological features, 693–694 Sebaceous differentiation basal cell carcinoma with, 581f superficial epithelioma with, 691–692 differential diagnosis, 692 histopathological features, 692 Sebaceous hyperplasia, 689–691 clinical features, 689–690 differential diagnosis, 690 giant solitary, 690 histopathological features, 690 linear, 690 Sebaceous tumors, 689–720 Sebocrine adenoma, 692 Sebomatricoma, 691 Seborrheic dermatitis, 22, 31f, 73 clinical features, 22 histopathological features, 22 Seborrheic keratosis, 5f, 565–567 acanthotic, 565 adenoidal, 565 clinical features, 565 clonal, 565 histopathological features, 565–567 hyperkeratotic, 565 irritated, 566 macular, 565 miscellaneous, 566 pedunculated, 565–566, 767 Secondary cutaneous B-cell lymphomas, 931 Secondary cutaneous ossification, 384 Secondary scarring alopecia, 224–225, 232, 238t Secondary syphilis, 58, 446, 447t, 448–449, 449f clinical features, 58 differential diagnosis, 78, 448–449 histopathological features, 58, 78 Secondary systemic amyloidosis, 372–374 histopathological features, 373–374 Secondary yaws, 450 Senile purpura, 209f Sentinel lymph node biopsy (SLNB), 638 Septa, 250 Septal panniculitis, 251–261, 255t Serotonin, 77 Serum sickness, 281 clinical features, 292 diagnosis, 185–186 drug-associated vasculitis, 292–293 drugs associated with, 186t histopathological features, 292 Sezary cell, 906, 950 Sezary syndrome, 73, 75 clinical features, 914 definition of, 914 diagnosis, 915 differential diagnosis, 915

Sezary syndrome (Cont.): genotypic features, 915 histopathologic features, 914–915 immunophenotypic features, 915 SFTS. See Solitary fibrous tumor of the skin Shadow cells, 702 Shagreen patches, 392 Shave specimen, 3 SHORT syndrome, 275 Shoulder parakeratosis, 69 Shulman syndrome, 259–261, 276 Signet ring cells, 966 Signet ring squamous cell carcinoma, 594f Silicone, 271 Silver deposition, 355 histopathological features, 355 SIMP, 655, 660, 664, 666 Simulium, 531 SIN. See Squamous intraepithelial neoplasia Sindbis, 503 Sinonasal carcinomas, 968 clinical features, 968 differential diagnosis, 968 histopathologic features, 968 immunohistochemistry, 968 special stains, 968 Sinusoidal hemangioma, 838 Sister Mary Joseph nodule, 416, 967f Sjögren syndrome, 90, 275, 452 Sjögren-Larsson syndrome, 319 clinical features, 319 differential diagnosis, 319 histopathological features, 319 SJS. See Stevens-Johnson syndrome Skeletal muscle, 872–876 Skin appendages, disorders of, 12 Skin tags, 766–767, 858 Skin-limited amyloidosis, 373t, 374–379 SLC89A4, 77 Slide initial examination of, 3 interpretation of, 3 SLNB. See Sentinel lymph node biopsy SM. See Spitzoid melanoma Small cell eccrine carcinomas, 749 differential diagnosis of, 750t Small cell melanoma, 631f, 670, 673–674 clinical features, 673–674 in elderly, 673–674 histopathologic features, 673–674 mimicking Merkel cell, 673 Small cerebriform lymphocyte, 906 Small congenital nevus, 628–630 Small lymphocytes, 906 B-type, 929 Small round cell cutaneous tumors, differential diagnosis, 899 Small-diameter melanoma, 670 Small-plague parapsoriasis (SPP), 71 Small-vessel neutrophilic vasculitis, 182–183 clinical features, 182 diagnostic approach to, 183–186 histopathological features, 182–183 Smokeless tobacco keratosis (STK), 1008 clinical features, 1008 differential diagnosis, 1008 histopathological features, 1008

Spindle cell hemangioma (SCH), 807–808, 807t, 808f angiosarcoma and, 807, 830 CD31 and, 808 CD34 and, 808 CH and, 827 early-onset varicose veins and, 807 Epithelioid hemangioendothelioma and, 808 Human herpes virus and, 808 Klippel-Trenaunay syndrome and, 807 KS and, 808, 823 Maffucci syndrome and, 807–808, 838 Milroy disease and, 807 phlebolith and, 808 Ulex europaeus lectin-1 and, 808 VM and, 839 von Willebrand factor and, 808 Spindle cell lipoma, 859–860, 860f, 860t myolipoma and, 862 WDL/ALT and, 866 Spindle cell liposarcoma, 865 Spindle cell melanomas, 668, 780 Spindle cell rhabdomyosarcoma, 874 Spindle cell squamous cell carcinomas (SCSCCs), 593 Spindle cell tumors, differential diagnosis of, 995t Spindle cells, 634 Spindle-shaped cells, 893 SPINK5, 323 Spinous layer vesiculation, 327–332 Spiradenoma, 728f benign, 746 eccrine, 725–726, 727t, 728t, 745–746 Spitz nevus or Spitz tumor, 620, 632–635, 633f, 633t, 663 absent or rare mitosis in, 635 adnexal epithelium, 635 angiomatoid, 639 atypical, 636, 637t clinical features, 632–635 compound, 637f dermal component, 637–638 differential diagnosis, 638 desmoplastic, 638–639, 639t, 640t epidermal hyperplasia, 635 halo, 639 histopathologic features, 634–635 hyalinizing, 639 intraepidermal component, 636 junctional cleavage, 635 kamino bodies, 635 lymph node involvement, 638 maturation (zonation), 635 pagetoid, 636 pagetoid spread, 635 perivascular inflammatory cell infiltrates, 635 plexiform, 639 prominent pagetoid spread, 636 tubular, 639 variants, 639 Spitzoid melanoma (SM), 670, 674 Splendore-Hoeppli phenomenon, 482, 486

Spongiosis, 137 conventional, 6f eosinophilic, 6f, 15, 25f follicular, 6f with lymphocyte exocytosis, 29f miliarial, 6f neutrophilic, 6f, 15, 26f skin diseases with, 26t Spongiotic dermatitis, 8–9, 8t, 15–34, 138, 306 acute changes in, 7f, 15 algorithm for, 16f chronic changes in, 7f, 15 clinical features in, 17t differential diagnosis for, 16t histopathological features in, 17t secondary changes in, 15, 24t skin diseases with, 16t subacute, 15, 19f Spongiotic drug eruptions, 27–28 clinical features, 27–28 histopathological features, 27–28 Sporothrix, 474 Sporotrichosis, 459t, 474–475 differential diagnosis, 475 histopathological features, 475 SPP. See Small-plague parapsoriasis Squamous cell carcinoma, 544, 590–596, 596t, 693, 961, 1017–1018 acantholytic, 593–594, 595, 1018 clinical features, 996, 1017 differential diagnosis, 595–596, 996 histopathological features, 591–595, 996, 1017 metastatic disease in, 591 papillary, 595 perineural invasion in, 591 pseudoglandular, 1018 pseudovascular adenoid, 594–595 signet ring, 594f spindle cell, 593 subcutaneous, 595 transplants and, 591 Squamous intraepithelial neoplasia (SIN), 1016 Squamous papilloma, 1005 clinical features, 1005 differential diagnosis, 1005 histopathologic features, 1005 Squirting papillae, 66 Staphylococcal scalded-skin syndrome, 424–425 clinical features, 424 differential diagnosis, 424–425 histopathological features, 424 Staphylococcal scarlet fever, 424 Staphylococcus aureus, 234, 267, 415, 421, 501, 990 Stasis dermatitis, 25, 32t, 33f. See also Acroangiodermatitis Steatocystoma, 548 differential diagnosis, 548 histopathological features, 548 Stela, 213 Stem cells, 736, 1022–1023 epidermal, 1022

INDEX

Smooth muscle, 868–872 Smooth muscle hamartoma, 719 clinical features, 719 differential diagnosis, 719 histopathological features, 719 myolipoma and, 862 SM-PTL. See Primary cutaneous CD4+ pleomorphic T-cell lymphoma SN. See Sclerema neonatorum Soft fibroma, 766–767 Soft tissue amyloidoma, 378 Soft tissue chondroma, 876f Soft tissue myxoma, 867 Soft tissue osteosarcomas, 792 Soft tissue perineuriomas, 889f, 890t Solar elastotic syndromes, 402 clinical features, 402 histopathological features, 402 Solar lentigo, 615–616 clinical features, 615 differential diagnosis, 616 histopathological features, 615–616 Solar melanoma, 660–661 in situ, 661, 664f Solid and cystic hidradenoma, 732 Solid angioleiomyomas, 870 Solitary fibrous tumor, 790–791 clinical features, 790–791 differential diagnosis, 791 histopathological features, 791 Solitary fibrous tumor of the skin (SFTS), hemangiopericytoma and, 825 Solitary myofibroma, 782–784, 783t clinical features, 782 differential diagnosis, 783 histopathologic features, 782–783 Solitary myofibromatosis, hemangiopericytoma and, 825 Solitary schwannoma, 891f Sonar elastotic syndromes, 402 Sotalia fluvialis, 488 South American blastomycosis. See Paracoccidioidomycosis SOX10, 341 SP. See Syringocystadenoma papilliferum Sparganosis, 537–538 clinical features, 537 differential diagnosis, 537–538 histopathological features, 537–538 Specimen curettage, 3 excisional, 3 punch, 3 shave, 3 type of, 3 Spider angioma. See Arterial spider Spider nevus. See Arterial spider Spider telangiectasis. See Arterial spider Spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with angioma of lumbosacral localization syndrome (SACRAL), 831 Spindle cell carcinoma, 962 leiomyosarcoma and, 871

1077

INDEX 1078

Stevens-Johnson syndrome (SJS), 172, 293–294, 294t Stewart-Treves syndrome APL and, 844 IPEH and, 816 KS and, 820 STK. See Smokeless tobacco keratosis Storiform collagenoma, 769, 770f histopathologic features, 769 Storiform pattern, 796–797 Stratified squamous epithelium, cysts lined by, 534, 545t Stratum corneum, 90 alterations of, 14, 313–335 Stratum granulosum, hyperorthokeratosis and, 317–322 Streamer, 213 Streptococcus, 267, 415, 421, 501, 1006 Streptomyces, 478, 480 Striae disease, 393–394 clinical features, 393 differential diagnosis, 394 histopathological features, 394 Striatum spinosum, 448 Strongyloides, 535 Strongyloidiasis, 530, 531 cutaneous, 536 Stucco keratosis, 601 clinical features, 601 differential diagnosis, 601 histopathological features, 601 Sturge-Weber syndrome, 832 Subacute cutaneous lupus erythematosus, 48, 51 differential diagnosis, 51 Subacute lupus erythematosus, 50f Subacute spongiotic dermatitides, 72–73 clinical features, 73 differential diagnosis, 73 histopathological features, 73 Subcorneal pustular dermatosis of SneddonWilkinson, 67, 153 clinical features, 153 histopathological features, 153 Subcorneal substratum granulosum, 6f Subcutaneous fat ischemic necrosis, 255 microanatomy of, 250 necrosis, 265 reactions of, 250–251 vasculitis, 255 vasculopathic reaction, 255 Subcutaneous fat necrosis of newborn, 266–267 clinical features, 266 differential diagnosis, 267 histopathological features, 266–267 Subcutaneous panniculitic lymphoma, 263–265 clinical features, 264 differential diagnosis, 265 histopathological features, 264 Subcutaneous panniculitis-like T-cell lymphoma, 919, 920f clinical features, 919 definition, 919 differential diagnosis, 919

Subcutaneous panniculitis-like T-cell lymphoma (Cont.): genotypic features, 919 histopathologic features, 919 immunophenotypic features, 919 Subcutaneous processes, 3 Subcutaneous squamous cell carcinoma, 595 Subepidermal blistering diseases, 156–175 algorithm, 157f autoimmune, 157–160 basement membrane zone mutations, 169–171 coma blisters, 174–175 cutaneous BM zone, 156 histopathology of, 157–169 lamina densa, 156–157 lamina lucida, 156 miscellaneous, 172–174 ultrastructure and, 156 Subepidermal bullous dermatitis, 10f Subepidermal vesicular dermatitis, 10t Subungual exostosis, 384 Subungual hyperkeratosis, 983 Subungual keratoacanthoma, 577 Subungual melanoma, 659 Sudamina. See Miliaria crystallina Sudan IV stains, 693 Sulfamethoxazole-trimethoprim, 287 Sulfhydryl, 288 Sulzberger-Garbe syndrome, 23 Sun exposure, in lupus erythematosus, 92 Sun nevus. See Nevus fuscoceruleus zygomaticus Superficial, basal cell carcinoma, 582–583 Superficial acral fibromyxoma, 994 clinical features, 994 differential diagnosis, 996 histopathologic features, 994 Superficial angiomyxoma, 795–796, 867 clinical features, 795–796 differential diagnosis, 796 histopathological features, 796 Superficial arteriovenous hemangioma. See Arteriovenous malformations Superficial epithelioma, with sebaceous differentiation, 691–692 differential diagnosis, 692 histopathological features, 692 Superficial filamentous infections, 458–463 Superficial mucocele, 369 Superficial multicentric basal cell carcinoma, 582 Superficial perivascular dermatitis, 11, 81–94 Superficial spreading, 657 Superficial thrombophlebitis, 201–202 clinical features, 201 histopathological features, 201–202 Supernumerary digit, 410–411 differential diagnosis, 411 with focal nail formation, 411f histopathological features, 411 Supernumerary nipple. See Accessory nipple Suppurative granulomatous infiltrates, 111–113 blastomycosis-like pyoderma, 111 follicular cysts and sinuses, 111–113 follicular occlusion triad, 111

Suppurative granulomatous infiltrates (Cont.): halogenodermas, 111, 113t infectious causes, 112 ruptured follicles, 111–113 Suprabasilar, 6f Sweat apparatus, disorders of, 13 Sweat gland adenomas, 735–737 Sweat gland carcinoma, 738, 753 Sweat gland necrosis, 245 clinical features, 245 differential diagnosis, 245 histopathological features, 245 Sweat gland pseudoneoplastic lesions, 755–759 Sweat gland tumors, 725–759 benign, 725–733 differential diagnosis, 758t immunohistochemical findings in, 758t, 759 malignant, 737–738 Sweet syndrome, 124–126, 190f, 191, 940 atypical, 128 classic, 188–190 clinical features, 124–125 Swimmer’s itch, 307t, 539 Symmetrical lipomatosis. See Madelung disease Symplastic glomus tumor, 841 Synaptophysin, 963 Syndecan-1, 594 Synovial chondromatosis, extraskeletal chondroma and, 876 Synovial sarcoma extraskeletal osteosarcoma and, 879 hemangiopericytoma and, 825 Syphilis benign tertiary, 446 endemic, 451 in HIV, 501 primary, 446, 447–448, 447t secondary, 58, 78, 446–449 tertiary, 446, 447t, 449 venereal, 446–447 Syringoacanthoma, 729 Syringocystadenoma papilliferum (SP), 731, 734, 735f clinical features, 734 differential diagnosis, 734 histopathological features, 734 Syringoid carcinoma, 743 Syringolymphoid hyperplasia, 911–912 Syringoma, 729f anaplastic, 743 chondroid, 733, 735–737, 737t, 738f clinical features, 726–727 differential diagnosis, 727–728 histopathological features, 727 Syringomatous adenoma of nipple (SAN), 745 Syringometaplasias, 755–756, 756f Syringotropic mycosis fungoides, 911–912, 912f Systemic amyloid A amyloidosis, 372–374 Systemic amyloid light chain amyloidosis, 371–372, 373f histopathological features, 372

Systemic amyloidosis, 371–374 secondary, 372–374 Systemic candidiasis, 464 Systemic lupus erythematosus, 284 bullous, 168–169 classification of, 92t Systemic mastocytosis, 130 Systemic mycoses, 468–474 Systemic scleroderma, 388–390 clinical features, 388–389 differential diagnosis, 390 histopathological features, 389 Systemic vasculitis, 197

Tinea corporis, 461 clinical features, 461 differential diagnosis, 461 histopathological features, 461 Tinea cruris, 462 clinical features, 462 histopathological features, 462 Tinea favosa, 460 Tinea manuum, 462 clinical features, 462 differential diagnosis, 462 Tinea nigra, 477, 479f clinical features, 477 histopathological features, 477 Tinea pedis, 462 clinical features, 462 differential diagnosis, 462 histopathological features, 462 Tinea unguium, 462–463 clinical features, 462–463 differential diagnosis, 463 Tinea versicolor, 466f Tinea yaws, 450 Titanium, 355 histopathological features, 355 TL. See Trichilemmoma TLC. See Trichilemmal carcinoma T-lymphoblasts, 906 T-lymphocytes, 264, 499 TMEP. See Telangiectasia macularis eruptiva perstans TNF. See Tumor necrosis factor TNF-alpha, 240 TNM classification. See Tumor, node, metastasis classification Tobacco use, 596 Togaviruses, 503 Touton-type giant cells, 776 Townes-Brocks syndrome, 408 Toxic epidermal necrolysis, 42–43, 172, 293–294, 294t clinical features of, 42–43, 172, 173 differential diagnosis, 172, 173 erythema multiform v., 42t histopathological features, 43, 172, 173 Toxic erythema of pregnancy, 84 clinical features, 84 differential diagnosis, 84 histopathological features, 84 Toxic shock syndrome, 425 clinical features, 425 differential diagnosis, 425 histopathological features, 425 Toxocara canis, 133, 275 Toxoplasma gondii, 523 Toxoplasmosis, 523–524 clinical features, 523 differential diagnosis, 524 histopathological features, 523 TP1. See Telomerase-associated protein Traction alopecia, 220–221, 226, 227f, 228f clinical features, 220 differential diagnosis, 220 histopathological features, 220 Transglutaminase, 318

INDEX

T T cell clonality, 911 TA. See Tufted angioma Tachyzoites, 523 Taenia multiceps, 537f Taenia solium, 536 Takayasu arteritis, 202 clinical findings, 202 differential diagnosis, 202 histopathological features, 202 Tanapox, 512 TAP. See Transporter associated with antigen processing Tapeworm larvae, 531 Target blue nevus, 648 Targeted biological therapy reactions, 296–297 Targetoid hemosiderotic hemangioma (THH), 809–811, 810f, 810t APL and, 810, 811 D2-40 antibody and, 809 HHV and, 810 histologic features of, 823t KS and, 810–811, 823 MVH and, 809 Retiform hemangioendothelioma and, 810 RH and, 811, 827 sclerosing hemangioma and, 811 Ulex europaeus lectin-1 and, 810 Vascular endothelial growth factor and, 809 von Willebrand factor and, 810 Tattoos, 354 differential diagnosis, 354 histopathological features, 354 Tazarotene, PG from, 813 T-cell lymphoproliferations, benign, 908–926 T-cell prolymphocytic leukemia, 949–951 clinical features, 949 histopathologic features, 949–950 immunohistochemical findings, 950–951 T-cell pseudolymphomas, 908–909 clinical features, 908 definition, 908 differential diagnosis, 909 genotypic features, 909 histopathological features, 908–909 immunophenotypic features, 909 T-cell series, ontogeny of, 906 TdT. See Terminal deoxynucleotidyl transferase Telangiectasia, 579

Telangiectasia macularis eruptiva perstans (TMEP), 130 Telangiectatic metastasis, 960–961 Telangiectatic osteosarcoma, 879 Telogen, 216 effluvium, 217 Telogen hairs, 215t Telomerase-associated protein (TP1), 578 Temperature grading gel electrophoresis, 908 Temporal arteritis, 202–203 clinical features, 202 differential diagnosis, 203 histopathological features, 202–203 Tendon sheath fibroma, 769–770 Tendon sheath giant cell tumor, 780–781 Terbinafine, 93 Terminal deoxynucleotidyl transferase (TdT), 897, 967 Terminal hairs, 213, 215t Tertiary syphilis, 446, 447t, 449 benign, 446 Tertiary yaws, 450 histopathological features, 450 Tetanus toxoid, 271 Tetrasomy 12p, 344 TF. See Trichofolliculoma TGFβ, HHT and, 833 TGM5, 332 Th1. See T-helper lymphocyte type 1 Th2, 519 Thalidomide, 297 T-helper, 289, 519, 907 T-helper lymphocyte type 1 (Th1), 306 Thermal burns, 150–152 THH. See Targetoid hemosiderotic hemangioma Thiazides, 281 Thiol, 288 Thromboangiitis obliterans, 201t Thrombophlebitis, 259 Thrombosed capillary aneurysm, 848 Thrombospondins (TSPs), 259 Thymic cysts, 549 differential diagnosis, 549 Thymoma, 146 Thyroglossal duct cysts, 550–551, 551f differential diagnosis, 550–551 histopathological features, 550–551 Thyroid carcinomas, 961, 963 Thyroid transcription factor 1 (TTF-1), 962 Thyroid tumors, 970–971 clinical features, 970 differential diagnosis, 970 histopathologic features, 970 immunohistochemistry, 970–971 special stains, 970 Ticks, 308, 309f T-immunoblasts, 906 Tinea barbae, 461–462 clinical features, 461–462 differential diagnosis, 462 histopathological features, 462 Tinea capitis, 231–232, 238f, 458–461 clinical features, 231 differential diagnosis, 231–232, 461 histopathological features, 231, 460–461

1079

INDEX 1080

Transient acantholytic dermatosis, 149–150, 328, 331–332, 332f clinical features, 149, 332 differential diagnosis, 150, 332 histopathological features, 149, 332 Transient neonatal pustular melanosis, 154 clinical features, 154 differential diagnosis, 154 histopathological features, 154 Transitional areas, 867 Transporter associated with antigen processing (TAP), 196 Transverse section techniques advantages of, 217t disadvantages of, 217t vertical section techniques v., 213–215 TRAPS. See Tumor necrosis factor receptor superfamily 1A-associated periodic syndrome Trauma reactions, 301 clinical features, 301 differential diagnosis, 301 histopathological features, 301 Trauma-related panniculitis, 270–271 Traumatic neuromas, 886t, 887f Traumatic onychitis, 991–992 clinical features, 991 histopathologic features, 991 Traumatic pseudoaneurysm, 813 Traumatic ulcerative granuloma, 1006 Trematodes, 530, 538–540 adult, 531, 532 Treponema pallidum, 78 Treponemal diseases, 446–449 Tretinoin, PG from, 813 Triatomid bugs, 520 Trichilemmal carcinoma (TLC), 694, 715–716 clinical features, 715 differential diagnosis, 715–716 histopathologic features, 715 Trichilemmoma (TL), 696, 699–700, 700t, 701f, 715, 729 clinical features, 699 differential diagnosis, 700 histopathologic features, 699–700 Trichoadenoma, 698–699, 699f, 699t clinical features, 698 histopathologic features, 698–699 Trichoblastomas, 588, 708, 709–710, 710f clinical features, 710 differential diagnosis, 710 histopathologic features, 710 Trichoderma, 488–490 Trichodiscoma, 711, 712t, 713f clinical features, 711–712 differential diagnosis, 713 histopathological features, 712–713 Trichoepithelioma, 728 desmoplastic, 705–706 malignant, 717 Trichoepitheliomas, 588, 692, 703–705, 704f, 705f clinical features, 703 differential diagnosis, 704–705 histopathological features, 704

Trichofolliculoma (TF), 690, 702–703, 702t, 703f clinical features, 702 differential diagnosis, 702–703 histopathological features, 702 Trichogenic adnexal tumor, 709 Trichogerminoma, 707–708 clinical features, 707 differential diagnosis, 708 histopathologic features, 707–708 Trichomalacia, 219 Trichome vitiligo, 340 Trichomycosis, 429 clinical features, 430 differential diagnosis, 430 histopathological features, 430 Trichophyton schoenleinii, 221, 458 Trichophyton tonsurans, 221 Trichosporon asahii, 463, 468 Trichosporon cutaneum, 430 Trichosporonosis, 467 Trichothiodystrophy, 316 clinical features, 316 differential diagnosis, 316 histopathological features, 316 Trichotillomania, 218, 219–220, 225f, 226f clinical features, 219 differential diagnosis, 220 histopathological features, 219–220 Trisomy 18, 344 Triton tumor, 896 embryonal rhabdomyosarcoma and, 874 Trombiculid mites, 308 Tropheryma whippelii, 113 Trophozoites, 525 Trousseau sign, 259 Trypanosoma brucei gambiense, 520, 521, 522 Trypanosoma brucei rhodesiense, 520, 521, 522 Trypanosoma cruzi, 520–522 Trypanosomiasis, 520–523 clinical features, 520–521 differential diagnosis, 523 histopathological features, 521–523 Trypomastigotes, 520 Tryptophan, 77 fasciitis and, 260 TS. See Tuberous sclerosis TSPs. See Thrombospondins TTF-1. See Thyroid transcription factor 1 Tuberculoid leprosy, 438f Tuberculosis, 431–432, 433t differential diagnosis, 432 histopathological features, 432 Tuberculosis verrucosa cutis, 434f Tuberous sclerosis (TS), 341 ash leaf spots of, 343 Tubular apocrine adenoma, 731, 735, 737f clinical features, 735 differential diagnosis, 735 histopathologic features, 735 Tubular Spitz nevus, 639 Tubulopapillary hidradenoma, 731 Tufted angioma (TA), 803, 803t, 805–806, 806f angiosarcoma and, 806 Crohn disease and, 805–806 eccrine glands and, 806 GH and, 816

Tufted angioma (TA) (Cont.): Kaposiform hemangioendothelioma and, 805 KHE and, 824 KMS and, 805, 824 KS and, 806 Lobular capillary hemangioma and, 805 MVH and, 809 periodic acid-Schiff and, 806 Ulex europaeus lectin-1 and, 806 von Willebrand factor and, 806 Tularemia, 439–441 clinical features, 439 differential diagnosis, 439 histopathological features, 439 Tumid lupus erythematosus, 50 Tumor(s). See also specific types Abrikosoff, 894–895 Ackerman, 596 adnexal, 689 atypical lipomatous, 858, 864–866, 865f, 865t bednar, 787 benign adipocytic, 858, 858t benign fibrohistiocytic, 775–781 benign fibrous, 766–776 benign hair follicle, 697–714 benign proliferating pilar, 701–702 benign sweat gland, 725–733 benign vascular, 802–811 biphasic, 797 borderline sebaceous, 692–693 Buschke-Loewenstein, 596–598 clear cell cutaneous, 716t dermal duct, 730f digital, 797 eccrine, 725 ectomesenchymal chondromyxoid, 1018 fibrohistiocytic, 766–797 benign, 775–781 of childhood, 781–786, 797 intermediate, 775–781 of intermediate malignancy, 786–791 malignant, 791–795 plexiform, 788–789 fibrous, 766–797 benign, 766–776 of childhood, 781–786, 797 of intermediate malignancy, 786–791 malignant, 791–795 solitary, 790–791 follicular infundibulum, 697, 729 giant cell, 780–781, 876 glomus, 839–841, 840f, 840t, 841f, 996 clinical features, 996 differential diagnosis, 996 histopathologic features, 996 granular cell, 894–895, 895t clinical features, 894, 1018 different diagnosis, 1018 differential diagnosis, 895 histopathologic features, 894–895, 1018 hair follicle, 689–720 hyalinizing spindle cell, 794 Koenen, 392 lobulated, 797 malignant, 578–600 malignant basomelanocytic, 581

Tumoral amyloidosis, 378 Tumoral calcinosis, 383f extraskeletal chondroma and, 876 Tumors genital tract, 970 germinative follicular epithelium, 702 melanocyte, 615–681 mesenchymal, 631–632 osteocartilaginous, 994–996 small round cell cutaneous, 899 spindle cell, 995t Tunga penetrans, 309 Turk cells, 497 Tursiops truncatus, 488 Type 2 leprosy reaction, 270 Type A cells, 618 Type VII collagen, 157 Typical melanocytic proliferations, 997 clinical features, 997 differential diagnosis, 997 histopathologic features, 997 Tyrosinase, 680 TYRP1. See Tyrosinase U Ulcerative colitis, 197 Ulceroglandular disease, 434 Ulerythema ophryogenes, 233 Ulex, 596 Ulex europaeus lectin-1, 803, 815 angiosarcoma and, 830 APL and, 844 EHE and, 828 GH and, 816 hemangiopericytoma and, 825 KHE and, 824 KS and, 822 RAE and, 818 SCH and, 808 TA and, 806 THH and, 810 Ultrastructure, 156, 157f, 514 subepidermal blistering diseases, 156 Ultraviolet, 304, 338, 590 Ultraviolet B (UVB), 51 Umbilical lesions, 415–416 metastatic, 416 Umbilicus, benign neoplasms of, 415t Uncertain malignant potential, 871 Undifferentiated pleomorphic sarcoma, 791–792, 972 Unilateral nevoid telangiectasia, 832, 835 HHT and, 834 Urachal remnants, 416 clinical features, 416 differential diagnosis, 416 histopathological features, 416 Urinary tract tumors, 968–969 clinical features, 968–969 differential diagnosis, 969 histopathological features, 969 immunohistochemistry, 969 special stains, 969 UROD. See Uroporphyrinogen decarboxylase Uroporphyrinogen decarboxylase (UROD), 173

Urticaria, 81–84 chronic, 81 common forms of, 82t clinical features, 81–83 differential diagnosis, 83–84 histopathological features, 83 Urticarial papules, 29–30 clinical features, 29 differential diagnosis of, 30 histopathological features, 29 Urticarial vasculitis, diagnosis, 184–185 UVB. See Ultraviolet B V VACTERL, 408 Vacuolar interface dermatitis, 40–48 Varicella, 496t, 504–506 clinical features, 505–506 differential diagnosis, 506 histopathological features, 506 Vascular cell adhesion molecule-1 (VCAM-1), 587 Vascular endothelial growth factor (VEGF), 343 THH and, 809 Vascular endothelial growth factor receptor (VEGFR) angiosarcoma and, 830 KHE and, 824 KS and, 822 LM and, 843 PILA and, 826 Vascular injury absence of, 10–11 definitions of, 179t histopathological features of, 179t inflammatory conditions without, 6f Vascular leiomyoma, 869–870 Vascular malformations, 831–832, 832t Vascular markers, 802 Vascular occlusive conditions, 203 Vascular reactions, 192 inflammatory, 180 lymphocytic, 192 lymphomatoid, 194 neutrophilic, 180, 188 Vascular slits, 821 Vascular tumors, 802–850. See also specific types Vasculitis, 12t, 179–209. See also Pseudovasculitis ANCA-associated, 184, 195–196 approach to, 182t clinical features, 179–180 cutaneous neutrophilic small vessel, 182t definitions of, 180t drug-induced, 186 with granulomatosis, 194–195 granulomatous, 196f histopathological features, 179–180 infectious, 183–184 of large vessels, 200–203 leukocytoclastic, 181, 182–183, 281 localized fibrosing small-vessel, 187 lymphocytic, 192 lymphomatoid, 194 of medium vessels, 200–203 nodular, 255, 268–269

INDEX

Tumor(s) (Cont.): malignant fibrohistiocytic, 791–795 malignant fibrous, 791–795 malignant mixed, 748–749 malignant peripheral nerve sheath, 887, 895–896, 896t clinical features, 895 differential diagnosis, 896 extra skeletal osteosarcoma and, 879 histopathological features, 895–896 malignant proliferating pilar, 716–717, 717f malignant sweat gland, 737–738 myxoid, 797 neural, 883–901 neuroblastic, 900 neuroendocrine, 971 classification, 883 clinical features, 971 differential diagnosis, 971 histopathologic features, 971 paucicellular, 797 pilar benign proliferating, 701–702 malignant proliferating, 716–717, 717f proliferating, 702f plexiform fibrohistiocytic, 101, 788–789 primitive neuroectodermal, 874, 897 alveolar rhabdomyosarcoma and, 875 extraskeletal osteosarcoma and, 879 proliferating pilar, 702f recurring digital fibrous, 781 sebaceous, 689–720 silhouette, 5 solitary fibrous, 790–791, 825 sweat gland, 725–759 benign, 725–733 differential diagnosis, 758t immunohistochemical findings in, 758t, 759 malignant, 737–738 symplastic glomus, 841 tendon sheath giant cell, 780–781 thyroid, 970–971 clinical features, 970 differential diagnosis, 970 histopathologic features, 970 immunohistochemistry, 970–971 special stains, 970 trichogenic adnexal, 709 Triton, 874, 896 urinary tract, 968–969 clinical features, 968–969 differential diagnosis, 969 histopathological features, 969 immunohistochemistry, 969 special stains, 969 vascular, 802–850 Wilms, 874–875, 963 Tumor, node, metastasis (TNM) classification, 906 Tumor necrosis factor (TNF), 263, 270, 296, 297, 341 Tumor necrosis factor receptor superfamily 1A-associated periodic syndrome (TRAPS), 190, 191, 263

1081

INDEX 1082

Vasculitis (Cont.): paraneoplastic, 186 Pauci-immune, 196 physical factors, 186 pustular, 182 small-vessel neutrophilic, 182–183 subcutaneous fat, 255 systemic, 180t, 197 Wegener, 198 Vasculopathic reaction, 180f, 203–209, 204t atrophie blanche, 206, 207f calciphylaxis, 207–208, 208t, 209f coagulopathies, 203 connective tissue deficiency, 209 cryoglobulinemias, 203–204 cutaneous cholesterol embolism, 204 Degos syndrome, 206 livedo reticularis, 205 subcutaneous fat, 255 vascular occlusive conditions, 203 Vasculopathy, 180 lymphocytic, 193 Vasopressin, 274 VCAM-1. See Vascular cell adhesion molecule-1 VDRL. See Venereal Disease Research Laboratory VE-cadherin, KS and, 822 VEGF. See Vascular endothelial growth factor VEGFR. See Vascular endothelial growth factor receptor Velcade, 297 Vellus hair cysts, 544–547 differential diagnosis, 547 eruptive, 547 Vellus hairs, 213, 215t Vellus-like hairs, 213 Venereal Disease Research Laboratory (VDRL), 437, 447 Venereal syphilis, 446–447 Venolymphatic malformation, 842 Venous angioleiomyomas, 870 Venous lake, 847–848, 848f Venous malformation (VM), 838–839, 839f AVMs, 847 GVM and, 840 IPEH and, 816 Maffucci syndrome and, 838 Verocay bodies, 887, 890 Verruca, 992 clinical features, 992 differential diagnosis, 992 histopathological features, 992 Verruca plana, 507, 507t, 509, 510f Verruca plantaris, 507t, 508, 510f Verruca vulgaris, 507, 507t, 509, 700 VH and, 838 Verruciform xanthoma, 114–115, 1014 aAVM and, 845t clinical features, 115, 1014 differential diagnosis, 115, 1014 histopathological features, 115, 1014 Verrucous carcinoma, 596–598 clinical features, 597 differential diagnosis, 598 histopathological features, 597–598 oral, 596, 597f plantar, 596

Verrucous hemangioma (VH), 809, 836–838, 837f, 837t angiokeratoma and, 836 Verrucous hyperplasia, 1017 Verrucous melanoma, 672–673 clinical features, 672–673 histopathologic features, 672–673 Verrucous psoriasis, 66 Vertical growth phase, 660 Vertical section techniques, transverse section techniques v., 213–215 Vesicles, 136 Vesicopustule, 136 Vesicular and bullous dermatitis, 9–10 Vesiculopustular diseases, 152–154 Vessel wall alteration, 208–209 VH. See Verrucous hemangioma Vibrio cholerae, 435 Vide infra, 713 Vimentin, 582, 586, 593, 594, 595, 676, 889, 896, 962, 973 angiosarcoma and, 830 chondroid lipoma and, 861 extraskeletal osteosarcoma and, 879 hemangiopericytoma and, 825 Viral exanthems, 495–503, 498f clinical features, 503 differential diagnosis, 503 histopathological features, 503 Viral folliculitis, 235 clinical features, 235 histopathological features, 235 Viral infections, 495–515. See also specific types active, 495 general principles of, 495 lateral, 495 Visceral leishmaniasis, 518 Vitamin K, 271, 390 Vitiligo, 61, 340–341, 340f, 343t differential diagnosis, 341 histopathological features, 341 trichome, 340 VM. See venous malformation Vogt-Koyanagi-Harada syndrome, 340–341 Vohwinkel syndrome, 320 von Kossa stain, 316 von Recklinghausen disease, 887 von Willebrand factor, 802, 815 angiosarcoma and, 830 APL and, 844 EHE and, 828 GH and, 816 hemangiopericytoma and, 825 KHE and, 824 KS and, 822 RAE and, 818 SCH and, 808 TA and, 806 THH and, 810 Vulva ciliated cysts of, 551–552 compound nevus of, 626f Vulvitis, plasma cell, 128 Vulvovaginitis, 464

W Waldenstrom macroglobulinemia, 375, 379 histopathological features, 379 Wangiella dermatitidis, 477 Warfarin, 258 Warthin-Finkeldey giant cells, 497 EH and, 813 Warthin-Starry reaction, 261, 275, 437, 520 Warty dyskeratoma, 563–564 clinical features, 563 differential diagnosis, 563–564 histopathological features, 563 Waterhouse-Friderichsen syndrome, 430 Wattles, 408 WDL. See Well-differentiated liposarcoma Weber-Christian disease, 251, 261–263 Weber-Cockayne variant, 326 Wegener granulomatosis, 109, 184, 197–199, 198t clinical features, 198 differential diagnosis, 198–199 histopathological features, 198 Wegener syndrome, 198 Wegener vasculitis, 198 Weibel-Pelade bodies, 595 Well-differentiated liposarcoma (WDL), 858, 865–866, 865f, 865t lipoblastoma and, 864 myolipoma and, 862 myxoid liposarcoma and, 867 spindle cell lipoma and, 860 Wells syndrome, 131–133, 197, 275 clinical features, 131 differential diagnosis, 132–133 histopathological features, 131–132 Werner syndrome, 399 clinical features, 399 differential diagnosis, 399 histopathological features, 399 West Nile virus, 503 White piedra, 459t, 467t White sponge nevus, 1003f clinical features, 1002 differential diagnosis, 1002 histopathologic features, 1002 White superficial onychomycosis (WSO), 462 Wickham striae, 37 Wilms tumor, embryonal rhabdomyosarcoma and, 874–875 Wilms tumor protein (WT1), 963 Winterbottom sign, 498 Wiskott-Aldrich syndrome, MVH and, 809 Wohlfahrtia, 309 Woolsorter disease, 433 Wright stains, 521 WSO. See White superficial onychomycosis WT1. See Wilms tumor protein Wuchereria bancrofti, 533, 534 X Xanthogranuloma, 119 clinical features, 119 differential diagnosis, 119 histopathological features, 119 Xanthoma disseminatum, 120 clinical features, 120 histopathological features, 120

Y Yatapoxvirus, 512 Yaws, 449 attenuated, 450 crab, 450 daughter, 450 primary, 449–450 secondary, 450 tertiary, 450 tinea, 450 Yeast infections, 463–465 Yersinia enterocolitica, 435, 436 Yersinia pestis, 436 Yersinia pseudotuberculosis, 436

Yersiniosis, 436 clinical features, 436 differential diagnosis, 436 Z Ziehl-Neelsen staining, 270, 421, 520 Zip4, 77 ZMP-STE24, 274 Zoon balanitis, 128 Zoopagomycotina, 458, 483 Zosteriform hyperpigmentation, 347 Zygomycoses, 483–487 Zygomycota, 458

INDEX

Xanthomas, 113–114 clinical features, 113–114 differential diagnosis, 114 diffuse normolipemic plane, 114 histopathological features, 114 papular, 115–116 plexiform, 116 verruciform, 114–115 Xanthomatous reactions, 866 Xeroderma pigmentosum, ataxia telangiectasia and, 835 X-linked dominant ichthyosis with chondrodysplasia punctata, 316 focal dermal hypoplasia and, 857 X-linked recessive ichthyosis, 314, 317–318 clinical features, 317–318 differential diagnosis, 318 histopathological features, 318

1083